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Sample records for breast tumor metastasis

  1. Macroscopic Stiffness of Breast Tumors Predicts Metastasis

    PubMed Central

    Fenner, Joseph; Stacer, Amanda C.; Winterroth, Frank; Johnson, Timothy D.; Luker, Kathryn E.; Luker, Gary D.

    2014-01-01

    Mechanical properties of tumors differ substantially from normal cells and tissues. Changes in stiffness or elasticity regulate pro-metastatic behaviors of cancer cells, but effects have been documented predominantly in isolated cells or in vitro cell culture systems. To directly link relative stiffness of tumors to cancer progression, we combined a mouse model of metastatic breast cancer with ex vivo measurements of bulk moduli of freshly excised, intact tumors. We found a high, inverse correlation between bulk modulus of resected tumors and subsequent local recurrence and metastasis. More compliant tumors were associated with more frequent, larger local recurrences and more extensive metastases than mice with relatively stiff tumors. We found that collagen content of resected tumors correlated with bulk modulus values. These data establish that relative differences in tumor stiffness correspond with tumor progression and metastasis, supporting further testing and development of tumor compliance as a prognostic biomarker in breast cancer. PMID:24981707

  2. Tungsten targets the tumor microenvironment to enhance breast cancer metastasis.

    PubMed

    Bolt, Alicia M; Sabourin, Valérie; Molina, Manuel Flores; Police, Alice M; Negro Silva, Luis Fernando; Plourde, Dany; Lemaire, Maryse; Ursini-Siegel, Josie; Mann, Koren K

    2015-01-01

    The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients' years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans.

  3. Tungsten Targets the Tumor Microenvironment to Enhance Breast Cancer Metastasis

    PubMed Central

    Bolt, Alicia M.; Sabourin, Valérie; Molina, Manuel Flores; Police, Alice M.; Negro Silva, Luis Fernando; Plourde, Dany; Lemaire, Maryse; Ursini-Siegel, Josie; Mann, Koren K.

    2015-01-01

    The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients’ years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans. PMID:25324207

  4. Plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment.

    PubMed

    Li, Z; Xiao, J; Wu, X; Li, W; Yang, Z; Xie, J; Xu, L; Cai, X; Lin, Z; Guo, W; Luo, J; Liu, M

    2012-09-01

    Bone metastasis is a common and serious consequence of breast cancer. Bidirectional interaction between tumor cells and the bone marrow microenvironment drives a so-called 'vicious cycle' that promotes tumor cell malignancy and stimulates osteolysis. Targeting these interactions and pathways in the tumor-bone microenvironment has been an encouraging strategy for bone metastasis therapy. In the present study, we examined the effects of plumbagin on breast cancer bone metastasis. Our data indicated that plumbagin inhibited cancer cell migration and invasion, suppressed the expression of osteoclast-activating factors, altered the cancer cell induced RANKL/OPG ratio in osteoblasts, and blocked both cancer cell- and RANKL-stimulated osteoclastogenesis. In mouse model of bone metastasis, we further demonstrated that plumbagin significantly repressed breast cancer cell metastasis and osteolysis, inhibited cancer cell induced-osteoclastogenesis and the secretion of osteoclast-activating factors in vivo. At the molecular level, we found that plumbagin abrogated RANKL-induced NF-κB and MAPK pathways by blocking RANK association with TRAF6 in osteoclastogenesis, and by inhibiting the expression of osteoclast-activating factors through the suppression of NF-κB activity in breast cancer cells. Taken together, our data demonstrate that plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment and that plumbagin may serve as a novel agent in the treatment of tumor bone metastasis.

  5. [Pulmonary Metastasis from a Phyllodes Tumor of the Breast Developing Sixteen Years after Initial Surgery].

    PubMed

    Chang, Sung-Soo; Nakano, Takayuki; Okamoto, Taku; Takabatake, Daisuke

    2015-11-01

    We report a case of solitary pulmonary metastasis from a phyllodes tumor of the breast appearing 16 years after initial surgery. The patient was a 56-year-old woman who had undergone surgical extirpation of a left breast tumor diagnosed as phyllodes tumor (borderline malignancy) in 1998, and a right breast tumor diagnosed as fibromatosis in 2000. Sixteen years after the initial operation, she consulted our hospital because of a chest X-ray abnormality detected at a screening examination. Chest computed tomography revealed a well defined nodular shadow in the left upper lobe of the lung. Surgery was done since primary lung cancer was suspected. However, pathological diagnosis was a pulmonary metastasis from the phyllodes tumor of the left breast. Right breast tumor was also diagnosed as a metastasis from the left breast tumor by histopathological re-evaluation.

  6. Sunitinib treatment enhances metastasis of innately drug resistant breast tumors

    PubMed Central

    Wragg, Joseph W; Heath, Victoria L; Bicknell, Roy

    2017-01-01

    Anti-angiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. PMID:28011623

  7. Defining Tumor Cell and Immune Cell Behavior in Vivo during Pulmonary Metastasis of Breast Cancer

    DTIC Science & Technology

    2014-09-01

    outcome of which is still to be determined. 15. SUBJECT TERMS Lung Metastasis, Intravital Imaging , Tumor Immunology, Tumor Microparticles 16. SECURITY...metastatic fitness in the lung. 2) KEYWORDS: Metastasis, Intravital Imaging , Lung, Breast Cancer, 3) ACCOMPLISHMENTS: What were the major goals of the... intravital imaging of Lung Metastasis b) Characterization of Tumor Cell Behavior During Pulmonary Seeding via 2-photon microscopy c) Characterization of

  8. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.

    PubMed

    van Roosmalen, Wies; Le Dévédec, Sylvia E; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M; Look, Maxime P; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A C 't; Martens, John W M; Foekens, John A; Geiger, Benjamin; van de Water, Bob

    2015-04-01

    Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3-binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis.

  9. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

    PubMed Central

    van Roosmalen, Wies; Le Dévédec, Sylvia E.; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M.; Look, Maxime P.; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A.C. ‘t; Martens, John W.M.; Foekens, John A.; Geiger, Benjamin; van de Water, Bob

    2015-01-01

    Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3–binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis. PMID:25774502

  10. Modulation of the Proliferation and Metastasis of Human Breast Tumor Cells by SLUG (IDEA)

    DTIC Science & Technology

    2007-04-01

    E-cadherin preserved tumors is related to prognosis in patients with esophageal squamous cell carcinoma, Clin. Cancer Res. 11 (2005) 1174–1180. [2] A... human breast cells . 15. SUBJECT TERMS Breast cancer , SLUG, transcriptional silencing, molecular decoys, metastasis 16. SECURITY CLASSIFICATION OF: 17...SLUG activity and to evaluate the effects of this ablation on the proliferation, invasiveness and metastasis of these cancer cells in 3D-tissue culture

  11. Inhibition of primary breast tumor growth and metastasis using a neuropilin-1 transmembrane domain interfering peptide

    PubMed Central

    Arpel, Alexia; Gamper, Coralie; Spenlé, Caroline; Fernandez, Aurore; Jacob, Laurent; Baumlin, Nadège; Laquerriere, Patrice; Orend, Gertraud; Crémel, Gérard; Bagnard, Dominique

    2016-01-01

    The transmembrane domains (TMD) in membrane receptors play a key role in cell signaling. As previously shown by us a peptide targeting the TMD of neuropilin-1 (MTP-NRP1), blocks cell proliferation, cell migration and angiogenesis in vitro, and decreases glioblastoma growth in vivo. We now explored the clinical potential of MTP-NRP1 on breast cancer models and demonstrate that MTP-NRP1 blocks proliferation of several breast cancer lines including the MDA-MB-231, a triple negative human breast cancer cell line. In models with long term in vivo administration of the peptide, MTP-NRP1 not only reduced tumor volume but also decreased number and size of breast cancer metastases. Strikingly, treating mice before tumors developed protected from metastasis establishment/formation. Overall, our results report that targeting the TMD of NRP1 in breast cancer is a potent new strategy to fight against breast cancer and related metastasis. PMID:27351129

  12. Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis.

    PubMed

    Zhao, Helong; Ahirwar, Dinesh K; Oghumu, Steve; Wilkie, Tasha; Powell, Catherine A; Nasser, Mohd W; Satoskar, Abhay R; Li, Dean Y; Ganju, Ramesh K

    2016-02-01

    Targeting tumor angiogenesis is a promising alternative strategy for improvement of breast cancer therapy. Robo4 (roundabout homolog 4) signaling has been shown to protect endothelial integrity during sepsis shock and arthritis, and inhibit Vascular Endothelial Growth Factor (VEGF) signaling during pathological angiogenesis of retinopathy, which indicates that Robo4 might be a potential target for angiogenesis in breast cancer. In this study, we used immune competent Robo4 knockout mouse model to show that endothelial Robo4 is important for suppressing breast cancer growth and metastasis. And this effect does not involve the function of Robo4 on hematopoietic stem cells. Robo4 inhibits breast cancer growth and metastasis by regulating tumor angiogenesis, endothelial leakage and tight junction protein zonula occludens protein-1 (ZO-1) downregulation. Treatment with SecinH3, a small molecule drug which deactivates ARF6 downstream of Robo4, can enhance Robo4 signaling and thus inhibit breast cancer growth and metastasis. SecinH3 mediated its effect by reducing tumor angiogenesis rather than directly affecting cancer cell proliferation. In conclusion, endothelial Robo4 signaling is important for suppressing breast cancer growth and metastasis, and it can be targeted (enhanced) by administrating a small molecular drug.

  13. The Influence of Neuronal Activity on Breast Tumor Metastasis to the Brain

    DTIC Science & Technology

    2009-09-01

    drugs to alter brain activity: caffeine, methylphenidate and modafinil . While the smallest effect may be expected from caffeine which is not as potent...caffeine, we have initiated experiments to test the effects of modafinil on breast tumor metastasis to the brain in our model. Unfortunately, we have had

  14. Occult Primary Neuroendocrine Tumor Metastasis to the Breast Detected on Screening Mammogram

    PubMed Central

    Policeni, Fabiana; Pakalniskis, Brittany; Yang, Limin

    2016-01-01

    Metastatic tumors are rare in the breast. Well-differentiated neuroendocrine tumors (WDNETs) are slow-growing neoplasms that arise from neuroendocrine cells, particularly in the gastrointestinal tract and bronchial tree. Metastatic WDNET to the breast is a rare entity. We present a case report of ileal WDNET metastatic to the breast which was initially identified as a small mass in the patient's left breast on screening mammography. Targeted ultrasound identified a suspicious mass, and ultrasound-guided percutaneous core biopsy was performed. Pathology revealed metastatic WDNET. Breast magnetic resonance imaging (MRI) was then performed and demonstrated left axillary Level 2 lymphadenopathy, and liver lesions were suspicious for metastasis. The patient underwent abdominal computed tomography (CT) to evaluate for distant metastatic disease. A spiculated mass was found near the ileocecal valve, suggestive of primary ileal WDNET. In addition, CT identified multiple liver lesions, most compatible with metastasis. Indium 111 OctreoScan confirmed radiotracer uptake in the ileum consistent with primary neuroendocrine tumor. In this report, we review the imaging characteristics of metastatic WDNET to the breast by different imaging modalities including mammogram, ultrasound, and breast MRI. PMID:27761301

  15. Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes.

    PubMed

    Tabariès, Sébastien; Dupuy, Fanny; Dong, Zhifeng; Monast, Anie; Annis, Matthew G; Spicer, Jonathan; Ferri, Lorenzo E; Omeroglu, Atilla; Basik, Mark; Amir, Eitan; Clemons, Mark; Siegel, Peter M

    2012-08-01

    We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes.

  16. A Rare Tumor that Mimicked Metastasis in a Patient with Breast Cancer: Epithelioid Hemangioendothelioma

    PubMed Central

    Çabuk, Fatmagül Kuşku; Aktepe, Fatma; İlgün, Ahmet Serkan; Sarsenov, Dauren; Elbüken, Filiz; Özmen, Vahit

    2016-01-01

    A woman aged 50 years was diagnosed as having an invasive ductal carcinoma in the right breast and ductal carcinoma in situ in the left breast and underwent bilateral mastectomy eight years ago. A mass was identified during follow-up in positron-emission tomography (PET) image in the left infraclavicular region, indicating metastasis. Histopathologic examination showed a mass of 1.9 × 1 × 0.7 cm in dimensions characterized by spindle or round nuclei cells that formed island or cords in hyaline and myxoid ground and intracytoplasmic vacuoles containing erythrocytes. In the immunohistochemical analysis, tumor cells were widespread with diffuse positivity with CD34 and vimentin. These findings redirected us from a diagnosis of metastatic carcinoma to epithelioid hemangioendothelioma, a rare tumor of intermediate vascular tumor groups. In this respect, confirmation through biopsy from considered cases of metastasis is important in making a definite pathologic differential diagnosis.

  17. STC1 expression is associated with tumor growth and metastasis in breast cancer.

    PubMed

    Chang, Andy C-M; Doherty, Judy; Huschtscha, Lily I; Redvers, Richard; Restall, Christina; Reddel, Roger R; Anderson, Robin L

    2015-01-01

    Stanniocalcin-1 (STC1) is a secreted glycoprotein implicated in several pathologies including retinal degeneration, cerebral ischemia, angiogenesis and inflammation. Aberrant STC1 expression has been reported in breast cancer but the significance of this is not clear. High levels of STC1 expression were found in the aggressive 4T1 murine mammary tumor cells and in the MDA-MB-231 human breast cancer line. To investigate its significance, stable clones with STC1 down-regulation using shRNA were generated in both tumor models. The consequences of STC1 down-regulation on cell proliferation, chemotactic invasion, tumor growth and metastasis were assessed. Down-regulation of STC1 in the 4T1 murine mammary tumor cells had a major impact on mammary tumor growth. This observation was replicated in a second tumor model with the MDA-MB-231 human breast cancer line, with a significant reduction in primary tumor formation and a major inhibition of metastasis as well. Interestingly, in both models, proliferation in vitro was not affected. Subsequent microarray gene expression profiling identified 30 genes to be significantly altered by STC1 down-regulation, the majority of which are associated with known hallmarks of carcinogenesis. Furthermore, bioinformatic analysis of breast cancer datasets revealed that high expression of STC1 is associated with poor survival. This is the first study to show definitively that STC1 plays an oncogenic role in breast cancer, and indicates that STC1 could be a potential therapeutic target for treatment of breast cancer patients.

  18. Brain tumor imaging: imaging brain metastasis using a brain-metastasizing breast adenocarcinoma.

    PubMed

    Madden, Kelley S; Zettel, Martha L; Majewska, Ania K; Brown, Edward B

    2013-03-01

    Brain metastases from primary or secondary breast tumors are difficult to model in the mouse. When metastatic breast cancer cell lines are injected directly into the arterial circulation, only a small fraction of cells enter the brain to form metastatic foci. To study the molecular and cellular mechanisms of brain metastasis, we have transfected MB-231BR, a brain-homing derivative of a human breast adenocarcinoma line MDA-MB-231, with the yellow fluorescent protein (YFP) variant Venus. MB-231BR selectively enters the brain after intracardiac injection into the arterial circulation, resulting in accumulation of fluorescent foci of cells in the brain that can be viewed by standard fluorescence imaging procedures. We describe how to perform the intracardiac injection and the parameters used to quantify brain metastasis in brain sections by standard one-photon fluorescence imaging. The disadvantage of this model is that the kinetics of growth over time cannot be determined in the same animal. In addition, the injection technique does not permit precise placement of tumor cells within the brain. This model is useful for determining the molecular determinants of brain tumor metastasis.

  19. Breast Cancer Metastasis

    PubMed Central

    Marino, Natascia; Woditschka, Stephan; Reed, L. Tiffany; Nakayama, Joji; Mayer, Musa; Wetzel, Maria; Steeg, Patricia S.

    2014-01-01

    Despite important progress in adjuvant and neoadjuvant therapies, metastatic disease often develops in breast cancer patients and remains the leading cause of their deaths. For patients with established metastatic disease, therapy is palliative, with few breaks and with mounting adverse effects. Many have hypothesized that a personalized or precision approach (the terms are used interchangeably) to cancer therapy, in which treatment is based on the individual characteristics of each patient, will provide better outcomes. Here, we discuss the molecular basis of breast cancer metastasis and the challenges in personalization of treatment. The instability of metastatic tumors remains a leading obstacle to personalization, because information from a patient’s primary tumor may not accurately reflect the metastasis, and one metastasis may vary from another. Furthermore, the variable presence of tumor subpopulations, such as stem cells and dormant cells, may increase the complexity of the targeted treatments needed. Although molecular signatures and circulating biomarkers have been identified in breast cancer, there is lack of validated predictive molecular markers to optimize treatment choices for either prevention or treatment of metastatic disease. Finally, to maximize the information that can be obtained, increased attention to clinical trial design in the metastasis preventive setting is needed. PMID:23895915

  20. Functions and Epigenetic Regulation of Wwox in Bone Metastasis from Breast Carcinoma: Comparison with Primary Tumors

    PubMed Central

    Maroni, Paola; Matteucci, Emanuela; Bendinelli, Paola; Desiderio, Maria Alfonsina

    2017-01-01

    Epigenetic mechanisms influence molecular patterns important for the bone-metastatic process, and here we highlight the role of WW-domain containing oxidoreductase (Wwox). The tumor-suppressor Wwox lacks in almost all cancer types; the variable expression in osteosarcomas is related to lung-metastasis formation, and exogenous Wwox destabilizes HIF-1α (subunit of Hypoxia inducible Factor-1, HIF-1) affecting aerobic glycolysis. Our recent studies show critical functions of Wwox present in 1833-osteotropic clone, in the corresponding xenograft model, and in human bone metastasis from breast carcinoma. In hypoxic-bone metastatic cells, Wwox enhances HIF-1α stabilization, phosphorylation, and nuclear translocation. Consistently, in bone-metastasis specimens Wwox localizes in cytosolic/perinuclear area, while TAZ (transcriptional co-activator with PDZ-binding motif) and HIF-1α co-localize in nuclei, playing specific regulatory mechanisms: TAZ is a co-factor of HIF-1, and Wwox regulates HIF-1 activity by controlling HIF-1α. In vitro, DNA methylation affects Wwox-protein synthesis; hypoxia decreases Wwox-protein level; hepatocyte growth factor (HGF) phosphorylates Wwox driving its nuclear shuttle, and counteracting a Twist program important for the epithelial phenotype and metastasis colonization. In agreement, in 1833-xenograft mice under DNA-methyltransferase blockade with decitabine, Wwox increases in nuclei/cytosol counteracting bone metastasis with prolongation of the survival. However, Wwox seems relevant for the autophagic process which sustains metastasis, enhancing more Beclin-1 than p62 protein levels, and p62 accumulates under decitabine consistent with adaptability of metastasis to therapy. In conclusion, Wwox methylation as a bone-metastasis therapeutic target would depend on autophagy conditions, and epigenetic mechanisms regulating Wwox may influence the phenotype of bone metastasis. PMID:28045433

  1. Functions and Epigenetic Regulation of Wwox in Bone Metastasis from Breast Carcinoma: Comparison with Primary Tumors.

    PubMed

    Maroni, Paola; Matteucci, Emanuela; Bendinelli, Paola; Desiderio, Maria Alfonsina

    2017-01-01

    Epigenetic mechanisms influence molecular patterns important for the bone-metastatic process, and here we highlight the role of WW-domain containing oxidoreductase (Wwox). The tumor-suppressor Wwox lacks in almost all cancer types; the variable expression in osteosarcomas is related to lung-metastasis formation, and exogenous Wwox destabilizes HIF-1α (subunit of Hypoxia inducible Factor-1, HIF-1) affecting aerobic glycolysis. Our recent studies show critical functions of Wwox present in 1833-osteotropic clone, in the corresponding xenograft model, and in human bone metastasis from breast carcinoma. In hypoxic-bone metastatic cells, Wwox enhances HIF-1α stabilization, phosphorylation, and nuclear translocation. Consistently, in bone-metastasis specimens Wwox localizes in cytosolic/perinuclear area, while TAZ (transcriptional co-activator with PDZ-binding motif) and HIF-1α co-localize in nuclei, playing specific regulatory mechanisms: TAZ is a co-factor of HIF-1, and Wwox regulates HIF-1 activity by controlling HIF-1α. In vitro, DNA methylation affects Wwox-protein synthesis; hypoxia decreases Wwox-protein level; hepatocyte growth factor (HGF) phosphorylates Wwox driving its nuclear shuttle, and counteracting a Twist program important for the epithelial phenotype and metastasis colonization. In agreement, in 1833-xenograft mice under DNA-methyltransferase blockade with decitabine, Wwox increases in nuclei/cytosol counteracting bone metastasis with prolongation of the survival. However, Wwox seems relevant for the autophagic process which sustains metastasis, enhancing more Beclin-1 than p62 protein levels, and p62 accumulates under decitabine consistent with adaptability of metastasis to therapy. In conclusion, Wwox methylation as a bone-metastasis therapeutic target would depend on autophagy conditions, and epigenetic mechanisms regulating Wwox may influence the phenotype of bone metastasis.

  2. Tumor-Host Interaction in Breast Cancer Bone Metastasis

    DTIC Science & Technology

    2006-01-01

    of America. Twenty percent of women with early stage, node- negative breast cancer may subsequently develop metastatic disease , while as many as 90...the prolonged course of a disease with such complications as bone pain and pathological fractures severely reduces a patient’s quality of life, and...to the high incidence of bone metastases of this disease . One observation is the correlation between expression of parathyroid hormone related

  3. Bioenergy and Breast Cancer: A Report on Tumor Growth and Metastasis

    PubMed Central

    Greenwood, Mark; Schmidt, Jade

    2016-01-01

    As many as 80% of the 296,000 women and 2,240 men diagnosed with breast cancer in the United States will seek out complementary and alternative medicine (CAM) treatments. One such therapy is Healing Touch (HT), recognized by the National Center for Complementary and Integrative Health (NCCIH) as a treatment modality. Using a multiple experimental groups design, fifty-six six- to eight-week-old Balb/c mice were injected with 4T1 breast cancer tumor cells and randomly divided into intervention and positive control groups. Five days after tumor cell injection, mice in the intervention groups received HT either daily or every other day for 10 minutes by one HT practitioner. At 15 days after tumor cell injection, tumor size was measured, and metastasis was evaluated by a medical pathologist after necropsy. Tumor size did not differ significantly among the groups (F(3,52) = 0.75, p value = 0.53). The presence of metastasis did not differ across groups (chi-square(3) = 3.902, p = 0.272) or when compared within an organ (liver: chi-square(3) = 2.507, p = 0.474; lungs: chi-square(3) = 3.804, p = 0.283; spleen: chi-square(3) = 0.595, p = 0.898). However, these results did indicate a moderate, though insignificant, positive impact of HT and highlight the need for continued research into dose, length of treatment, and measurable outcomes (tumor size, metastasis) to provide evidence to suggest application for nursing care. PMID:27688787

  4. PRC2/EED-EZH2 Complex Is Up-Regulated in Breast Cancer Lymph Node Metastasis Compared to Primary Tumor and Correlates with Tumor Proliferation In Situ

    PubMed Central

    Yu, Hongxiang; Simons, Diana L.; Segall, Ilana; Carcamo-Cavazos, Valeria; Schwartz, Erich J.; Yan, Ning; Zuckerman, Neta S.; Dirbas, Frederick M.; Johnson, Denise L.; Holmes, Susan P.; Lee, Peter P.

    2012-01-01

    Background Lymph node metastasis is a key event in the progression of breast cancer. Therefore it is important to understand the underlying mechanisms which facilitate regional lymph node metastatic progression. Methodology/Principal Findings We performed gene expression profiling of purified tumor cells from human breast tumor and lymph node metastasis. By microarray network analysis, we found an increased expression of polycomb repression complex 2 (PRC2) core subunits EED and EZH2 in lymph node metastatic tumor cells over primary tumor cells which were validated through real-time PCR. Additionally, immunohistochemical (IHC) staining and quantitative image analysis of whole tissue sections showed a significant increase of EZH2 expressing tumor cells in lymph nodes over paired primary breast tumors, which strongly correlated with tumor cell proliferation in situ. We further explored the mechanisms of PRC2 gene up-regulation in metastatic tumor cells and found up-regulation of E2F genes, MYC targets and down-regulation of tumor suppressor gene E-cadherin targets in lymph node metastasis through GSEA analyses. Using IHC, the expression of potential EZH2 target, E-cadherin was examined in paired primary/lymph node samples and was found to be significantly decreased in lymph node metastases over paired primary tumors. Conclusions/Significance This study identified an over expression of the epigenetic silencing complex PRC2/EED-EZH2 in breast cancer lymph node metastasis as compared to primary tumor and its positive association with tumor cell proliferation in situ. Concurrently, PRC2 target protein E-cadherin was significant decreased in lymph node metastases, suggesting PRC2 promotes epithelial mesenchymal transition (EMT) in lymph node metastatic process through repression of E-cadherin. These results indicate that epigenetic regulation mediated by PRC2 proteins may provide additional advantage for the outgrowth of metastatic tumor cells in lymph nodes. This opens

  5. Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone

    PubMed Central

    Sloan, Erica K; Pouliot, Normand; Stanley, Kym L; Chia, Jenny; Moseley, Jane M; Hards, Daphne K; Anderson, Robin L

    2006-01-01

    Introduction Studies in xenograft models and experimental models of metastasis have implicated several β3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific αvβ3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. Methods We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of αvβ3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of αvβ3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. Results The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. αvβ3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, αvβ3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, αvβ3 increased 66cl4 tumor cell

  6. CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity.

    PubMed

    Zhu, Guiquan; Yan, H Hannah; Pang, Yanli; Jian, Jiang; Achyut, Bhagelu R; Liang, Xinhua; Weiss, Jonathan M; Wiltrout, Robert H; Hollander, M Christine; Yang, Li

    2015-12-22

    Chemokines and chemokine receptors have critical roles in cancer metastasis and have emerged as one of the targeting options in cancer therapy. However, the treatment efficacy on both tumor and host compartments needs to be carefully evaluated. Here we report that targeting CXCR3 decreased tumor cell migration and at the same time improved host anti-tumor immunity. We observed an increased expression of CXCR3 in metastatic tumor cells compared to those from non-metastatic tumor cells. Knockdown (KD) of CXCR3 in metastatic tumor cells suppressed tumor cell migration and metastasis. Importantly, CXCR3 expression in clinical breast cancer samples correlated with progression and metastasis. For the host compartment, deletion of CXCR3 in all host cells in 4T1 mammary tumor model significantly decreased metastasis. The underlying mechanisms involve a decreased expression of IL-4, IL-10, iNOs, and Arg-1 in myeloid cells and an increased T cell response. IFN-γ neutralization diminished the metastasis inhibition in the CXCR3 knockout (KO) mice bearing 4T1 tumors, suggesting a critical role of host CXCR3 in immune suppression. Consistently, targeting CXCR3 using a small molecular inhibitor (AMG487) significantly suppressed metastasis and improved host anti-tumor immunity. Our findings demonstrate that targeting CXCR3 is effective in both tumor and host compartments, and suggest that CXCR3 inhibition is likely to avoid adverse effects on host cells.

  7. Radio-Photothermal Therapy Mediated by a Single Compartment Nanoplatform Depletes Tumor Initiating Cells and Reduces Lung Metastasis in Orthotopic 4T1 Breast Tumor Model

    PubMed Central

    Zhou, Min; Zhao, Jun; Tian, Mei; Song, Shaoli; Zhang, Rui; Gupta, Sanjay; Tan, Dongfeng; Shen, Haifa; Ferrari, Mauro; Li, Chun

    2016-01-01

    Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and has demonstrated promising application in clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress breast tumor metastasis through eradication of TICs. Positron electron tomography (PET) imaging and biodistribution studies showed that more than 90% of [64Cu]CuS NPs was retained in subcutaneously grown BT474 breast tumor 24 h after intratumoral (i.t.) injection, indicating the NPs is suitable for the combination therapy. Combined RT/PTT therapy resulted in significant tumor growth delay in subcutaneous BT474 breast cancer model. Moreover, RT/PTT treatment significantly prolonged the survival of mice bearing orthotopic 4T1 breast tumors compared to no treatment, RT alone, or PTT alone. The RT/PTT combination therapy significantly reduced the number of tumor nodules in the lung and the formation of tumor mammospheres from treated 4T1 tumors. No obvious side effects of the CuS NPs were noted in the treated mice in a pilot toxicity study. Taken together, our data support the feasibility of a therapeutic approach for suppression of tumor metastasis through localized RT/PTT therapy. PMID:26376843

  8. PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

    PubMed Central

    Li, Jiarong; Karaplis, Andrew C.; Huang, Dao C.; Siegel, Peter M.; Camirand, Anne; Yang, Xian Fang; Muller, William J.; Kremer, Richard

    2011-01-01

    Parathyroid hormone–related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer — it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention. PMID:22056386

  9. ADAM12 transmembrane and secreted isoforms promote breast tumor growth: a distinct role for ADAM12-S protein in tumor metastasis.

    PubMed

    Roy, Roopali; Rodig, Scott; Bielenberg, Diane; Zurakowski, David; Moses, Marsha A

    2011-06-10

    Increased levels of ADAM12 have been reported in a variety of human cancers. We have previously reported that urinary ADAM12 is predictive of disease status in breast cancer patients and that ADAM12 protein levels in urine increase with progression of disease. On the basis of these findings, the goal of this study was to elucidate the contribution of ADAM12 in breast tumor growth and progression. Overexpression of both the ADAM12-L (transmembrane) and ADAM12-S (secreted) isoforms in human breast tumor cells resulted in a significantly higher rate of tumor take and increased tumor size. Cells expressing the enzymatically inactive form of the secreted isoform, ADAM12-S, had tumor take rates and tumor volumes similar to those of wild-type cells, suggesting that the tumor-promoting activity of ADAM12-S was a function of its proteolytic activity. Of the two isoforms, only the secreted isoform, ADAM12-S, enhanced the ability of tumor cells to migrate and invade in vitro and resulted in a higher incidence of local and distant metastasis in vivo. This stimulatory effect of ADAM12-S on migration and invasion was dependent on its catalytic activity. Expression of both ADAM12 isoforms was found to be significantly elevated in human malignant breast tissue. Taken together, our results suggest that ADAM12 overexpression results in increased tumor take, tumor size, and metastasis in vivo. These findings suggest that ADAM12 may represent a potential therapeutic target in breast cancer.

  10. Targeting Breast Cancer Metastasis

    PubMed Central

    Jin, Xin; Mu, Ping

    2015-01-01

    Metastasis is the leading cause of breast cancer-associated deaths. Despite the significant improvement in current therapies in extending patient life, 30–40% of patients may eventually suffer from distant relapse and succumb to the disease. Consequently, a deeper understanding of the metastasis biology is key to developing better treatment strategies and achieving long-lasting therapeutic efficacies against breast cancer. This review covers recent breakthroughs in the discovery of various metastatic traits that contribute to the metastasis cascade of breast cancer, which may provide novel avenues for therapeutic targeting. PMID:26380552

  11. Targeting Neuronal-like Metabolism of Metastatic Tumor Cells as a Novel Therapy for Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2016-03-01

    post-injection. It generally takes around 30- 60 days for MDA-MB-231 model to form brain metastasis in Rag 1 -/- mice. We have successfully finished...1 AWARD NUMBER: W81XWH-15-1-0021 TITLE: Targeting Neuronal-like Metabolism of Metastatic Tumor Cells as a Novel Therapy for Breast Cancer Brain ...Cancer Brain Metastasis 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0021 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Siyuan Zhang 5d. PROJECT

  12. Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2.

    PubMed

    Merino, D; Best, S A; Asselin-Labat, M-L; Vaillant, F; Pal, B; Dickins, R A; Anderson, R L; Strasser, A; Bouillet, P; Lindeman, G J; Visvader, J E

    2015-07-23

    Evasion of cell death is fundamental to the development of cancer and its metastasis. The role of the BCL-2-mediated (intrinsic) apoptotic program in these processes remains poorly understood. Here we have investigated the relevance of the pro-apoptotic protein BIM to breast cancer progression using the MMTV-Polyoma middle-T (PyMT) transgenic model. BIM deficiency in PyMT females did not affect primary tumor growth, but substantially increased the survival of metastatic cells within the lung. These data reveal a role for BIM in the suppression of breast cancer metastasis. Intriguingly, we observed a striking correlation between the expression of BIM and the epithelial to mesenchymal transition transcription factor SNAI2 at the proliferative edge of the tumors. Overexpression and knockdown studies confirmed that these two genes were coordinately expressed, and chromatin immunoprecipitation analysis further revealed that Bim is a target of SNAI2. Taken together, our findings suggest that SNAI2-driven BIM-induced apoptosis may temper metastasis by governing the survival of disseminating breast tumor cells.

  13. Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells.

    PubMed

    Lee, Hsueh-Te; Xue, Jianfei; Chou, Ping-Chieh; Zhou, Aidong; Yang, Phillip; Conrad, Charles A; Aldape, Kenneth D; Priebe, Waldemar; Patterson, Cam; Sawaya, Raymond; Xie, Keping; Huang, Suyun

    2015-04-30

    Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.

  14. Understanding Collagen Organization in Breast Tumors to Predict and Prevent Metastasis

    DTIC Science & Technology

    2015-11-01

    tran- siently increased MB-231 tumor growth , but only when social iso- lation was initiated when tumor growth was near exponential phase. No...receptors (AR). In animal models using b-AR–expressing cancer cell lines, stressor exposure or b-AR stimulation increased tumor growth and/or metastasis by...Uses bone marrow transfer after irradiation. Source animals are one of 7 knockouts, for 7 candidate genes. ~50x7= 350 mice. Produces identity of

  15. Radio-photothermal therapy mediated by a single compartment nanoplatform depletes tumor initiating cells and reduces lung metastasis in the orthotopic 4T1 breast tumor model

    NASA Astrophysics Data System (ADS)

    Zhou, Min; Zhao, Jun; Tian, Mei; Song, Shaoli; Zhang, Rui; Gupta, Sanjay; Tan, Dongfeng; Shen, Haifa; Ferrari, Mauro; Li, Chun

    2015-11-01

    Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress breast tumor metastasis through eradication of TICs. Positron electron tomography (PET) imaging and biodistribution studies showed that more than 90% of [64Cu]CuS NPs was retained in subcutaneously grown BT474 breast tumor 24 h after intratumoral (i.t.) injection, indicating the NPs are suitable for the combination therapy. Combined RT/PTT therapy resulted in significant tumor growth delay in the subcutaneous BT474 breast cancer model. Moreover, RT/PTT treatment significantly prolonged the survival of mice bearing orthotopic 4T1 breast tumors compared to no treatment, RT alone, or PTT alone. The RT/PTT combination therapy significantly reduced the number of tumor nodules in the lung and the formation of tumor mammospheres from treated 4T1 tumors. No obvious side effects of the CuS NPs were noted in the treated mice in a pilot toxicity study. Taken together, our data support the feasibility of a therapeutic approach for the suppression of tumor metastasis through localized RT/PTT therapy.Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress

  16. Chamaejasmenin B, a novel candidate, inhibits breast tumor metastasis by rebalancing TGF-beta paradox.

    PubMed

    Li, Qi; Wang, Yajie; Xiao, Hongbin; Li, Yujie; Kan, Xiaoxi; Wang, Xiaomin; Zhang, Ganlin; Wang, Zhixin; Yang, Qing; Chen, Xi; Weng, Xiaogang; Chen, Ying; Zhou, Bingbing; Guo, Yan; Liu, Xucen; Zhu, Xiaoxin

    2016-07-26

    Metastasis is the leading lethal factor severely restraining the effectiveness of clinical treatment. TGF-beta is the key regulator for metastasis and influences paradoxically on cancer progression. The known TGF-beta blockers exert little selectivity on its functions, indiscriminately causing the anti-metastatic and pro-growth effects. Under such circumstances, specifically rebalancing the oncological function of TGF-beta provides a crucial oncotarget against metastasis. In our study, we established the screening platform targeting cell motility and identified a potential flavonoid, Chamaejasmenin B (ICJ), extracted from Stellera chamaejasme L..It suppressed the migration and invasion in breast cancer cells in vitro. Moreover, by dynamical quantification of breast cancer progression in small-animal imaging system, ICJ was proved to be a potent inhibitor of metastasis with minimal toxic side effects. Mechanism study further revealed that ICJ efficiently blocked TGF-beta induced EMT, disrupted the interaction between β3 integrin-TβRII complex and, consequently, resulted in the selective inhibition of FAK:Src:p38 pathway. Meanwhile, specific blockage of this pathway largely attenuated the anti-metastatic function of ICJ. Importantly, in contrast with the antagonistic effects on TGF-beta induced metastasis, ICJ obviously sensitized its cytostatic activity, suggesting that it was not a pan-blocker but a rebalancer for the functional output of TGF-beta. Collectively, by targeting TGF-beta Paradox, we experimentally provided a promising candidate for metastatic intervention.

  17. Chamaejasmenin B, a novel candidate, inhibits breast tumor metastasis by rebalancing TGF-beta paradox

    PubMed Central

    Li, Qi; Wang, Yajie; Xiao, Hongbin; Li, Yujie; Kan, Xiaoxi; Wang, Xiaomin; Zhang, Ganlin; Wang, Zhixin; Yang, Qing; Chen, Xi; Weng, Xiaogang; Chen, Ying; Zhou, Bingbing; Guo, Yan; Liu, Xucen; Zhu, Xiaoxin

    2016-01-01

    Metastasis is the leading lethal factor severely restraining the effectiveness of clinical treatment. TGF-beta is the key regulator for metastasis and influences paradoxically on cancer progression. The known TGF-beta blockers exert little selectivity on its functions, indiscriminately causing the anti-metastatic and pro-growth effects. Under such circumstances, specifically rebalancing the oncological function of TGF-beta provides a crucial oncotarget against metastasis. In our study, we established the screening platform targeting cell motility and identified a potential flavonoid, Chamaejasmenin B (ICJ), extracted from Stellera chamaejasme L. It suppressed the migration and invasion in breast cancer cells in vitro. Moreover, by dynamical quantification of breast cancer progression in small-animal imaging system, ICJ was proved to be a potent inhibitor of metastasis with minimal toxic side effects. Mechanism study further revealed that ICJ efficiently blocked TGF-beta induced EMT, disrupted the interaction between β3 integrin-TβRII complex and, consequently, resulted in the selective inhibition of FAK:Src:p38 pathway. Meanwhile, specific blockage of this pathway largely attenuated the anti-metastatic function of ICJ. Importantly, in contrast with the antagonistic effects on TGF-beta induced metastasis, ICJ obviously sensitized its cytostatic activity, suggesting that it was not a pan-blocker but a rebalancer for the functional output of TGF-beta. Collectively, by targeting TGF-beta Paradox, we experimentally provided a promising candidate for metastatic intervention. PMID:27374079

  18. Gene expression markers in circulating tumor cells may predict bone metastasis and response to hormonal treatment in breast cancer.

    PubMed

    Wang, Haiying; Molina, Julian; Jiang, John; Ferber, Matthew; Pruthi, Sandhya; Jatkoe, Timothy; Derecho, Carlo; Rajpurohit, Yashoda; Zheng, Jian; Wang, Yixin

    2013-11-01

    Circulating tumor cells (CTCs) have recently attracted attention due to their potential as prognostic and predictive markers for the clinical management of metastatic breast cancer patients. The isolation of CTCs from patients may enable the molecular characterization of these cells, which may help establish a minimally invasive assay for the prediction of metastasis and further optimization of treatment. Molecular markers of proven clinical value may therefore be useful in predicting disease aggressiveness and response to treatment. In our earlier study, we identified a gene signature in breast cancer that appears to be significantly associated with bone metastasis. Among the genes that constitute this signature, trefoil factor 1 (TFF1) was identified as the most differentially expressed gene associated with bone metastasis. In this study, we investigated 25 candidate gene markers in the CTCs of metastatic breast cancer patients with different metastatic sites. The panel of the 25 markers was investigated in 80 baseline samples (first blood draw of CTCs) and 30 follow-up samples. In addition, 40 healthy blood donors (HBDs) were analyzed as controls. The assay was performed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) with RNA extracted from CTCs captured by the CellSearch system. Our study indicated that 12 of the genes were uniquely expressed in CTCs and 10 were highly expressed in the CTCs obtained from patients compared to those obtained from HBDs. Among these genes, the expression of keratin 19 was highly correlated with the CTC count. The TFF1 expression in CTCs was a strong predictor of bone metastasis and the patients with a high expression of estrogen receptor β in CTCs exhibited a better response to hormonal treatment. Molecular characterization of these genes in CTCs may provide a better understanding of the mechanism underlying tumor metastasis and identify gene markers in CTCs for predicting disease progression and

  19. Gene expression markers in circulating tumor cells may predict bone metastasis and response to hormonal treatment in breast cancer

    PubMed Central

    WANG, HAIYING; MOLINA, JULIAN; JIANG, JOHN; FERBER, MATTHEW; PRUTHI, SANDHYA; JATKOE, TIMOTHY; DERECHO, CARLO; RAJPUROHIT, YASHODA; ZHENG, JIAN; WANG, YIXIN

    2013-01-01

    Circulating tumor cells (CTCs) have recently attracted attention due to their potential as prognostic and predictive markers for the clinical management of metastatic breast cancer patients. The isolation of CTCs from patients may enable the molecular characterization of these cells, which may help establish a minimally invasive assay for the prediction of metastasis and further optimization of treatment. Molecular markers of proven clinical value may therefore be useful in predicting disease aggressiveness and response to treatment. In our earlier study, we identified a gene signature in breast cancer that appears to be significantly associated with bone metastasis. Among the genes that constitute this signature, trefoil factor 1 (TFF1) was identified as the most differentially expressed gene associated with bone metastasis. In this study, we investigated 25 candidate gene markers in the CTCs of metastatic breast cancer patients with different metastatic sites. The panel of the 25 markers was investigated in 80 baseline samples (first blood draw of CTCs) and 30 follow-up samples. In addition, 40 healthy blood donors (HBDs) were analyzed as controls. The assay was performed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) with RNA extracted from CTCs captured by the CellSearch system. Our study indicated that 12 of the genes were uniquely expressed in CTCs and 10 were highly expressed in the CTCs obtained from patients compared to those obtained from HBDs. Among these genes, the expression of keratin 19 was highly correlated with the CTC count. The TFF1 expression in CTCs was a strong predictor of bone metastasis and the patients with a high expression of estrogen receptor β in CTCs exhibited a better response to hormonal treatment. Molecular characterization of these genes in CTCs may provide a better understanding of the mechanism underlying tumor metastasis and identify gene markers in CTCs for predicting disease progression and

  20. Breast cancer metastasis to the pituitary gland.

    PubMed

    Magalhães, Julia Fragoso; Bacchin, Renata Prota; Costa, Priscila Scatena; Alves, Gisele Malavazi; Fraige Filho, Fadlo; Stella, Lenira Cristina

    2014-11-01

    Metastatic tumors to the pituitary gland are an unusual complication typically seen in elderly patients with diffuse malignant disease. Breast and lung are the commonest sites of the primary tumor. Prognosis of patients with breast cancer metastasis is poor and depends on the primary neoplastic extension. We report a 54 year-old woman with breast cancer metastasis to the pituitary stalk first diagnosed because of visual disturbance with no other symptoms. Pituitary gland stalk metastasis is a very uncommon find and this case report includes a literature review.

  1. Homocysteine Is an Oncometabolite in Breast Cancer, Which Promotes Tumor Progression and Metastasis

    DTIC Science & Technology

    2014-09-01

    tissues and compare the expression levels in normal mouse mammary gland . For this, we used biological triplicates by preparing RNA from tumor tissues...homocysteine to be increased 4.5-fold in MMTV-HRAS mouse breast tumor tissues compared to age-matched wild type mouse mammary tissues. Similarly, the...levels of homocysteine went up 7.3-fold in MMTV-PyMT mouse breast cancer tissues 3 compared to age-matched wild type mouse mammary tissues

  2. PHOSPHOLIPASE D (PLD) DRIVES CELL INVASION, TUMOR GROWTH AND METASTASIS IN A HUMAN BREAST CANCER XENOGRAPH MODEL

    PubMed Central

    Henkels, Karen M.; Boivin, Gregory P.; Dudley, Emily S.; Berberich, Steven J.; Gomez-Cambronero, Julian

    2014-01-01

    Breast cancer is one of the most common malignancies in human females in the world. One protein that has elevated enzymatic lipase activity in breast cancers in vitro is phospholipase D (PLD), which is also involved in cell migration. We demonstrate that the PLD2 isoform, which was analyzed directly in the tumors, is crucial for cell invasion that contributes critically to the growth and development of breast tumors and lung metastases in vivo. We used three complementary strategies in a SCID mouse model and also addressed the underlying molecular mechanism. First, the PLD2 gene was silenced in highly metastatic, aggressive breast cancer cells (MDA-MB-231) with lentivirus-based shRNA, which were xenotransplanted in SCID mice. The resulting mouse primary mammary tumors were reduced in size (65%, p<0.05) and their onset delayed when compared to control tumors. Second, we stably overexpressed PLD2 in low-invasive breast cancer cells (MCF-7) with a biscistronic MIEG retroviral vector and observed that these cells were converted into a highly aggressive phenotype, as primary tumors that formed following xenotransplantation were larger, grew faster and developed lung metastases more readily. Third, we implanted osmotic pumps into SCID xenotransplanted mice that delivered two different small-molecule inhibitors of PLD activity (FIPI and NOPT). These inhibitors led to significant (>70%, p<0.05) inhibition of primary tumor growth, metastatic axillary tumors and lung metastases. In order to define the underlying mechanism, we determined that the machinery of PLD-induced cell invasion is mediated by phosphatidic acid (PA), WASp, Grb2 and Rac2 signaling events that ultimately affect actin polymerization and cell invasion. In summary, this study shows that PLD has a central role in the development, metastasis and level of aggressiveness of breast cancer, raising the possibility that PLD2 could be used as a new therapeutic target. PMID:23752189

  3. GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis.

    PubMed

    Maric, G; Annis, M G; Dong, Z; Rose, A A N; Ng, S; Perkins, D; MacDonald, P A; Ouellet, V; Russo, C; Siegel, P M

    2015-10-01

    Glycoprotein nmb (GPNMB) promotes breast tumor growth and metastasis and its expression in tumor epithelium correlates with poor prognosis in breast cancer patients. Despite its biological and clinical significance, little is known regarding the molecular mechanisms engaged by GPNMB. Herein, we show that GPNMB engages distinct functional domains and mechanisms to promote primary tumor growth and metastasis. We demonstrate that neuropilin-1 (NRP-1) expression is increased in breast cancer cells that overexpress GPNMB. Interestingly, the GPNMB-driven increase in NRP-1 expression potentiated vascular endothelial growth factor signaling in breast cancer cells and was required for the growth, but not metastasis, of these cells in vivo. Interrogation of RNAseq data sets revealed a positive correlation between GPNMB and NRP-1 levels in human breast tumors. Furthermore, we ascribe pro-growth and pro-metastatic functions of GPNMB to its ability to bind α5β1 integrin and increase downstream signaling in breast cancer cells. We show that GPNMB enhances breast cancer cell adhesion to fibronectin, increases α5β1 expression and associates with this receptor through its RGD motif. GPNMB recruitment into integrin complexes activates Src and Fak signaling pathways in an RGD-dependent manner. Importantly, both the RGD motif and cytoplasmic tail of GPNMB are required to promote primary mammary tumor growth; however, only mutation of the RGD motif impaired the formation of lung metastases. Together, these findings identify novel and distinct molecular mediators of GPNMB-induced breast cancer growth and metastasis.

  4. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer.

    PubMed

    Futakuchi, Mitsuru; Fukamachi, Katsumi; Suzui, Masumi

    2016-04-01

    Bone is the most common target organ of metastasis of prostate and breast cancers. This produces considerable morbidity due to skeletal-related events, SREs, including bone pain, hypercalcemia, pathologic fracture, and compression of the spinal cord. The mechanism of bone metastasis is complex and involves cooperative reciprocal interaction among tumor cells, osteoblasts, osteoclasts, and the mineralized bone matrix. The interaction between the metastatic tumor and bone stromal cells has been commonly referred to as the "vicious cycle". Tumor cells stimulate osteoblasts, which in turn stimulate osteoclasts through the secretion of cytokines such as the TNF family member receptor activator of nuclear κB ligand (RANKL). Activated osteoclasts degrade the bone matrix by producing strong acid and proteinases. Bone degradation by osteoclasts releases TGFβ and other growth factors stored in the bone matrix, that further stimulate tumor cells. Bone modifying agents, targeting osteoclast activity, such as bisphosphonate and RANKL antibodies are considered as the standard of care for reducing SREs of patients with bone metastatic diseases. These agents decrease osteoclast activity and delay worsening of skeletal pain and aggravation of bone metastatic diseases. While the management of SREs by these agents may improve patients' lives, this treatment does not address the specific issues of the patients with bone metastasis such as tumor dormancy, drug resistance, or improvement of survival. Here, we review the mechanisms of bone metastasis formation, tumor heterogeneity in the bone microenvironment, and conventional therapy for bone metastatic diseases and discuss the potential development of new therapies targeting tumor heterogeneity in the bone microenvironment.

  5. The class I HDAC inhibitor Romidepsin targets inflammatory breast cancer tumor emboli and synergizes with paclitaxel to inhibit metastasis.

    PubMed

    Robertson, Fredika M; Chu, Khoi; Boley, Kimberly M; Ye, Zaiming; Liu, Hui; Wright, Moishia C; Moraes, Ricardo; Zhang, Xuejun; Green, Tessa L; Barsky, Sanford H; Heise, Carla; Cristofanilli, Massimo

    2013-01-01

    Inflammatory breast cancer (IBC) is the most metastatic variant of locally advanced breast cancer. IBC has distinctive characteristics including invasion of tumor emboli into the skin and rapid disease progression. Given our previous studies suggesting that HDAC inhibitors have promise in targeting IBC, the present study revealed that the class I HDAC inhibitor Romidepsin (FK-288, Istodax; Celgene Corporation, Summit, NJ) potently induced destruction of IBC tumor emboli and lymphatic vascular architecture. associated with inhibition of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha, (HIF1alpha) proteins in the Mary-X pre-clinical model of IBC. Romidepsin treatment induced clinically relevant biomarkers in including induction of acetylated Histone 3 (Ac-H3) proteins, apoptosis, and increased p21WAF1/CIP1. Romidepsin, alone and synergistically when combined with Paclitaxel, effectively eliminated both primary tumors and metastatic lesions at multiple sites formed by the SUM149 IBC cell line. This is the first report of the ability of an HDAC inhibitor to eradicate IBC tumor emboli, to destroy the integrity of lymphatic vessel architecture and to target metastasis. Furthermore, Romidepsin, in combination with a taxane, warrants evaluation as a therapeutic strategy that may effectively target the skin involvement and rapid metastasis that are hallmarks of IBC.

  6. The Action of Discoidin Domain Receptor 2 in Basal Tumor Cells and Stromal Cancer-Associated Fibroblasts Is Critical for Breast Cancer Metastasis.

    PubMed

    Corsa, Callie A S; Brenot, Audrey; Grither, Whitney R; Van Hove, Samantha; Loza, Andrew J; Zhang, Kun; Ponik, Suzanne M; Liu, Yuming; DeNardo, David G; Eliceiri, Kevin W; Keely, Patricia J; Longmore, Gregory D

    2016-06-14

    High levels of collagen deposition in human and mouse breast tumors are associated with poor outcome due to increased local invasion and distant metastases. Using a genetic approach, we show that, in mice, the action of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2) in both tumor and tumor-stromal cells is critical for breast cancer metastasis yet does not affect primary tumor growth. In tumor cells, DDR2 in basal epithelial cells regulates the collective invasion of tumor organoids. In stromal cancer-associated fibroblasts (CAFs), DDR2 is critical for extracellular matrix production and the organization of collagen fibers. The action of DDR2 in CAFs also enhances tumor cell collective invasion through a pathway distinct from the tumor-cell-intrinsic function of DDR2. This work identifies DDR2 as a potential therapeutic target that controls breast cancer metastases through its action in both tumor cells and tumor-stromal cells at the primary tumor site.

  7. Monitoring of tumor growth and metastasis potential in MDA-MB-435s/ tk-luc human breast cancer xenografts

    NASA Astrophysics Data System (ADS)

    Chang, Ya-Fang; Lin, Yi-Yu; Wang, Hsin-Ell; Liu, Ren-Shen; Pang, Fei; Hwang, Jeng-Jong

    2007-02-01

    Molecular imaging of reporter gene expression provides a rapid, sensitive and non-invasive monitoring of tumor behaviors. In this study, we reported the establishment of a novel animal model for longitudinal examination of tumor growth kinetics and metastatic spreading in vivo. The highly metastatic human breast carcinoma MDA-MB-435s cell line was engineered to stably express herpes simplex virus type 1 thymidine kinase (HSV-1- tk) and luciferase ( luc). Both 131I-FIAU and D-luciferin were used as reporter probes. For orthotopic tumor formation, MDA-MB-435s/ tk-luc cells were implanted into the first nipple of 6-week-old female NOD/SCID mice. For metastatic study, cells were injected via the lateral tail vein. Mice-bearing MDA-MB-435s/ tk-luc tumors were scanned for tumor growth and metastatsis using Xenogen IVIS50 system. Gamma scintigraphy and whole-body autoradiography were also applied to confirm the tumor localization. The results of bioluminescence imaging as well as histopathological finding showed that tumors could be detected in femur, spine, ovary, lungs, kidney, adrenal gland, lymph nodes and muscle at 16 weeks post i.v. injection, and correlated photons could be quantified. This MDA-MB-435s/ tk-luc human breast carcinoma-bearing mouse model combined with multimodalities of molecular imaging may facilitate studies on the molecular mechanisms of cancer invasion and metastasis.

  8. The milk protein α-casein functions as a tumor suppressor via activation of STAT1 signaling, effectively preventing breast cancer tumor growth and metastasis.

    PubMed

    Bonuccelli, Gloria; Castello-Cros, Remedios; Capozza, Franco; Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Tsirigos, Aristotelis; Xuanmao, Jiao; Whitaker-Menezes, Diana; Howell, Anthony; Lisanti, Michael P; Sotgia, Federica

    2012-11-01

    Here, we identified the milk protein α-casein as a novel suppressor of tumor growth and metastasis. Briefly, Met-1 mammary tumor cells expressing α-casein showed a ~5-fold reduction in tumor growth and a near 10-fold decrease in experimental metastasis. To identify the molecular mechanism(s), we performed genome-wide transcriptional profiling. Interestingly, our results show that α-casein upregulates gene transcripts associated with interferon/STAT1 signaling and downregulates genes associated with "stemness." These findings were validated by immunoblot and FACS analysis, which showed the upregulation and hyperactivation of STAT1 and a decrease in the number of CD44(+) "cancer stem cells." These gene signatures were also able to predict clinical outcome in human breast cancer patients. Thus, we conclude that a lactation-based therapeutic strategy using recombinant α-casein would provide a more natural and non-toxic approach to the development of novel anticancer therapies.

  9. LOXL4 knockdown enhances tumor growth and lung metastasis through collagen-dependent extracellular matrix changes in triple-negative breast cancer.

    PubMed

    Choi, Sul Ki; Kim, Hoe Suk; Jin, Tiefeng; Moon, Woo Kyung

    2017-01-02

    Lysyl oxidase (LOX) family genes catalyze collagen cross-link formation. To determine the effects of lysyl oxidase-like 4 (LOXL4) expression on breast tumor formation and metastasis, we evaluated primary tumor growth and lung metastasis in mice injected with LOXL4-knockdown MDA-MB-231 triple-negative human breast cancer cells. In addition, we analyzed overall survival in breast cancer patients based on LOXL4 expression using a public online database. In the mouse xenograft model, LOXL4 knockdown increased primary tumor growth and lung colonization as well as collagen I and IV, lysine hydroxylase 1 and 2, and prolyl 4-hydroxylase subunit alpha 1 and 2 levels. Second harmonic generation imaging revealed that LOXL4 knockdown resulted in the thickening of collagen bundles within tumors. In addition, weak LOXL4 expression was associated with poor overall survival in breast cancer patients from the BreastMark dataset, and this association was strongest in triple-negative breast cancer patients. These results demonstrate that weak LOXL4 expression leads to remodeling of the extracellular matrix through induction of collagen synthesis, deposition, and structural changes. These alterations in turn promote tumor growth and metastasis and are associated with poor clinical outcomes in triple-negative breast cancer.

  10. Suppressive effects of a proton beam on tumor growth and lung metastasis through the inhibition of metastatic gene expression in 4T1 orthotopic breast cancer model.

    PubMed

    Kwon, Yun-Suk; Lee, Kyu-Shik; Chun, So-Young; Jang, Tae Jung; Nam, Kyung-Soo

    2016-07-01

    A proton beam is a next generation tool to treat intractable cancer. Although the therapeutic effects of a proton beam are well known, the effect on tumor metastasis is not fully described. Here, we investigated the effects of a proton beam on metastasis in highly invasive 4T1 murine breast cancer cells and their orthotopic breast cancer model. Cells were irradiated with 2, 4, 8 or 16 Gy proton beam, and changes in cell proliferation, survival, and migration were observed by MTT, colony forming and wound healing assays. 4T1 breast cancer cell-implanted BALB/c mice were established and the animals were randomly divided into 4 groups when tumor size reached 200 mm3. Breast tumors were selectively irradiated with 10, 20 or 30 Gy proton beam. Breast tumor sizes were measured twice a week, and breast tumor and lung tissues were pathologically observed. Metastasis-regulating gene expression was assessed with quantitative RT-PCR. A proton beam dose-dependently decreased cell proliferation, survival and migration in 4T1 murine breast cancer cells. Also, growth of breast tumors in the 4T1 orthotopic breast cancer model was significantly suppressed by proton beam irradiation without significant change of body weight. Furthermore, fewer tumor nodules metastasized from breast tumor into lung in mice irradiated with 30 Gy proton beam, but not with 10 and 20 Gy, than in control. We observed correspondingly lower expression levels of urokinase plasminogen activator (uPA), uPA receptor, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF), which are important factors in cancer metastasis, in breast tumor irradiated with 30 Gy proton beam. Proton beam irradiation did not affect expressions of matrix metalloproteinase (MMP)-9 and MMP-2. Taken together, the data suggest that, although proton beam therapy is an effective tool for breast cancer treatment, a suitable dose is necessary to prevent metastasis-linked relapse and poor prognosis.

  11. Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis

    PubMed Central

    Gril, Brunilde; Palmieri, Diane; Qian, Yong; Smart, DeeDee; Ileva, Lilia; Liewehr, David J.; Steinberg, Seth M.; Steeg, Patricia S.

    2010-01-01

    Purpose Brain metastases of breast cancer contribute significantly to patient morbidity and mortality. We have tested pazopanib, a recently approved anti-angiogenic drug that targets VEGFR1-3, PDGFRβ, PDGFRα and c-kit, for prevention of experimental brain metastases and mechanism of action. Experimental Design In vitro assays included B-Raf enzymatic assays, western blots and angiogenesis assays. For in vivo assays, HER2 transfectants of the brain seeking sublines of MDA-MB-231 cells (231-BR-HER2) and MCF7 cells (MCF7-HER2-BR3, derived herein) were injected into the left cardiac ventricle of mice and treated with vehicle or pazopanib beginning on day 3 post-injection. Brain metastases were counted histologically, imaged and immunostained. Results Treatment with 100 mg/kg pazopanib resulted in a 73% decline in large 231-BR-HER2 metastases (p<0.0001) and 39% decline in micrometastases (p=0.004). In vitro, pazopanib was directly anti-proliferative to 231-BR-HER2 breast cancer cells and inhibited MEK and ERK activation in vitro despite B-Raf and Ras mutations. Enzymatic assays demonstrated that pazopanib directly inhibited the wild type and exon 11 oncogenic mutant, but not the V600E mutant forms of B-Raf. Activation of the B-Raf targets pERK1/2 and pMEK1/2 was decreased in pazopanib treated brain metastases while blood vessel density was unaltered. In the MCF7-HER2-BR3 experimental brain metastasis model, pazopanib reduced overall brain metastasis volume upon MRI imaging by 55% (p=0.067), without affecting brain metastasis vascular density. Conclusions The data identify a new activity for pazopanib directly on tumor cells as a pan-Raf inhibitor, and suggest its potential for prevention of brain metastatic colonization of HER2+ breast cancer. PMID:21081656

  12. Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages

    PubMed Central

    Smirnova, Tatiana; Bonapace, Laura; MacDonald, Gwen; Kondo, Shunya; Wyckoff, Jeffrey; Ebersbach, Hilmar; Fayard, Bérengère; Doelemeyer, Arno; Coissieux, Marie-May; Heideman, Marinus R.; Bentires-Alj, Mohamed; Hynes, Nancy E.

    2016-01-01

    The extracellular serine protease inhibitor serpinE2 is overexpressed in breast cancer and has been shown to foster metastatic spread. Here, we investigated the hypothesis that serpinE2 creates tumor-promoting conditions in the tumor microenvironment (TME) by affecting extracellular matrix remodeling. Using two different breast cancer models, we show that blocking serpinE2, either by knock-down (KD) in tumor cells or in response to a serpinE2 binding antibody, decreases metastatic dissemination from primary tumors to the lungs. We demonstrate that in response to serpinE2 KD or antibody treatment there are dramatic changes in the TME. Multiphoton intravital imaging revealed deposition of a dense extracellular collagen I matrix encapsulating serpinE2 KD or antibody-treated tumors. This is accompanied by a reduction in the population of tumor-promoting macrophages, as well as a decrease in chemokine ligand 2, which is known to affect macrophage abundance and polarization. In addition, TIMP-1 secretion is increased, which may directly inhibit matrix metalloproteases critical for collagen degradation in the tumor. In summary, our findings suggest that serpinE2 is required in the extracellular milieu of tumors where it acts in multiple ways to regulate tumor matrix deposition, thereby controlling tumor cell dissemination. PMID:27793045

  13. ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis

    PubMed Central

    Romagnoli, Mathilde; Mineva, Nora D; Polmear, Michael; Conrad, Catharina; Srinivasan, Srimathi; Loussouarn, Delphine; Barillé-Nion, Sophie; Georgakoudi, Irene; Dagg, Áine; McDermott, Enda W; Duffy, Michael J; McGowan, Patricia M; Schlomann, Uwe; Parsons, Maddy; Bartsch, Jörg W; Sonenshein, Gail E

    2014-01-01

    The transmembrane metalloprotease-disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple-negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. In vivo, treatment with an anti-ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination. Subject Category Cancer PMID:24375628

  14. ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis.

    PubMed

    Romagnoli, Mathilde; Mineva, Nora D; Polmear, Michael; Conrad, Catharina; Srinivasan, Srimathi; Loussouarn, Delphine; Barillé-Nion, Sophie; Georgakoudi, Irene; Dagg, Áine; McDermott, Enda W; Duffy, Michael J; McGowan, Patricia M; Schlomann, Uwe; Parsons, Maddy; Bartsch, Jörg W; Sonenshein, Gail E

    2014-02-01

    The transmembrane metalloprotease-disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple-negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. In vivo, treatment with an anti-ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.

  15. "A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies"

    PubMed Central

    2012-01-01

    Background The study of breast cancer metastasis depends on the use of established breast cancer cell lines that do not accurately represent the heterogeneity and complexity of human breast tumors. A tumor model was developed using primary breast tumor-initiating cells isolated from patient core biopsies that would more accurately reflect human breast cancer metastasis. Methods Tumorspheres were isolated under serum-free culture conditions from core biopsies collected from five patients with clinical diagnosis of invasive ductal carcinoma (IDC). Isolated tumorspheres were transplanted into the mammary fat pad of NUDE mice to establish tumorigenicity in vivo. Tumors and metastatic lesions were analyzed by hematoxylin and eosin (H+E) staining and immunohistochemistry (IHC). Results Tumorspheres were successfully isolated from all patient core biopsies, independent of the estrogen receptor α (ERα)/progesterone receptor (PR)/Her2/neu status or tumor grade. Each tumorsphere was estimated to contain 50-100 cells. Transplantation of 50 tumorspheres (1-5 × 103 cells) in combination with Matrigel into the mammary fat pad of NUDE mice resulted in small, palpable tumors that were sustained up to 12 months post-injection. Tumors were serially transplanted three times by re-isolation of tumorspheres from the tumors and injection into the mammary fat pad of NUDE mice. At 3 months post-injection, micrometastases to the lung, liver, kidneys, brain and femur were detected by measuring content of human chromosome 17. Visible macrometastases were detected in the lung, liver and kidneys by 6 months post-injection. Primary tumors variably expressed cytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear β catenin and fibronectin but were negative for ERα and vimentin. In lung and liver metastases, variable redistribution of E-cadherin and β catenin to the membrane of tumor cells was observed. ERα was re-expressed in lung metastatic cells in two of five samples. Conclusions

  16. Expression of endoplasmic reticulum stress proteins is a candidate marker of brain metastasis in both ErbB-2+ and ErbB-2- primary breast tumors.

    PubMed

    Sanz-Pamplona, Rebeca; Aragüés, Ramón; Driouch, Keltouma; Martín, Berta; Oliva, Baldo; Gil, Miguel; Boluda, Susana; Fernández, Pedro L; Martínez, Antonio; Moreno, Víctor; Acebes, Juan J; Lidereau, Rosette; Reyal, Fabien; Van de Vijver, Marc J; Sierra, Angels

    2011-08-01

    The increasing incidence of breast cancer brain metastasis in patients with otherwise well-controlled systemic cancer is a key challenge in cancer research. It is necessary to understand the properties of brain-tropic tumor cells to identify patients at risk for brain metastasis. Here we attempt to identify functional phenotypes that might enhance brain metastasis. To obtain an accurate classification of brain metastasis proteins, we mapped organ-specific brain metastasis gene expression signatures onto an experimental protein-protein interaction network based on brain metastatic cells. Thirty-seven proteins were differentially expressed between brain metastases and non-brain metastases. Analysis of metastatic tissues, the use of bioinformatic approaches, and the characterization of protein expression in tumors with or without metastasis identified candidate markers. A multivariate analysis based on stepwise logistic regression revealed GRP94, FN14, and inhibin as the best combination to discriminate between brain and non-brain metastases (ROC AUC = 0.85, 95% CI = 0.73 to 0.96 for the combination of the three proteins). These markers substantially improve the discrimination of brain metastasis compared with ErbB-2 alone (AUC = 0.76, 95% CI = 0.60 to 0.93). Furthermore, GRP94 was a better negative marker (LR = 0.16) than ErbB-2 (LR = 0.42). We conclude that, in breast carcinomas, certain proteins associated with the endoplasmic reticulum stress phenotype are candidate markers of brain metastasis.

  17. Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

    PubMed Central

    De, Pradip; Carlson, Jennifer H.; Wu, Hui; Marcus, Adam; Leyland-Jones, Brian; Dey, Nandini

    2016-01-01

    Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronection-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship

  18. Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and Metastasis

    DTIC Science & Technology

    2014-10-01

    transforming growth factor- beta (TGF-ß) were measured in tumor homogenates (14). DEX treatment did not alter tumor MMP-2, -3, and pro-MMP-9 (Fig. 4A-C) or...progression and should be further explored, especially in the context of evaluating the safety of ß- blockers in breast cancer patients...of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 6: 240-8 3. Cole SW, Sood AK. 2012. Molecular pathways: beta

  19. Delayed cardiac metastasis from phyllodes breast tumor presenting as cardiogenic shock.

    PubMed

    Garg, Naveen; Moorthy, Nagaraja; Agrawal, Surendra K; Pandey, Santanu; Kumari, Niraj

    2011-01-01

    Malignant metastases to the heart and pericardium, which occur far more often than do primary cardiac neoplasms, typically lead to fatal outcomes. The phyllodes tumor is a rare, predominantly benign fibroepithelial breast neoplasm with variable malignancy potential. Herein, we describe the case of a 35-year-old woman who, 3 years after undergoing a simple mastectomy for a rapidly enlarging breast neoplasm, presented with cardiogenic shock and was found to have a large right ventricular tumor that obstructed the right ventricular outflow tract. Despite successful resection of the ventricular mass and a right atrial mass of organized thrombus, the patient died 8 days postoperatively of multiorgan failure due to severe right ventricular dysfunction. Histopathologic analysis determined that the right ventricular mass was a malignant, metastatic phyllodes tumor. To our knowledge, this is only the 2nd reported case of a phyllodes tumor that metastasized to the heart and presented as an intracavitary mass with cardiogenic shock. In addition to discussing our patient's case, we review the pertinent medical literature.

  20. Labeling of breast cancer patient-derived xenografts with traceable reporters for tumor growth and metastasis studies

    PubMed Central

    Hanna, Colton; Kwok, Letty; Finlay-Schultz, Jessica; Sartorius, Carol A; Cittelly, Diana M

    2017-01-01

    We describe a method for stable labeling of patient-derived xenografts (PDXs) with lentiviral particles expressing green-fluorescent protein and luciferase reporters. This method allows for tracking the growth of PDXs at the primary site, as well as detecting spontaneous and experimental metastases using in vivo imaging systems. The use of preclinical models to study tumor biology and response to treatment is central to cancer research. Long-established human cell lines, and many transgenic mouse models, often fail to recapitulate the key aspects of human malignancies. Thus, alternative models that better represent the heterogeneity of patients’ tumors and their metastases are being developed. Patient-derived xenograft (PDX) models in which surgically resected tumor samples are engrafted into immunocompromised mice have become an attractive alternative as they can be transplanted through multiple generations, and more efficiently reflect tumor heterogeneity than xenografts derived from human cancer cell lines. A limitation to the use of PDXs is that they are difficult to transfect or transduce to introduce traceable reporters or to manipulate gene expression. The current protocol describes methods to transduce dissociated tumor cells from PDXs with high transduction efficiency, and the use of labeled PDXs for experimental models of breast cancer metastases. The protocol also demonstrates the use of labeled PDXs in experimental metastasis models to study the organ-colonization process of the metastatic cascade. Metastases to different organs can be easily visualized and quantified using bioluminescent imaging in live animals, or GFP expression during dissection and in excised organs. These methods provide a powerful tool to extend the use of multiple types of PDXs to metastasis research. PMID:27929464

  1. Transcriptional evidence for the "Reverse Warburg Effect" in human breast cancer tumor stroma and metastasis: similarities with oxidative stress, inflammation, Alzheimer's disease, and "Neuron-Glia Metabolic Coupling".

    PubMed

    Pavlides, Stephanos; Tsirigos, Aristotelis; Vera, Iset; Flomenberg, Neal; Frank, Philippe G; Casimiro, Mathew C; Wang, Chenguang; Pestell, Richard G; Martinez-Outschoorn, Ubaldo E; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2010-04-01

    Caveolin-1 (-/-) null stromal cells are a novel genetic model for cancer-associated fibroblasts and myofibroblasts. Here, we used an unbiased informatics analysis of transcriptional gene profiling to show that Cav-1 (-/-) bone-marrow derived stromal cells bear a striking resemblance to the activated tumor stroma of human breast cancers. More specifically, the transcriptional profiles of Cav-1 (-/-) stromal cells were most closely related to the primary tumor stroma of breast cancer patients that had undergone lymph-node (LN) metastasis. This is consistent with previous morphological data demonstrating that a loss of stromal Cav-1 protein (by immuno-histochemical staining in the fibroblast compartment) is significantly associated with increased LN-metastasis. We also provide evidence that the tumor stroma of human breast cancers shows a transcriptional shift towards oxidative stress, DNA damage/repair, inflammation, hypoxia, and aerobic glycolysis, consistent with the "Reverse Warburg Effect". Finally, the tumor stroma of "metastasis-prone" breast cancer patients was most closely related to the transcriptional profiles derived from the brains of patients with Alzheimer's disease. This suggests that certain fundamental biological processes are common to both an activated tumor stroma and neuro-degenerative stress. These processes may include oxidative stress, NO over-production (peroxynitrite formation), inflammation, hypoxia, and mitochondrial dysfunction, which are thought to occur in Alzheimer?s disease pathology. Thus, a loss of Cav-1 expression in cancer-associated myofibroblasts may be a protein biomarker for oxidative stress, aerobic glycolysis, and inflammation, driving the "Reverse Warburg Effect" in the tumor micro-environment and cancer cell metastasis.

  2. Decreased FOXF2 mRNA expression indicates early-onset metastasis and poor prognosis for breast cancer patients with histological grade II tumor.

    PubMed

    Kong, Peng-Zhou; Yang, Fan; Li, Lin; Li, Xiao-Qing; Feng, Yu-Mei

    2013-01-01

    The transcription factor, FOXF2, plays an important role in tissue development, extracellular matrix synthesis, and epithelial-mesenchymal interactions, implying that it may be associated with the metastatic capabilities of cancer cells. However, the relationship between FOXF2 expression and breast cancer progression, metastasis, and prognosis, remains to be elucidated. In this study, FOXF2 mRNA levels in 305 primary breast cancer tissues were examined using RT-QPCR. Results showed that FOXF2 mRNA levels in primary breast cancer were negatively associated with tumor progression, including tumor size, number of metastatic lymph nodes, and clinical stage. Patients with low FOXF2 mRNA levels had a high risk of relapse and metastasis within three years. Low FOXF2 mRNA levels could predict shorter disease-free survival for those patients with histological grade II and triple-negative breast cancer. Taken together, we conclude that decreased FOXF2 expression indicates the early-onset metastasis and poor prognosis for patients with histological grade II and triple-negative breast cancer.

  3. Breast metastasis of anaplastic oligodendroglioma: a case report.

    PubMed

    Alacacioglu, Ahmet; Unal, Serkan; Canpolat, Selin; Yurt, Alaattin; Oztekin, Ozgur; Coskun, Ali; Karatas, Ayse; Postaci, Hakan; Sop, Gulten

    2012-11-01

    Extracranial metastasis of primary brain tumors is rarely observed. Of all brain malignancies, glioblastomas, medulloblastomas and astrocytomas metastasize most frequently. Metastasis of oligondendroglioma is rare. We present a case of breast metastasis in a 58-year-old man with an anaplastic oligodendroglioma.

  4. Interaction of platelet-derived autotaxin with tumor integrin αVβ3 controls metastasis of breast cancer cells to bone.

    PubMed

    Leblanc, Raphael; Lee, Sue-Chin; David, Marion; Bordet, Jean-Claude; Norman, Derek D; Patil, Renukadevi; Miller, Duane; Sahay, Debashish; Ribeiro, Johnny; Clézardin, Philippe; Tigyi, Gabor J; Peyruchaud, Olivier

    2014-11-13

    Autotaxin (ATX), through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers, and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. In this study, we show that ATX is stored in α-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231 and MDA-B02) demonstrate that nontumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin αvβ3-Δ744 or treatment with the anti-human αvβ3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αvβ3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells, and demonstrate the therapeutic potential of disrupting the binding of nontumor-derived ATX with the tumor cells for the prevention of metastasis.

  5. Interaction of platelet-derived autotaxin with tumor integrin αVβ3 controls metastasis of breast cancer cells to bone

    PubMed Central

    Leblanc, Raphael; Lee, Sue-Chin; David, Marion; Bordet, Jean-Claude; Norman, Derek D.; Patil, Renukadevi; Miller, Duane; Sahay, Debashish; Ribeiro, Johnny; Clézardin, Philippe; Tigyi, Gabor J.

    2014-01-01

    Autotaxin (ATX), through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers, and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. In this study, we show that ATX is stored in α-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231 and MDA-B02) demonstrate that nontumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin αvβ3-Δ744 or treatment with the anti-human αvβ3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αvβ3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells, and demonstrate the therapeutic potential of disrupting the binding of nontumor-derived ATX with the tumor cells for the prevention of metastasis. PMID:25277122

  6. Expression of tripartite motif-containing protein 28 in primary breast carcinoma predicts metastasis and is involved in the stemness, chemoresistance, and tumor growth.

    PubMed

    Damineni, Surekha; Balaji, Sai A; Shettar, Abhijith; Nayanala, Swetha; Kumar, Neeraj; Kruthika, Banavathy S; Subramanian, Kalyanasundaram; Vijayakumar, M; Mukherjee, Geetashree; Gupta, Vaijayanti; Kondaiah, Paturu

    2017-04-01

    The prediction of who develops metastasis has been the most difficult aspect in the management of breast cancer patients. The lymph node metastasis has been the most useful predictor of prognosis and patient management. However, a good proportion of patients with lymph node positivity remain disease free for 5 years or more, while about a third of those who were lymph node negative develop distant metastasis within the same period. This warrants a robust biomarker(s), preferably gene expression based. In order to elucidate gene-based biomarkers for prognosis of breast cancers, gene expression profiling of primary tumors and follow-up for over 5 years has been performed. The analysis revealed a network of genes centered around the tripartite motif-containing protein 28 as an important indicator of disease progression. Short hairpin RNA-mediated knockdown of tripartite motif-containing protein 28 in breast cancer cells revealed a decreased expression of epithelial-to-mesenchymal transition markers and increased expression of epithelial markers, decreased migration and invasion, and increased chemosensitivity to doxorubicin, 5-fluorouracil, and methotrexate. Furthermore, knockdown of tripartite motif-containing protein 28 resulted in the decrease of stemness as revealed by sphere formation assay as well as decreased expression of CD44 and Bmi1. Moreover, tripartite motif-containing protein 28 knockdown significantly reduced the tumor size and lung metastasis in orthotopic tumor xenograft assay in immunocompromised mice. The tumor size was further reduced when these mice were treated with doxorubicin. These data provide evidence for tripartite motif-containing protein 28 as a biomarker and a potential therapeutic target for breast cancer.

  7. Hypothyroidism Enhances Tumor Invasiveness and Metastasis Development

    PubMed Central

    Martínez-Iglesias, Olaia; García-Silva, Susana; Regadera, Javier; Aranda, Ana

    2009-01-01

    Background Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients Methodology/Principal Findings In this work we have analyzed the influence of hypothyroidism on tumor progression and metastasis development using xenografts of parental and TRβ1–expressing human hepatocarcinoma (SK-hep1) and breast cancer cells (MDA-MB-468). In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRβ–expressing cells were injected into euthyroid nude mice. Whereas tumor growth was retarded when cells were inoculated into hypothyroid hosts, tumors had a more mesenchymal phenotype, were more invasive and metastatic growth was enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs. Conclusions/Significance These results show that changes in the stromal cells secondary to host hypothyroidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer. PMID:19641612

  8. Blockade of Fas signaling in breast cancer cells suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation.

    PubMed

    Liu, Qiuyan; Tan, Qinchun; Zheng, Yuanyuan; Chen, Kun; Qian, Cheng; Li, Nan; Wang, Qingqing; Cao, Xuetao

    2014-04-18

    Mechanisms for cancer-related inflammation remain to be fully elucidated. Non-apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. It has yet to be determined if targeting Fas signaling can control tumor progression through suppression of cancer-related inflammation. In the current study we found that breast cancer cells with constitutive Fas expression were resistant to apoptosis induction by agonistic anti-Fas antibody (Jo2) ligation or Fas ligand cross-linking. Higher expression of Fas in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. To determine whether blockade of Fas signaling in breast cancer could suppress tumor progression, we prepared an orthotopic xenograft mouse model with mammary cancer cells 4T1 and found that blockade of Fas signaling in 4T1 cancer cells markedly reduced tumor growth, inhibited tumor metastasis in vivo, and prolonged survival of tumor-bearing mice. Mechanistically, blockade of Fas signaling in cancer cells significantly decreased systemic or local recruitment of myeloid derived suppressor cells (MDSCs) in vivo. Furthermore, blockade of Fas signaling markedly reduced IL-6, prostaglandin E2 production from breast cancer cells by impairing p-p38, and activity of the NFκB pathway. In addition, administration of a COX-2 inhibitor and anti-IL-6 antibody significantly reduced MDSC accumulation in vivo. Therefore, blockade of Fas signaling can suppress breast cancer progression by inhibiting proinflammatory cytokine production and MDSC accumulation, indicating that Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for treatment of breast cancer.

  9. Breast cancer metastasis and the lymphatic system

    PubMed Central

    RAHMAN, MUNAZZAH; MOHAMMED, SULMA

    2015-01-01

    Breast cancer remains the leading cause of cancer mortality worldwide, despite a significant decline in death rates due to early detection. The majority of cancer mortalities are due to the metastasis of tumor cells to other organs. Metastasis or tumor cell dissemination occurs via the hematogenous and lymphatic systems. For many carcinomas, the dissemination of tumor cells via lymphatic drainage of the tumor is the most common metastatic route. Such lymphatic drainage collects at the regional lymph nodes and the dissection and pathological examination of these nodes for lodged cancer cells is the gold standard procedure to detect metastasis. The present report provides an overview of the lymphatic system and its clinical significance as a prognostic factor, in addition to the interactions between the primary tumor and its microenvironment, and the influence of genomic subtypes on the resulting organ-specific pattern of tumor cell dissemination. It also examines the seemingly protracted asymptomatic period, during which the disseminated cells remain dormant, leading to the manifestation of metastasis decades after the successful treatment of the primary tumor. PMID:26622656

  10. Molecular Alterations that Reduce Cortical Containment of Tubulin Microtentacles and their Impact on Breast Tumor Metastasis

    DTIC Science & Technology

    2009-10-01

    NUMBER 081263 metastasis 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Balzer, Eric M. 5d. PROJECT NUMBER Email: ebalz001@umaryland.edu 5e...first 12 months of this award was projected to be primarily on Specific Aim 1, with additional attention on Specific Aim 3 given sufficient progress...jasplak- inolide promoted the extension of microtubule-based projections and microtentacle protrusions in adherent and suspended cells, respectively. These

  11. Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt-survival pathways in breast cancer cells and suppresses tumor survival and metastasis

    PubMed Central

    Yang, Eric; Boire, Adrienne; Agarwal, Anika; Nguyen, Nga; O'Callaghan, Katie; Tu, Powen; Kuliopulos, Athan; Covic, Lidija

    2009-01-01

    Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that is not expressed in normal breast epithelia, but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide ‘pepducin’, P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor demonstrated attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with taxotere alone in advanced, metastatic breast cancer. PMID:19622769

  12. Metastasis-Free Interval Is Closely Related to Tumor Characteristics and Has Prognostic Value in Breast Cancer Patients with Distant Relapse

    PubMed Central

    Kim, Hee Jun; Ahn, Sung Gwe; Lee, Hak Min; Park, Jong Tae; Han, Kyunghwa; Lee, Seung Ah

    2015-01-01

    Purpose We investigated the relationships between metastasis-free interval (MFI) and tumor characteristics, and assessed the prognostic value of MFI for survival after metastasis in patients with metastatic breast cancer. Furthermore, we compared MFI among the subtypes. Methods We identified 335 patients with postoperative tumor recurrence at distant site(s). All patients underwent curative resection and had a MFI of at least 6 months. MFI was categorized as short (<2 years), intermediate (≥2 years and <5 years), or long (≥5 years). Overall survival after metastasis (OSM) was estimated. Results Patients with a shorter MFI were younger, more likely to have initial metastasis to visceral organs, and had a larger tumor with a higher stage and grade as well as a higher rate of nodal involvement at initial diagnosis. Among 136 patients with known disease subtypes, shorter MFI was associated with the triple-negative subtype while longer MFI was associated with the hormone receptor-positive/human epidermal growth factor receptor 2 negative subtype. Mortality after metastasis declined sharply with increasing MFI up to approximately 2 years, and continued gradually declining between 2 and 5 years. An MFI longer than 5 years did not add any survival benefit. MFI was a significant prognostic factor for OSM independent of nodal status, stage, metastatic site, and hormone receptor status of the metastasized cancer. Conclusion MFI is closely related to biological characteristics of both primary tumors and their metastases, and has a prognostic value for survival after metastasis. We therefore suggest investigation into treatments targeting improvement of MFI as a potential novel strategy. PMID:26770244

  13. Rhus coriaria suppresses angiogenesis, metastasis and tumor growth of breast cancer through inhibition of STAT3, NFκB and nitric oxide pathways

    PubMed Central

    El Hasasna, Hussain; Saleh, Alaaeldin; Samri, Halima Al; Athamneh, Khawlah; Attoub, Samir; Arafat, Kholoud; Benhalilou, Nehla; Alyan, Sofyan; Viallet, Jean; Dhaheri, Yusra Al; Eid, Ali; Iratni, Rabah

    2016-01-01

    Recently, we reported that Rhus coriaria exhibits anticancer activities by promoting cell cycle arrest and autophagic cell death of the metastatic triple negative MDA-MB-231 breast cancer cells. Here, we investigated the effect of Rhus coriaria on the migration, invasion, metastasis and tumor growth of TNBC cells. Our current study revealed that non-cytotoxic concentrations of Rhus coriaria significantly inhibited migration and invasion, blocked adhesion to fibronectin and downregulated MMP-9 and prostaglandin E2 (PgE2). Not only did Rhus coriaria decrease their adhesion to HUVECs and to lung microvascular endothelial (HMVEC-L) cells, but it also inhibited the transendothelial migration of MDA-MB-231 cells through TNF-α-activated HUVECs. Furthermore, we found that Rhus coriaria inhibited angiogenesis, reduced VEGF production in both MDA-MB-231 and HUVECs and downregulated the inflammatory cytokines TNF-α, IL-6 and IL-8. The underlying mechanism for Rhus coriaria effects appears to be through inhibiting NFκB, STAT3 and nitric oxide (NO) pathways. Most importantly, by using chick embryo tumor growth assay, we showed that Rhus coriaria suppressed tumor growth and metastasis in vivo. The results described in the present study identify Rhus coriaria as a promising chemopreventive and therapeutic candidate that modulate triple negative breast cancer growth and metastasis. PMID:26888313

  14. Ets2 Contributions of the Tumor Microenvironment in Breast Cancer Metastasis

    DTIC Science & Technology

    2009-03-01

    Martin S. Vonau, Zachary M. Rossfeld, Brett M. Hall, Jillian Werbeck, Joseph J. Pinzone. Dickkopf-1 ( DKK1 ) inhibits differentiation of bone marrow... DKK1 ) inhibits differentiation of bone marrow-derived human mesenchymal stem cells (hMSC) and promotes growth of breast cancer cells in the presence of

  15. Chemokines: novel targets for breast cancer metastasis

    PubMed Central

    Ali, Simi; Lazennec, Gwendal

    2007-01-01

    Recent studies have highlighted the possible involvement of chemokines and their receptors in breast cancer progression and metastasis. Chemokines and their receptors constitute a superfamily of signalling factors whose prognosis value in breast cancer progression remains unclear. We will examine here the expression pattern of chemokines and their receptors in mammary gland physiology and carcinogenesis. The nature of the cells producing chemokines or harboring chemokine receptors appears to be crucial in certain conditions for example, the infiltration of the primary tumor by leukocytes and angiogenesis. In addition, chemokines, their receptors and the interaction with glycosaminoglycan (GAGs) are key players in the homing of cancer cells to distant metastasis sites. Several lines of evidence, including in vitro and in vivo models, suggest that the mechanism of action of chemokines in cancer development involves the modulation of proliferation, apoptosis, invasion, leukocyte recruitment or angiogenesis. Furthermore, we will discuss the regulation of chemokine network in tumor neovascularity by decoy receptors. The reasons accounting for the deregulation of chemokines and chemokine receptors expression in breast cancer are certainly crucial for the comprehension of chemokine role in breast cancer and are in several cases linked to estrogen receptor status. The targeting of chemokines and chemokine receptors by antibodies, small molecule antagonists, viral chemokine binding proteins and heparins appears as promising tracks to develop therapeutic strategies. Thus there is significant interest in developing strategies to antagonize the chemokine function, and an opportunity to interfere with metastasis, the leading cause of death in most patients. PMID:17717637

  16. Understanding Collagen Organization in Breast Tumors to Predict and Prevent Metastasis

    DTIC Science & Technology

    2014-09-01

    stratification based upon metastatic risk, in order to minimize ‘over treatment’ of patients who only require local therapy after resection, not systemic ...cell motility in a relatively “clean” collagen gel system , in which confounding upstream actors are not present. The SHG measure of microstructure we...ordering, predicted lymphatic metastatic burden in patent breast cancer samples, and also revealed several intriguing relationships between stromal

  17. Understanding Collagen Organization in Breast Tumors to Predict and Prevent Metastasis

    DTIC Science & Technology

    2012-09-01

    biopsies taken for other reasons) can serve as a marker for increased risk of future invasive carcinomas (ILC or IDC) in either breast [3]. With the...mortality is a r esult of metastatic events [4]. It is therefore becoming increasingly important to uncover prognostic markers that can predict the...lymph node (N) incorporates multiple degrees of staging as opposed to metastatic staging (M), which is a binary system determined simply by the

  18. Breast tumors induced by N-methyl-N-nitrosourea are damaging to bone strength, structure, and mineralization in the absence of metastasis in rats.

    PubMed

    Thorpe, Matthew P; Valentine, Rudy J; Moulton, Christopher J; Wagoner Johnson, Amy J; Evans, Ellen M; Layman, Donald K

    2011-04-01

    Current theory on the influence of breast cancer on bone describes metastasis of tumor cells to bone tissue, followed by induction of osteoclasts and bone degradation. Tumor influences on bone health in pre- or nonmetastatic models are unknown. Female rats (n = 48, 52 days old) were injected with N-methyl-N-nitrosourea (MNU) to induce breast cancer. Animals were euthanized 10 weeks later, and tumors were weighed and classified histologically. Right femurs were extracted for testing of bone mineral density (BMD) by dual X-ray absorptiometry (DXA), bone mechanical strength by three-point bending and femoral neck bending tests, and structure by micro-computed tomography (µCT). Of 48 rats, 22 developed one or more tumors in response to MNU injection by 10 weeks. Presence of any tumor predicted significantly poorer bone health in 17 of 28 measures. In tumored versus nontumored animals, BMD was adversely affected by 3%, force at failure of the femoral midshaft by 4%, force at failure of the femoral neck by 12%, and various trabecular structural parameters by 6% to 27% (all p < .05). Similarly, greater tumor burden, represented by total tumor weight, adversely correlated with bone outcomes: r = -0.51 for BMD, -0.42 and -0.35 for femur midshaft force and work at failure, and between 0.36 and 0.59 (absolute values) for trabecular architecture (all p < .05). Presence of MNU-induced tumors and total tumor burden showed a negative association with bone health of the femur in rats in the absence of metastasis. Further study is required to elucidate mechanisms for this association.

  19. Modulation of the Proliferation and Metastasis of Human Breast Tumor Cells by SLUG (IDEA)

    DTIC Science & Technology

    2008-04-01

    transcription. Mol. Cell. Biol. 20, 5087-5095. 4. Tripathi, M. K., Misra, S., Khedkar, S. V., Hamilton, N., Irvin -Wilson, C., Sharan, C., Sealy, L...Narvaez, G. Zinser, J. Welsh , Functions of 1 alpha,25-dihydroxyvitamin D(3) in mammary gland: from normal development to breast cancer, Steroids 66 (2001...301-308. [2] J. Welsh , J.A. Wietzke, G.M. Zinser, S. Smyczek, S. Romu, E. Tribble, J.C. Welsh , B. Byrne, C.J. Narvaez, Impact of the Vitamin D3

  20. An unexpected metastasis of breast cancer mimicking wheal rush

    PubMed Central

    DAMASKOS, C.; DIMITROULIS, D.; PERGIALIOTIS, V.; DOULA, C.; KOULERMOU, G.; ANTONIOU, E.A.; FRANGOULIS, M.; STERGIOS, K.; KONTZOGLOU, K.

    2016-01-01

    Breast cancer is the most common cancer among women and ranks second in cancer deaths worldwide. Breast cancer can metastasize to the skin but rarely, cutaneous metastases may be the first indication of the cancer. Skin metastases of breast cancer are usually found on the chest and close to the point of the mastectomy. We present the rare clinical entity of a breast cancer which was first diagnosed due to the skin metastasis away from the breast tumor. This is a rare case because the skin lesions usually appear simultaneously or secondary. Also, while the existing metastasis; the only symptom was the wheal rash. PMID:27734799

  1. Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis.

    PubMed

    Montenegro, M F; Sánchez-Del-Campo, L; González-Guerrero, R; Martínez-Barba, E; Piñero-Madrona, A; Cabezas-Herrera, J; Rodríguez-López, J N

    2016-11-24

    During the course of cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, and this plasticity is enabled by underlying shifts in epigenetic regulation. Our results identified a negative feedback loop in which SET9 controls DNA methyltransferase-1 protein stability, which represses the transcriptional activity of the SET9 promoter in coordination with Snail. The modulation of SET9 expression in breast cancer cells revealed a connection with E2F1 and the silencing of SET9 was sufficient to complete an epigenetic program that favored epithelial-mesenchymal transition and the generation of cancer stem cells, indicating that SET9 plays a role in modulating breast cancer metastasis. SET9 expression levels were significantly higher in samples from patients with pathological complete remission than in samples from patients with disease recurrence, which indicates that SET9 acts as a tumor suppressor in breast cancer and that its expression may serve as a prognostic marker for malignancy.

  2. Reduced ING1 levels in breast cancer promotes metastasis

    PubMed Central

    Chen, Jie; Tran, Uyen; Yang, Yang; Salazar, Carolina; Magliocco, Anthony; Klimowicz, Alexander; Jirik, Frank R.; Riabowol, Karl

    2014-01-01

    INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast cancer development and metastasis is unknown. ING1 levels were quantified in >500 patient samples using automated quantitative fluorescence immunohistochemistry, and data were analysed for correlations to patient outcome. Effects of altering ING levels were examined in microarrays and metastasis assays in vitro, and in a mouse metastasis model in vivo. ING1 levels were lower in tumors compared to adjacent normal breast tissue and correlated with tumor size (p=0.019) and distant recurrence (p=0.001) in ER- or Her2+ patients. In these patients ING1 predicted disease-specific and distant metastasis-free survival. Transcriptome analysis showed that the pathway most affected by ING1 was breast cancer (p = 0.0008). Decreasing levels of ING1 increased, and increasing levels decreased, migration and invasion of MDA-MB231 cells in vitro. ING1 overexpression also blocked cancer cell metastasis in vivo and eliminated tumor-induced mortality in mouse models. Our data show that ING1 protein levels are downregulated in breast cancer and for the first time, we show that altering their levels regulates metastasis in vitro and in vivo, which indicates that ING1 may have a therapeutic role for inhibiting metastasis of breast cancer. PMID:24962136

  3. Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis

    PubMed Central

    Pavlovic, Milica; Arnal-Estapé, Anna; Rojo, Federico; Bellmunt, Anna; Tarragona, Maria; Guiu, Marc; Planet, Evarist; Garcia-Albéniz, Xabier; Morales, Mónica; Urosevic, Jelena; Gawrzak, Sylwia; Rovira, Ana; Prat, Aleix; Nonell, Lara; Lluch, Ana; Jean-Mairet, Joël; Coleman, Robert; Albanell, Joan

    2015-01-01

    Background: There are currently no biomarkers for early breast cancer patient populations at risk of bone metastasis. Identification of mediators of bone metastasis could be of clinical interest. Methods: A de novo unbiased screening approach based on selection of highly bone metastatic breast cancer cells in vivo was used to determine copy number aberrations (CNAs) associated with bone metastasis. The CNAs associated with bone metastasis were examined in independent primary breast cancer datasets with annotated clinical follow-up. The MAF gene encoded within the CNA associated with bone metastasis was subjected to gain and loss of function validation in breast cancer cells (MCF7, T47D, ZR-75, and 4T1), its downstream mechanism validated, and tested in clinical samples. A multivariable Cox cause-specific hazard model with competing events (death) was used to test the association between 16q23 or MAF and bone metastasis. All statistical tests were two-sided. Results: 16q23 gain CNA encoding the transcription factor MAF mediates breast cancer bone metastasis through the control of PTHrP. 16q23 gain (hazard ratio (HR) for bone metastasis = 14.5, 95% confidence interval (CI) = 6.4 to 32.9, P < .001) as well as MAF overexpression (HR for bone metastasis = 2.5, 95% CI = 1.7 to 3.8, P < .001) in primary breast tumors were specifically associated with risk of metastasis to bone but not to other organs. Conclusions: These results suggest that MAF is a mediator of breast cancer bone metastasis. 16q23 gain or MAF protein overexpression in tumors may help to select patients at risk of bone relapse. PMID:26376684

  4. Collagen Prolyl Hydroxylases are Essential for Breast Cancer Metastasis

    PubMed Central

    Gilkes, Daniele M.; Chaturvedi, Pallavi; Bajpai, Saumendra; Wong, Carmen Chak-Lui; Wei, Hong; Pitcairn, Stephen; Hubbi, Maimon E.; Wirtz, Denis; Semenza, Gregg L.

    2013-01-01

    Metastasis is the leading cause of death among patients with breast cancer. Understanding the role of the extracellular matrix in the metastatic process may lead to the development of improved therapies for cancer patients. Intratumoral hypoxia is found in the majority of breast cancers and is associated with an increased risk of metastasis and patient mortality. Here we demonstrate that hypoxia-inducible factor 1 activates the transcription of genes encoding collagen prolyl hydroxylases that are critical for collagen deposition by breast cancer cells. We show that expression of collagen prolyl hydroxylases promotes cancer cell alignment along collagen fibers, resulting in enhanced invasion and metastasis to lymph nodes and lungs. Lastly, we establish the prognostic significance of collagen prolyl hydroxylase mRNA expression in human breast cancer biopsies, and demonstrate that ethyl 3,4-dihydroxybenzoate, a prolyl hydroxylase inhibitor, decreases tumor fibrosis and metastasis in a mouse model of breast cancer. PMID:23539444

  5. Role of patient and tumor characteristics in sentinel lymph node metastasis in patients with luminal early breast cancer: an observational study.

    PubMed

    La Verde, Nicla; Biagioli, Elena; Gerardi, Chiara; Cordovana, Andrea; Casiraghi, Chiara; Floriani, Irene; Bernardin, Elena; Farina, Gabriella; Di Cosimo, Serena; Dazzani, Maria Chiara; Gherardi, Giorgio

    2016-01-01

    Predicting the risk of sentinel lymph node (SLN) metastasis is important for clinical decision-making in the setting of early breast cancer (EBC). This study is aimed to identify tumor and patient characteristics that influenced the SLN metastatic involvement, with a focus on luminal subtypes. An observational study including women treated for EBC from 2005 to 2013 was conducted. Regression analyses were used to assess the association between SLN metastasis and age, menopausal status, tumor size, histological grading, presence of extensive "in situ" carcinoma components, lymphovascular invasion (LVI), and expression of Ki-67, hormone receptors, and HER2. Of 345 women, 84 (24.3 %) had at least one SLN metastasis; 63.1 % were macrometastases. Among all patients, 31.6 % exhibited LVI. In univariate analyses, tumor size, histological grade, and LVI were associated with SLN metastasis. The multivariate model confirmed only the association between LVI and SLN status (OR 3.27, 95 % CI 1.85-5.68; p < 0.0001). Luminal subtypes were detected in 86.1 % of women. In this subgroup, the multivariate model confirmed a significant relationship between LVI and SLN status (OR 3.47, 95 % CI 1.90-6.33; p < 0.0001). Since a proper histopathological assessment of LVI is not possible prior to surgery, this factor cannot be used to guide decisions on performing SLN biopsies. Nevertheless, when a SLN biopsy is refused or contraindicated, an LVI assessment on an excisional biopsy of the tumor could facilitate prognosis determination and treatment management.

  6. Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and Metastasis

    DTIC Science & Technology

    2015-10-01

    injected intraperitoneally (IP) with sterile saline or 10 µg/kg DEX beginning 2 days prior to injection of 2x105 tumor cells into a mammary fat pad and...IP) with sterile saline or 5 mg/kg salmeterol beginning 2 days prior to injection of 2x105 tumor cells into a mammary fat pad and continuing daily...74. 8. Wang Q, Lu R, Zhao J, Limbird LE. Arrestin serves as a molecular switch, linking endogenous alpha2-adrenergic receptor to SRC-dependent, but

  7. Low local blood perfusion, high white blood cell and high platelet count are associated with primary tumor growth and lung metastasis in a 4T1 mouse breast cancer metastasis model.

    PubMed

    Wang, Chuan; Chen, Ying-Ge; Gao, Jian-Li; Lyu, Gui-Yuan; Su, Jie; Zhang, Q I; Ji, Xin; Yan, Ji-Zhong; Qiu, Qiao-Li; Zhang, Yue-Li; Li, Lin-Zi; Xu, Han-Ting; Chen, Su-Hong

    2015-08-01

    It was originally thought that no single routine blood test result would be able to indicate whether or not a patient had cancer; however, several novel studies have indicated that the median survival and prognosis of cancer patients were markedly associated with the systemic circulation features of cancer patients. In addition, certain parameters, such as white blood cell (WBC) count, were largely altered in malignant tumors. In the present study, routine blood tests were performed in order to observe the change of blood cells in tumor-bearing mice following the implantation of 4T1 breast cancer cells into the mammary fat pad; in addition, blood flow in breast tumor sites was measured indirectly using laser Doppler perfusion imaging (LDPI), in an attempt to explain the relevance between the blood circulation features and the growth or metastasis of breast cancer in mice model. The LDPI and blood test results indicated that the implantation of 4T1 breast cancer cells into BALB/c mice led to thrombosis as well as high WBC count, high platelet count, high plateletcrit and low blood perfusion. Following implantation of the 4T1 cells for four weeks, the lung metastatic number was determined and the Pearson correlation coefficient revealed that the number of visceral lung metastatic sites had a marked negative association with the ratio of basophils (BASO%; r=-0.512; P<0.01) and the mean corpuscular hemoglobin was significantly correlated with primary tumor weight (r=0.425; P<0.05). In conclusion, the results of the present study demonstrated that tumor growth led to thrombosis and acute anemia in mice; in addition, when blood BASO% was low, an increased number of lung metastases were observed in tumor-bearing mice.

  8. Receptor Activator of NF-kB (RANK) Expression in Primary Tumors Associates with Bone Metastasis Occurrence in Breast Cancer Patients

    PubMed Central

    Vincenzi, Bruno; Gaeta, Laura; Pantano, Francesco; Russo, Antonio; Ortega, Cinzia; Porta, Camillo; Galluzzo, Sara; Armento, Grazia; La Verde, Nicla; Caroti, Cinzia; Treilleux, Isabelle; Ruggiero, Alessandro; Perrone, Giuseppe; Addeo, Raffaele; Clezardin, Philippe; Muda, Andrea Onetti; Tonini, Giuseppe

    2011-01-01

    Background Receptor activator of NFkB (RANK), its ligand (RANKL) and the decoy receptor of RANKL (osteoprotegerin, OPG) play a pivotal role in bone remodeling by regulating osteoclasts formation and activity. RANKL stimulates migration of RANK-expressing tumor cells in vitro, conversely inhibited by OPG. Materials and Methods We examined mRNA expression levels of RANKL/RANK/OPG in a publicly available microarray dataset of 295 primary breast cancer patients. We next analyzed RANK expression by immunohistochemistry in an independent series of 93 primary breast cancer specimens and investigated a possible association with clinicopathological parameters, bone recurrence and survival. Results Microarray analysis showed that lower RANK and high OPG mRNA levels correlate with longer overall survival (P = 0.0078 and 0.0335, respectively) and disease-free survival (P = 0.059 and 0.0402, respectively). Immunohistochemical analysis of RANK showed a positive correlation with the development of bone metastases (P = 0.023) and a shorter skeletal disease-free survival (SDFS, P = 0.037). Specifically, univariate analysis of survival showed that “RANK-negative” and “RANK-positive” patients had a SDFS of 105.7 months (95% CI: 73.9–124.4) and 58.9 months (95% CI: 34.7–68.5), respectively. RANK protein expression was also associated with accelerated bone metastasis formation in a multivariate analysis (P = 0.029). Conclusions This is the first demonstration of the role of RANK expression in primary tumors as a predictive marker of bone metastasis occurrence and SDFS in a large population of breast cancer patients. PMID:21559440

  9. Polyphenolics from peach (Prunus persica var. Rich Lady) inhibit tumor growth and metastasis of MDA-MB-435 breast cancer cells in vivo.

    PubMed

    Noratto, Giuliana; Porter, Weston; Byrne, David; Cisneros-Zevallos, Luis

    2014-07-01

    The tumor growth inhibition and anti-metastatic effects of peach polyphenolics were investigated in vivo using a xenograft model and MDA-MB-435 breast cancer cells. Results showed that tumor growth and lung metastasis were inhibited in vivo by peach polyphenolics in a dose range of 0.8-1.6 mg/day, and these effects were mediated by inhibition of metalloproteinases gene expression. Modulation of metalloproteinase-2, metalloproteinase-3 and metalloproteinase-13 gene expression may be some of the molecular targets for anti-metastatic activity of peach polyphenolics. Therefore, these compounds may constitute a novel chemopreventive tool to reduce the risk of metastasis in the combination therapy when primary cancer is diagnosed. Conversion to equivalent human intake for future clinical studies using the body surface area normalization method gave a dose of ~370.6 mg/day for a human adult of 60 kg, which can be supplied by consuming two to three peach fruit per day or alternatively using a dietary supplement peach polyphenol extract powder.

  10. Gastric Metastasis of Breast Cancer: A Case Series.

    PubMed

    Dos Santos Fernandes, Gustavo; Batista Bugiato Faria, Luiza D; de Assis Pereira, Isadora; Neves, Natália C Moreira; Vieira, Yasmine Oliveira; Leal, Alessandro I Cavalcanti

    2016-09-05

    Gastric metastasis is rare but it can be the initial symptom of cancer. The second leading cause of this type of metastasis is breast cancer. A lack of clinical signs and nonspecific side effects of the treatment of primary tumors can lead to the misdiagnosis of metastatic gastric cancer. Upper gastrointestinal endoscopy with biopsy and immunohistochemistry should be used for diagnosis. Treatment is palliative; it includes chemo, endocrine, and radiation therapies. Four patients with breast cancer and gastric metastasis were identified. All the patients tested positive for estrogen and progesterone receptors, and received chemotherapy and hormone therapy. One patient underwent surgery and two received radiation therapy. Patients with breast cancer and gastrointestinal symptoms should be investigated for gastric metastasis, given its morbidity and negative impact on quality of life.

  11. Integrin activation controls metastasis in human breast cancer

    PubMed Central

    Felding-Habermann, Brunhilde; O'Toole, Timothy E.; Smith, Jeffrey W.; Fransvea, Emilia; Ruggeri, Zaverio M.; Ginsberg, Mark H.; Hughes, Paul E.; Pampori, Nisar; Shattil, Sanford J.; Saven, Alan; Mueller, Barbara M.

    2001-01-01

    Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin αvβ3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin αvβ3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated αvβ3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant αvβ3D723R, but not αvβ3WT, in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin αvβ3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer. PMID:11172040

  12. Integrin activation controls metastasis in human breast cancer

    NASA Astrophysics Data System (ADS)

    Felding-Habermann, Brunhilde; O'Toole, Timothy E.; Smith, Jeffrey W.; Fransvea, Emilia; Ruggeri, Zaverio M.; Ginsberg, Mark H.; Hughes, Paul E.; Pampori, Nisar; Shattil, Sanford J.; Saven, Alan; Mueller, Barbara M.

    2001-02-01

    Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin v3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin v3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated αvβ3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant αvβ3D723R, but not αvβ3WT, in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin αvβ3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer.

  13. Oncogenic role of SIRT1 associated with tumor invasion, lymph node metastasis, and poor disease-free survival in triple negative breast cancer.

    PubMed

    Chung, Soo Young; Jung, Yoon Yang; Park, In Ae; Kim, Hyojin; Chung, Yul Ri; Kim, Ji Young; Park, Soo Young; Im, Seock-Ah; Lee, Kyung-Hun; Moon, Hyeong-Gon; Noh, Dong-Young; Han, Wonshik; Lee, Chul; Kim, Tae-Yong; Ryu, Han Suk

    2016-02-01

    The aim of this study is to evaluate the biological role and clinical implications of silent mating type information regulation 2 homolog 1 (SIRT1) as a novel candidate for target therapy in triple negative breast cancer (TNBC) for which there is no specific agent. 344 patients who received surgical resection for TNBC from January 2003 to December 2006 at Seoul National University Hospital were enrolled, and the role of SIRT1 protein was evaluated via immunohistochemistry on tissue samples. In vivo experiments to evaluate tumor invasiveness were carried out with three human TNBC cell lines following SIRT1-siRNA transfection. Expression of SIRT1 significantly correlated with lymph node metastasis (p = 0.008). In multivariate analysis, SIRT1 expression (p = 0.011), T stage (p = 0.014), and lymphatic invasion (p < 0.001) were revealed to be independent predictive factors for lymph node metastasis. Combination of these three parameters revealed predictive performance for lymph node metastasis with an area under the curve (AUC) of 0.689 on receiver operating characteristics (ROC) curves analysis. SIRT1 expression correlated with shorter disease-free survival (P = 0.003) but not with overall survival. Inhibition of SIRT1 with small interfering RNA (siRNA) conspicuously suppressed the invasiveness of TNBC cell lines. This study reveals the role of SIRT1 on tumor invasiveness and unfavorable clinical outcomes, and we suggest its potential role as a prognostic indicator as well as a novel therapeutic target in TNBC.

  14. Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis

    PubMed Central

    Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Fan, Bo; Kang, Lin; Gao, Zhonggao

    2016-01-01

    Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis. PMID:27729789

  15. Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis.

    PubMed

    Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Fan, Bo; Kang, Lin; Gao, Zhonggao

    Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis.

  16. Bcl-3 regulates TGFβ signaling by stabilizing Smad3 during breast cancer pulmonary metastasis

    PubMed Central

    Chen, Xi; Cao, Xinwei; Sun, Xiaohua; Lei, Rong; Chen, Pengfei; Zhao, Yongxu; Jiang, Yuhang; Yin, Jie; Chen, Ran; Ye, Deji; Wang, Qi; Liu, Zhanjie; Liu, Sanhong; Cheng, Chunyan; Mao, Jie; Hou, Yingyong; Wang, Mingliang; Siebenlist, Ulrich; Eugene Chin, Y; Wang, Ying; Cao, Liu; Hu, Guohong; Zhang, Xiaoren

    2016-01-01

    Transforming growth factor beta (TGFβ) signaling in breast cancer is selectively associated with pulmonary metastasis. However, the underlying mechanisms remain unclear. Here we show that Bcl-3, a member of the IκB family, serves as a critical regulator in TGFβ signaling to modulate breast cancer pulmonary metastasis. Bcl-3 expression was significantly associated with metastasis-free survival in breast cancer patients. Bcl-3 deletion inhibited the migration and invasion of breast cancer cells in vitro, as well as breast cancer lung metastasis in vivo. Bcl-3 was required for the expression of downstream TGFβ signaling genes that are involved in breast cancer lung metastasis. Bcl-3 knockdown enhanced the degradation of Smad3 but not Smad2 following TGFβ treatment. Bcl-3 could bind to Smad3 and prevent the ubiquitination and degradation of Smad3 protein. These results indicate that Bcl-3 serves as a promising target to prevent breast tumor lung metastasis. PMID:27906182

  17. Metastasis genetics, epigenetics, and the tumor microenvironment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    KISS1 is a member of a family of genes known as metastasis suppressors, defined by their ability to block metastasis without blocking primary tumor development and growth. KISS1 re-expression in multiple metastatic cell lines of diverse cellular origin suppresses metastasis; yet, still allows comple...

  18. Positive lymph-node breast cancer patients – activation of NF-κB in tumor-associated leukocytes stimulates cytokine secretion that promotes metastasis via C-C chemokine receptor CCR7.

    PubMed

    El-Ghonaimy, Eslam A; El-Shinawi, Mohamed; Ibrahim, Sherif A; El-Ghazaly, Hisham; Abd-El-Tawab, Reda; Nouh, Mohamed A; El-Mamlouk, Tahani; Mohamed, Mona M

    2015-01-01

    Tumor metastasis to lymph nodes is most deadly complication among breast cancer patients. Herein, we investigated the molecular mechanism by which tumor-associated leukocytes (TALs) mediate lymph node metastasis. The density of different leukocyte subtypes infiltrating the tumor microenvironment of negative and positive lymph nodes (nLNs, pLNs) in breast cancer patients was measured using immunohistochemistry. In addition, we isolated TALs from blood drained from the axillary tributaries of nLN and pLN patients during breast surgery. Secretions of TALs were subjected to cytokine profiling using a cytokine antibody array. Our results showed an increase in the number of infiltrated CD45+ cells in the carcinoma tissues of pLN patients with the major proportion being myeloid subsets compared with nLN patients. Furthermore, TALs of pLN patients show a significant fivefold increase in the secretion of interleukin (IL)-1α, interferon-γ, IL-5, IL-3 and tumor necrosis factor-β, and are characterized by enhanced constitutive NF-κB/p65 signaling compared with TALs isolated from nLN patients. Using an invasion assay, cytokines secreted by TALs of pLN patients were shown to augment the invasive phenotype of breast cancer MCF-7 and SKBR3 cells compared with nLN patients. Using flow cytometry, we found that C-C chemokine receptor 7 (CCR7) is significantly overexpressed in breast carcinoma of pLN patients compared with nLNs patients. Intriguingly, CCR7, a mechanistic clue for metastasis, is upregulated in MCF-7 cells upon stimulation with TAL-conditioned media of pLN patients. Our findings show that the molecular cues secreted by TALs alone or in combination with CCR7 may emerge as future therapeutic targets for lymph node metastasis in breast cancer patients.

  19. Mechanism of tumor Metastasis Suppression by the KAI1 Gene

    DTIC Science & Technology

    2005-02-01

    significantly reduced in breast tumor cells, particularly in cysteine, Ni2 +, N-Myc and PTEN ( Kokame et al., 1996; patients with lymph node or bone metastasis...SC, Hirota S, Hosobe S, Kokame K, Kato H and Miyata T. (1996). J. Biol. Chem., 271, Miura K, Saito K, Commes T, Hayashi S, Watabe M and 29659-29665

  20. Dietary Fish Oil in Reducing Bone Metastasis of Breast Cancer

    DTIC Science & Technology

    2005-09-01

    polyunsaturated fatty acids ( PUFAs ) (1) increase the level of tumor suppressor protein PTEN, (2) inhibit the activity of PI 3 kinase, thus blocking a potent...15. SUBJECT TERMS Omega 3- fatty acids , bone morphogenetic protein-2 (BMP-2), breast cancer bone metastasis 16. SECURITY CLASSIFICATION OF: 17...complications must be of highest priority in formulating breast cancer therapy. Fish oil, rich in (o-3 polyunsaturated fatty acids ( PUFAs ) such as

  1. Phosphorylation of serine 367 of FOXC2 by p38 regulates ZEB1 and breast cancer metastasis, without impacting primary tumor growth

    PubMed Central

    Werden, S J; Sphyris, N; Sarkar, T R; Paranjape, A N; LaBaff, A M; Taube, J H; Hollier, B G; Ramirez-Peña, E Q; Soundararajan, R; den Hollander, P; Powell, E; Echeverria, G V; Miura, N; Chang, J T; Piwnica-Worms, H; Rosen, J M; Mani, S A

    2016-01-01

    Metastatic competence is contingent upon the aberrant activation of a latent embryonic program, known as the epithelial–mesenchymal transition (EMT), which bestows stem cell properties as well as migratory and invasive capabilities upon differentiated tumor cells. We recently identified the transcription factor FOXC2 as a downstream effector of multiple EMT programs, independent of the EMT-inducing stimulus, and as a key player linking EMT, stem cell traits and metastatic competence in breast cancer. As such, FOXC2 could serve as a potential therapeutic target to attenuate metastasis. However, as FOXC2 is a transcription factor, it is difficult to target by conventional means such as small-molecule inhibitors. Herein, we identify the serine/threonine-specific kinase p38 as a druggable upstream regulator of FOXC2 stability and function that elicits phosphorylation of FOXC2 at serine 367 (S367). Using an orthotopic syngeneic mouse tumor model, we make the striking observation that inhibition of p38-FOXC2 signaling selectively attenuates metastasis without impacting primary tumor growth. In this model, circulating tumor cell numbers are significantly reduced in mice treated with the p38 inhibitor SB203580, relative to vehicle-treated counterparts. Accordingly, genetic or pharmacological inhibition of p38 decreases FOXC2 protein levels, reverts the EMT phenotype and compromises stem cell attributes in vitro. We also identify the EMT-regulator ZEB1—known to directly repress E-cadherin/CDH1—as a downstream target of FOXC2, critically dependent on its activation by p38. Consistent with the notion that activation of the p38-FOXC2 signaling axis represents a critical juncture in the acquisition of metastatic competence, the phosphomimetic FOXC2(S367E) mutant is refractory to p38 inhibition both in vitro and in vivo, whereas the non-phosphorylatable FOXC2(S367A) mutant fails to elicit EMT and upregulate ZEB1. Collectively, our data demonstrate that FOXC2 regulates EMT

  2. Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor.

    PubMed

    Calderon, Lindsay E; Keeling, Jonathan K; Rollins, Joseph; Black, Carrie A; Collins, Kendall; Arnold, Nova; Vance, Diane E; Ndinguri, Margaret W

    2017-02-15

    A new targeting chemotherapeutic agent, Pt-Mal-LHRH, was synthesized by linking activated cisplatin to luteinizing hormone releasing hormone (LHRH). The compound's efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, since the Pt-Mal-LHRH malonate linker chelates platinum in a similar manner to carboplatin. Breast cancer and normal cell viability were analyzed by an MTT assay comparing Pt-Mal-LHRH with carboplatin. Cells were also treated with either Pt-Mal-LHRH or carboplatin to evaluate platinum uptake by ICP-MS and cell migration using an in vitro scratch-migration assay. Tumor volume and metastasis were evaluated using an in vivo 4T1 mouse tumor model. Mice were administered Pt-Mal-LHRH (carboplatin molar equivalent dosage) through ip injection and compared to those treated with carboplatin (5 (mg/kg)/week), no treatment, and LHRH plus carboplatin (unbound) controls. An MTT assay showed a reduction in cell viability (p < 0.01) in 4T1 and MDA-MB-231 breast cancer cells treated with Pt-Mal-LHRH compared to carboplatin. Pt-Mal-LHRH was confirmed to be cytotoxic by flow cytometry using a propidium iodide stain. Pt-Mal-LHRH displayed a 20-fold increase in 4T1 cellular uptake compared to carboplatin. There was a decrease (p < 0.0001) in 4T1 cell viability compared to 3T3 normal fibroblast cells. Treatment with Pt-Mal-LHRH also resulted in a significant decrease in cell-migration compared to carboplatin. In vivo testing found a significant reduction in tumor volume (p < 0.05) and metastatic tumor colonization in the lungs with Pt-Mal-LHRH compared to carboplatin. There was a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicate that Pt-Mal-LHRH is a more potent and selective chemotherapeutic agent than untargeted carboplatin.

  3. Metaplastic Breast Carcinoma With Multiple Muscle Metastasis

    PubMed Central

    Liu, Chung Hsiung; Chang, Chen; Sy, Edgar; Lai, Hung-Wen; Kuo, Yao-Lung

    2015-01-01

    Abstract Metaplastic breast carcinoma (MBC) is a rare type of breast carcinoma. Recurrence presenting as chest wall invasion is common but rarely as metastasis to distal skeletal muscle in which most patients present with a painful mass. Herein, we report a rare case of 65-year-old woman, with MBC and recurrence presenting as distal multiple muscle metastasis. The patient received surgical excision for symptomatic relief. Unfortunately, she died 12 months postoperatively due to disease progression with multiple lung metastasis. In addition to radiotherapy and chemotherapy, surgical excision is an alternative option in selected patients such as those with painful, isolated, and easily approachable mass. PMID:25929895

  4. EGFR and HER2 signaling in breast cancer brain metastasis

    PubMed Central

    Sirkisoon, Sherona R.; Carpenter, Richard L.; Rimkus, Tadas; Miller, Lance; Metheny-Barlow, Linda; Lo, Hui-Wen

    2016-01-01

    Breast cancer occurs in approximately 1 in 8 women and 1 in 37 women with breast cancer succumbed to the disease. Over the past decades, new diagnostic tools and treatments have substantially improved the prognosis of women with local diseases. However, women with metastatic disease still have a dismal prognosis without effective treatments. Among different molecular subtypes of breast cancer, the HER2-enriched and basal-like subtypes typically have higher rates of metastasis to the brain. Basal-like metastatic breast tumors frequently express EGFR. Consequently, HER2- and EGFR-targeted therapies are being used in the clinic and/or evaluated in clinical trials for treating breast cancer patients with brain metastases. In this review, we will first provide an overview of the HER2 and EGFR signaling pathways. The roles that EGFR and HER2 play in breast cancer metastasis to the brain will then be discussed. Finally, we will summarize the preclinical and clinical effects of EGFR- and HER2-targeted therapies on breast cancer metastasis. PMID:26709660

  5. ANGPTL2 increases bone metastasis of breast cancer cells through enhancing CXCR4 signaling.

    PubMed

    Masuda, Tetsuro; Endo, Motoyoshi; Yamamoto, Yutaka; Odagiri, Haruki; Kadomatsu, Tsuyoshi; Nakamura, Takayuki; Tanoue, Hironori; Ito, Hitoshi; Yugami, Masaki; Miyata, Keishi; Morinaga, Jun; Horiguchi, Haruki; Motokawa, Ikuyo; Terada, Kazutoyo; Morioka, Masaki Suimye; Manabe, Ichiro; Iwase, Hirotaka; Mizuta, Hiroshi; Oike, Yuichi

    2015-03-16

    Bone metastasis of breast cancer cells is a major concern, as it causes increased morbidity and mortality in patients. Bone tissue-derived CXCL12 preferentially recruits breast cancer cells expressing CXCR4 to bone metastatic sites. Thus, understanding how CXCR4 expression is regulated in breast cancer cells could suggest approaches to decrease bone metastasis of breast tumor cells. Here, we show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) increases responsiveness of breast cancer cells to CXCL12 by promoting up-regulation of CXCR4 in those cells. In addition, we used a xenograft mouse model established by intracardiac injection of tumor cells to show that ANGPTL2 knockdown in breast cancer cells attenuates tumor cell responsiveness to CXCL12 by decreasing CXCR4 expression in those cells, thereby decreasing bone metastasis. Finally, we found that ANGPTL2 and CXCR4 expression levels within primary tumor tissues from breast cancer patients are positively correlated. We conclude that tumor cell-derived ANGPTL2 may increase bone metastasis by enhancing breast tumor cell responsiveness to CXCL12 signaling through up-regulation of tumor cell CXCR4 expression. These findings may suggest novel therapeutic approaches to treat metastatic breast cancer.

  6. miR-203 facilitates tumor growth and metastasis by targeting fibroblast growth factor 2 in breast cancer

    PubMed Central

    He, Shuqian; Zhang, Guihui; Dong, He; Ma, Maoqiang; Sun, Qing

    2016-01-01

    Breast cancer is the second leading cause of cancer mortality in women worldwide. Molecular therapy is needed to improve the outcome in patients with breast cancer. miR-203 participates in cancer cell proliferation, transformation, and apoptosis. This study showed that miR-203 was upregulated in breast cancer tissues and the MCF-7 cell line. miR-203 knockdown suppressed colony formation and transformation and also limited migration in MCF-7 cells. Fibroblast growth factor 2 (FGF2) was confirmed as a novel target of miR-203, as miR-203 knockdown induced an enhanced expression of FGF2 in MCF-7 cells. Moreover, FGF2 can reverse transforming growth factor-β signal pathway to suppress breast cancer. These findings provide new insights with potential therapeutic applications for the treatment of breast cancer. PMID:27785068

  7. Tumor Microenvironment Regulates Metastasis and Metastasis Genes of Mouse MMTV-PymT Mammary Cancer Cells In Vivo

    PubMed Central

    Werbeck, J. L.; Thudi, N. K.; Martin, C. K.; Premanandan, C.; Yu, L.; Ostrowksi, M. C.; Rosol, T. J.

    2014-01-01

    Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment. PMID:24091811

  8. Tumor microenvironment regulates metastasis and metastasis genes of mouse MMTV-PymT mammary cancer cells in vivo.

    PubMed

    Werbeck, J L; Thudi, N K; Martin, C K; Premanandan, C; Yu, L; Ostrowksi, M C; Rosol, T J

    2014-07-01

    Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment.

  9. Bladder metastasis from primary breast cancer: a case report and literature review

    PubMed Central

    Ghaida, Rami Abou; Ayoub, Hajar; Nasr, Rami; Issa, Ghada

    2013-01-01

    Breast cancer is the most common malignancy in woman. The urinary bladder is an unusual site for metastasis from primary tumors of the breast, especially when it is the only organ involved. We present the case of a female patient with known breast cancer stage T2N3M0 who developed isolated bladder metastasis five years after the primary diagnosis. We reviewed the literature for similar cases and discussed the clinical presentation, pathophysiology, and prognosis of this entity. PMID:24579023

  10. Organotropic metastasis: role of tumor exosomes.

    PubMed

    Liu, Yang; Cao, Xuetao

    2016-02-01

    A recent paper in Nature shows that tumor exosomes expressing unique integrins can determine organotropic metastasis by preparing pre-metastatic niche through their integrins-mediated fusion with and fertilization of organ-specific resident cells.

  11. Primary Tumor and MEF Cell Isolation to Study Lung Metastasis.

    PubMed

    Dong, Shengli; Maziveyi, Mazvita; Alahari, Suresh K

    2015-05-20

    In breast tumorigenesis, the metastatic stage of the disease poses the greatest threat to the affected individual. Normal breast cells with altered genotypes now possess the ability to invade and survive in other tissues. In this protocol, mouse mammary tumors are removed and primary cells are prepared from tumors. The cells isolated from this procedure are then available for gene profiling experiments. For successful metastasis, these cells must be able to intravasate, survive in circulation, extravasate to distant organs, and survive in that new organ system. The lungs are the typical target of breast cancer metastasis. A set of genes have been discovered that mediates the selectivity of metastasis to the lung. Here we describe a method of studying lung metastasis from a genetically engineered mouse model.. Furthermore, another protocol for analyzing mouse embryonic fibroblasts (MEFs) from the mouse embryo is included. MEF cells from the same animal type provide a clue of non-cancer cell gene expression. Together, these techniques are useful in studying mouse mammary tumorigenesis, its associated signaling mechanisms and pathways of the abnormalities in embryos.

  12. Oncofetal H19 RNA promotes tumor metastasis.

    PubMed

    Matouk, Imad J; Raveh, Eli; Abu-lail, Rasha; Mezan, Shaul; Gilon, Michal; Gershtain, Eitan; Birman, Tatiana; Gallula, Jennifer; Schneider, Tamar; Barkali, Moshe; Richler, Carmelit; Fellig, Yakov; Sorin, Vladimir; Hubert, Ayala; Hochberg, Abraham; Czerniak, Abraham

    2014-07-01

    The oncofetal H19 gene transcribes a long non-coding RNA(lncRNA) that is essential for tumor growth. Here we found that numerous established inducers of epithelial to mesenchymal transition(EMT) also induced H19/miR-675 expression. Both TGF-β and hypoxia concomitantly induced H19 and miR-675 with the induction of EMT markers. We identified the PI3K/AKT pathway mediating the inductions of Slug, H19 RNA and miR-675 in response to TGF-β treatment, while Slug induction depended on H19 RNA. In the EMT induced multidrug resistance model, H19 level was also induced. In a mouse breast cancer model, H19 expression was tightly correlated with metastatic potential. In patients, we detected high H19 expression in all common metastatic sites tested, regardless of tumor primary origin. H19 RNA suppressed the expression of E-cadherin protein. H19 up-regulated Slug expression concomitant with the suppression of E-cadherin protein through a mechanism that involved miR-675. Slug also up-regulated H19 expression and activated its promoter. Altogether, these results may support the existence of a positive feedback loop between Slug and H19/miR-675, that regulates E-cadherin expression. H19 RNA enhanced the invasive potential of cancer cells in vitro and enhanced tumor metastasis in vivo. Additionally, H19 knockdown attenuated the scattering and tumorigenic effects of HGF/SF. Our results present novel mechanistic insights into a critical role for H19 RNA in tumor progression and indicate a previously unknown link between H19/miR-675, Slug and E-cadherin in the regulation of cancer cell EMT programs.

  13. Integrated genomic and epigenomic analysis of breast cancer brain metastasis.

    PubMed

    Salhia, Bodour; Kiefer, Jeff; Ross, Julianna T D; Metapally, Raghu; Martinez, Rae Anne; Johnson, Kyle N; DiPerna, Danielle M; Paquette, Kimberly M; Jung, Sungwon; Nasser, Sara; Wallstrom, Garrick; Tembe, Waibhav; Baker, Angela; Carpten, John; Resau, Jim; Ryken, Timothy; Sibenaller, Zita; Petricoin, Emanuel F; Liotta, Lance A; Ramanathan, Ramesh K; Berens, Michael E; Tran, Nhan L

    2014-01-01

    The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.

  14. Altered Tumor-Cell Glycosylation Promotes Metastasis

    PubMed Central

    Häuselmann, Irina; Borsig, Lubor

    2014-01-01

    Malignant transformation of cells is associated with aberrant glycosylation presented on the cell-surface. Commonly observed changes in glycan structures during malignancy encompass aberrant expression and glycosylation of mucins; abnormal branching of N-glycans; and increased presence of sialic acid on proteins and glycolipids. Accumulating evidence supports the notion that the presence of certain glycan structures correlates with cancer progression by affecting tumor-cell invasiveness, ability to disseminate through the blood circulation and to metastasize in distant organs. During metastasis tumor-cell-derived glycans enable binding to cells in their microenvironment including endothelium and blood constituents through glycan-binding receptors – lectins. In this review, we will discuss current concepts how tumor-cell-derived glycans contribute to metastasis with the focus on three types of lectins: siglecs, galectins, and selectins. Siglecs are present on virtually all hematopoietic cells and usually negatively regulate immune responses. Galectins are mostly expressed by tumor cells and support tumor-cell survival. Selectins are vascular adhesion receptors that promote tumor-cell dissemination. All lectins facilitate interactions within the tumor microenvironment and thereby promote cancer progression. The identification of mechanisms how tumor glycans contribute to metastasis may help to improve diagnosis, prognosis, and aid to develop clinical strategies to prevent metastasis. PMID:24592356

  15. Gene Expression Profiling of Breast Cancer Brain Metastasis

    PubMed Central

    Lee, Ji Yun; Park, Kyunghee; Lee, Eunjin; Ahn, TaeJin; Jung, Hae Hyun; Lim, Sung Hee; Hong, Mineui; Do, In-Gu; Cho, Eun Yoon; Kim, Duk-Hwan; Kim, Ji-Yeon; Ahn, Jin Seok; Im, Young-Hyuck; Park, Yeon Hee

    2016-01-01

    The biology of breast cancer brain metastasis (BCBM) is poorly understood. We aimed to explore genes that are implicated in the process of brain metastasis of primary breast cancer (BC). NanoString nCounter Analysis covering 252 target genes was used for comparison of gene expression levels between 20 primary BCs that relapsed to brain and 41 BCBM samples. PAM50-based intrinsic subtypes such as HER2-enriched and basal-like were clearly over-represented in BCBM. A panel of 22 genes was found to be significantly differentially expressed between primary BC and BCBM. Five of these genes, CXCL12, MMP2, MMP11, VCAM1, and MME, which have previously been associated with tumor progression, angiogenesis, and metastasis, clearly discriminated between primary BC and BCBM. Notably, the five genes were significantly upregulated in primary BC compared to BCBM. Conversely, SOX2 and OLIG2 genes were upregulated in BCBM. These genes may participate in metastatic colonization but not in primary tumor development. Among patient-matched paired samples (n = 17), a PAM50 molecular subtype conversion was observed in eight cases (47.1%), with a trend toward unfavorable subtypes in patients with the distinct gene expression. Our findings, although not conclusive, reveal differentially expressed genes that might mediate the brain metastasis process. PMID:27340107

  16. Investigating the Role of Indoleamine 2,3- dioxygenase (IDO) in Breast Cancer Metastasis

    DTIC Science & Technology

    2012-09-01

    in Breast Cancer Metastasis” PRINCIPAL INVESTIGATOR: Courtney Smith, Ph.D. CONTRACTING ORGANIZATION: Lankenau Institute for Medical...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W Investigating the Role of Indoleamine 2,3-Dioxygenase (IDO) in Breast Cancer Metastasis 5b. GRANT...2,3-dioxygenase) has since been implicated in tumor escape from the host immune system. Primary tumor growth of the metastatic 4T1 breast cancer

  17. Induction of erythropoiesis by hypoxia-inducible factor prolyl hydroxylase inhibitors without promotion of tumor initiation, progression, or metastasis in a VEGF-sensitive model of spontaneous breast cancer

    PubMed Central

    Seeley, Todd W; Sternlicht, Mark D; Klaus, Stephen J; Neff, Thomas B; Liu, David Y

    2017-01-01

    The effects of pharmacological hypoxia-inducible factor (HIF) stabilization were investigated in the MMTV-Neundl-YD5 (NeuYD) mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF), using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs), FG-4497 or roxadustat (FG-4592). In NeuYD mice, HIF-PHI treatments elevated erythropoiesis markers, but no differences were detected in tumor onset or the phenotypes of established tumors. PMID:28331872

  18. Pigment epithelium-derived factor (PEDF) inhibits breast cancer metastasis by down-regulating fibronectin.

    PubMed

    Hong, Honghai; Zhou, Ti; Fang, Shuhuan; Jia, Minghan; Xu, Zumin; Dai, Zhiyu; Li, Cen; Li, Shuai; Li, Lei; Zhang, Ting; Qi, Weiwei; Bardeesi, Adham Sameer A; Yang, Zhonghan; Cai, Weibin; Yang, Xia; Gao, Guoquan

    2014-11-01

    Pigment epithelium-derived factor (PEDF) plays an important role in the tumor growth and metastasis inhibition. It has been reported that PEDF expression is significantly reduced in breast cancer, and associated with disease progression and poor patient outcome. However, the exact mechanism of PEDF on breast cancer metastasis including liver and lung metastasis remains unclear. The present study aims to reveal the impact of PEDF on breast cancer. The orthotopic tumor mice model inoculated by MDA-MB-231 cells stably expressing PEDF or control cells was used to assess liver and lung metastasis of breast cancer. In vitro, migration and invasion experiments were used to detect the metastatic abilities of MDA-MB-231 and SKBR3 breast cancer cells with or without overexpression of PEDF. The metastatic-related molecules including EMT makers, fibronectin, and p-AKT and p-ERK were detected by qRT-PCR, Western blot, and Fluorescent immunocytochemistry. PEDF significantly inhibited breast cancer growth and metastasis in vivo and in vitro. Mechanically, PEDF inhibited breast cancer cell migration and invasion by down-regulating fibronectin and subsequent MMP2/MMP9 reduction via p-ERK and p-AKT signaling pathways. However, PEDF had no effect on EMT conversion in the breast cancer cells which was usually involved in cancer metastasis. Furthermore, the study showed that laminin receptor mediated the down-regulation of fibronectin by PEDF. These results reported for the first time that PEDF inhibited breast cancer metastasis by down-regulating fibronectin via laminin receptor/AKT/ERK pathway. Our findings demonstrated PEDF as a dual effector in limiting breast cancer growth and metastasis and highlighted a new avenue to block breast cancer progression.

  19. Bone metastasis risk factors in breast cancer

    PubMed Central

    Pulido, Catarina; Vendrell, Inês; Ferreira, Arlindo R; Casimiro, Sandra; Mansinho, André; Alho, Irina; Costa, Luís

    2017-01-01

    Bone is the single most frequent site for bone metastasis in breast cancer patients. Patients with bone-only metastasis have a fairly good prognosis when compared with patients with visceral disease. Nevertheless, cancer-induced bone disease carries an important risk of developing skeletal related events that impact quality of life (QoL). It is therefore particularly important to stratify patients according to their risk of developing bone metastasis. In this context, several risk factors have been studied, including demographic, clinicopathological, genetic, and metabolic factors. Most of them show conflicting or non-definitive associations and are not validated for clinical use. Nonetheless, tumour intrinsic subtype is widely accepted as a major risk factor for bone metastasis development and luminal breast cancer carries an increased risk for bone disease. Other factors such as gene signatures, expression of specific cytokines (such as bone sialoprotein and bone morphogenetic protein 7) or components of the extracellular matrix (like bone crosslinked C-telopeptide) might also influence the development of bone metastasis. Knowledge of risk factors related with bone disease is of paramount importance as it might be a prediction tool for triggering the use of targeted agents and allow for better patient selection for future clinical trials. PMID:28194227

  20. FOXP3 suppresses breast cancer metastasis through downregulation of CD44.

    PubMed

    Zhang, Cun; Xu, Yujin; Hao, Qiang; Wang, Shuning; Li, Hong; Li, Jialin; Gao, Yuan; Li, Meng; Li, Weina; Xue, Xiaochang; Wu, Shouzhen; Zhang, Yingqi; Zhang, Wei

    2015-09-15

    Forkhead box protein 3 (FOXP3) plays an important role in breast cancer as an X-linked tumor suppressor gene. However, the biological functions and significance of FOXP3 in breast cancer metastasis remain unclear. Here, we find that, clinically, nuclear FOXP3 expression is inversely correlated with breast cancer metastasis. Moreover, we demonstrate that FOXP3 significantly inhibits adhesion, invasion and metastasis of breast cancer cells in vivo and in vitro. In addition, the adhesion molecule CD44 is found to be suppressed by FOXP3 through transcriptome sequence analysis (RNA-seq). A luciferase reporter assay, chromatin immunoprecipitation and electrophoretic mobility shift assay identify CD44 as a direct target of FOXP3. The expression of CD44 is downregulated by FOXP3 in breast cancer cells. Importantly, anti-CD44 antibody reverses the FOXP3 siRNA-induced effects on the breast cancer cells in vitro and FOXP3 expression level in the nucleus of breast cancer cells is inversely correlated with CD44 expression level in clinic breast cancer tissues. Taken together, the results from the present study suggest that FOXP3 is a suppressor of breast cancer metastasis. FOXP3 directly binds to the promoter of CD44 and inhibits its protein expression, thereby suppressing adhesion and invasion of human breast cancer cells. This finding highlights the therapeutic potential of FOXP3-CD44 signaling to inhibit breast cancer metastasis.

  1. DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis.

    PubMed

    Wang, Yufeng; Lei, Rong; Zhuang, Xueqian; Zhang, Ning; Pan, Hong; Li, Gang; Hu, Jing; Pan, Xiaoqi; Tao, Qian; Fu, Da; Xiao, Jianru; Chin, Y Eugene; Kang, Yibin; Yang, Qifeng; Hu, Guohong

    2014-04-01

    Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho-TGF-β crosstalk in osteolytic bone metastasis.

  2. Gastric metastasis of bilateral breast cancer

    PubMed Central

    Belaïd, Asma; Mghirbi, Fahmi; Béhi, Khalil; Doghri, Raoudha; Benna, Farouk

    2017-01-01

    Breast cancer is the most common malignancy in women. The most frequent metastatic sites are lung, bone, liver and brain. On the other hand, gastric metastases are rare. Synchronous bilateral breast cancer (SBBC) occurs rarely. Lobular carcinoma is the histological type most often associated with bilateral breast carcinomas and gastric metastases. We made a retrospective study including four patients followed in the Salah Azaiez Institute, for a bilateral breast cancer with gastric metastases. We analyzed the epidemiological, anatomoclinical and therapeutic particularities of this rare entity. Symptoms were unspecific. The diagnosis of gastric metastasis of the SBBC was confirmed by a histopathological examination of an endoscopic biopsy. The median age was 46.2 years (range, 36–51 years) and the median time until the gastric involvement was 19 months (range, 0–41 months). None of patients had a surgical treatment for the gastric location. All Patients received at least one line of chemotherapy and radiotherapy. Median survival following the detection of gastric involvement was 22 months (range, 1–56 months). Gastric metastases from breast cancer are rare and frequently associated with other distant metastasis. Symptoms are unspecific and endoscopy may not be contributive. Therefore, gastric involvement is underestimated. Lobular infiltrating carcinoma (LIC) is the most histological type incriminated in its occurrence. The supply of immunohistochemistry is crucial to distinguish between primary or metastatic gastric cancer. PMID:28280631

  3. Microenvironmental regulation of tumor progression and metastasis

    PubMed Central

    Quail, DF; Joyce, JA

    2014-01-01

    Cancers develop in complex tissue environments, which they depend upon for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable, and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that reeducation of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here, we will discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, and recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects. PMID:24202395

  4. Blockade of extracellular NM23 or its endothelial target slows breast cancer growth and metastasis

    PubMed Central

    Yokdang, Nucharee; Nordmeier, Senny; Speirs, Katie; Burkin, Heather R.; Buxton, Iain L. O.

    2015-01-01

    Background Nucleoside Diphosphate Kinase (NDPK), described as NM23 a metastasis suppressor, is found in the culture medium of cancer cells lines suggesting that the kinase may have an extracellular role. We propose that extracellular NM23 released from breast cancers in vivo stimulates tumor cell migration, proliferation and endothelial cell angiogenesis in support of metastasis development. Methods NM23 in the bloodstream of immunocompromised mice carrying human triple-negative breast cancers or in breast cancer patients was measured by ELISA. Primary and metastatic tumor development, the impact of blockade of NM23 and/or its stimulation of nucleotide receptors were measured using in vivo imaging. NM23 expression data in the Curtis breast dataset was examined to test our hypothesis that NM23 may play a mechanistic role in breast cancer development. Results SCID mice carrying metastatic MDA-MB-231Luc+ triple-negative human breast tumor cells elaborate NM23 into the circulation correlated with primary tumor growth. Treatment of mice with the NM23 inhibitor ellagic acid (EA) or the purinergic receptor antagonist MRS2179 slowed primary tumor growth. At 16 weeks following implantation, lung metastases were reduced in mice treated with EA, MRS2179 or the combination. Expression of NM23 in the Curtis breast dataset confirmed a likely role for NM23 in tumor metastasis. Conclusions Extracellular NM23 may constitute both a biomarker and a therapeutic target in the management of breast cancer. PMID:26413311

  5. MiRNA-101 inhibits breast cancer growth and metastasis by targeting CX chemokine receptor 7.

    PubMed

    Li, Jun-Tang; Jia, Lin-Tao; Liu, Ning-Ning; Zhu, Xiao-Shan; Liu, Qin-Qin; Wang, Xiu-Li; Yu, Feng; Liu, Yan-Li; Yang, An-Gang; Gao, Chun-Fang

    2015-10-13

    Whereas miR-101 is involved in the development and progression of breast cancer, the underlying molecular mechanisms remain to be elucidated. Here, we report that miR-101 expression is inversely correlated with the clinical stage, lymph node metastasis and prognosis in breast cancers. Introduction of miR-101 inhibited breast cancer cell proliferation and invasion in vitro and suppressed tumor growth and lung metastasis of in vivo. CX chemokine receptor 7 (CXCR7) is a direct target of miR-101, positively correlating with the histological grade and the incidence of lymph node metastasis in breast cancer patients. The effects of miR-101 were mimicked and counteracted by CXCR7 depletion and overexpression, respectively. STAT3 signaling downstream of CXCR7 is involved in miR-101 regulation of breast cancer cell behaviors. These findings have implications for the potential application of miR-101 in breast cancer treatment.

  6. Visualization of GFP-expressing tumors and metastasis in vivo.

    PubMed

    Hoffman, R M

    2001-05-01

    We have developed mouse models of metastatic cancer with genetically fluorescent tumors that can be imaged in fresh tissue, in situ, as well as externally. To achieve this capability, we have transduced the green fluorescent protein (GFP) gene, cloned from the bioluminescent jellyfish Aequorea victoria, into a series of human and rodent cancer cell lines that were selected in vitro to stably express GFP in vivo after transplantation to metastatic rodent models. Techniques were also developed for transduction of tumors by GFP in vivo. With this fluorescent tool, we detected and visualized for the first time tumors and metastasis in fresh viable tissue or in situ in host organs down to the single-cell level. GFP tumors on the colon, prostate, breast, brain, liver, lymph nodes, lung, pancreas, bone, and other organs can also be visualized externally, transcutaneously by quantitative whole-body fluorescence optical imaging. Real-time tumor and metastatic growth and angiogenesis and inhibition by representative drugs can be imaged and quantified for rapid antitumor, antimetastatic, and antiangiogenesis drug screening. The GFP-transfected tumor cells enabled a fundamental advance in the visualization of tumor growth and metastasis in real time in vivo.

  7. Specific expression of the human voltage-gated proton channel Hv1 in highly metastatic breast cancer cells, promotes tumor progression and metastasis

    SciTech Connect

    Wang, Yifan; Li, Shu Jie; Pan, Juncheng; Che, Yongzhe; Yin, Jian; Zhao, Qing

    2011-08-26

    Highlights: {yields} Hv1 is specifically expressed in highly metastatic human breast tumor tissues. {yields} Hv1 regulates breast cancer cytosolic pH. {yields} Hv1 acidifies extracellular milieu. {yields} Hv1 exacerbates the migratory ability of metastatic cells. -- Abstract: The newly discovered human voltage-gated proton channel Hv1 is essential for proton transfer, which contains a voltage sensor domain (VSD) without a pore domain. We report here for the first time that Hv1 is specifically expressed in the highly metastatic human breast tumor tissues, but not in poorly metastatic breast cancer tissues, detected by immunohistochemistry. Meanwhile, real-time RT-PCR and immunocytochemistry showed that the expression levels of Hv1 have significant differences among breast cancer cell lines, MCF-7, MDA-MB-231, MDA-MB-468, MDA-MB-453, T-47D and SK-BR-3, in which Hv1 is expressed at a high level in highly metastatic human breast cancer cell line MDA-MB-231, but at a very low level in poorly metastatic human breast cancer cell line MCF-7. Inhibition of Hv1 expression in the highly metastatic MDA-MB-231 cells by small interfering RNA (siRNA) significantly decreases the invasion and migration of the cells. The intracellular pH of MDA-MB-231 cells down-regulated Hv1 expression by siRNA is obviously decreased compared with MDA-MB-231 with the scrambled siRNA. The expression of matrix metalloproteinase-2 and gelatinase activity in MDA-MB-231 cells suppressed Hv1 by siRNA were reduced. Our results strongly suggest that Hv1 regulates breast cancer intracellular pH and exacerbates the migratory ability of metastatic cells.

  8. The Role of Megakaryocytes in Breast Cancer Metastasis to Bone.

    PubMed

    Jackson, Walter; Sosnoski, Donna M; Ohanessian, Sara E; Chandler, Paige; Mobley, Adam W; Meisel, Kacey D; Mastro, Andrea M

    2017-02-15

    Little is known about how megakaryocytes affect metastasis apart from serving as the source of platelets. We noted an increase in the number of megakaryocytes in the femurs of metastases-bearing athymic mice four weeks following intracardiac inoculation of MDA-MB-231 human breast cancer cells. How did the megakaryocytes relate to the metastases? Did megakaryocytes prepare a niche or did they increase in response to metastases? To test these possibilities, we examined two models of experimental metastasis, intracardiac inoculation of human MDA-MB-231 into athymic mice, and intramammary injection of mouse tumor cells, 4T1.2 (metastatic) or 67NR (non-metastatic) in BALB/c mice. In both models, metastatic, but not primary tumor growth was associated with increased megakaryopoiesis. At 4 weeks post injection, megakaryocytes increased ~ two-fold in the bone marrow of mice with MDA-MB-231 bone metastasis. BALB/c mice injected orthotopically with murine 4T1.2 cells showed extramedullary hematopoiesis resulting in a four-fold increase in megakaryocytes in the spleen. These findings led us to speculate that a reduction in megakaryocytes would result in reduced metastasis. Thrombopoietin knockout mice exhibited a 90% decrease in megakaryocytes compared to wild type mice. Nonetheless, they developed more aggressive metastasis than wild type. We also found with human clinical samples, an increase in megakaryocytes in the bone marrow of 75% (6/8) of patients with metastatic breast cancer compared to age and gender matched controls. The data suggested that the increase in megakaryocytes occurs in response to metastatic cells in the bone, and that megakaryocytes are in some measure protective against metastases.

  9. Genomic Analyses of Breast Cancer Progression Reveal Distinct Routes of Metastasis Emergence

    PubMed Central

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Brasch-Andersen, Charlotte; Lænkholm, Anne-Vibeke; Knoop, Ann S.; Jensen, Jeanette Dupont; Bak, Martin; Mollenhauer, Jan; Thomassen, Mads; Kruse, Torben A.

    2017-01-01

    A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. The genetic concordance between different steps of malignant progression is mostly unexplored as very few studies have included cancer samples separated by both space and time. We applied whole exome sequencing and targeted deep sequencing to 26 successive samples from six patients with metastatic estrogen receptor (ER)-positive breast cancer. Our data provide support for both linear and parallel progression towards metastasis. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence. This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis. PMID:28276460

  10. Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0214 TITLE: Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis PRINCIPAL INVESTIGATOR: Dario...5a. CONTRACT NUMBER Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis 5b. GRANT NUMBER W81XWH-14-1-0214 5c. PROGRAM ELEMENT NUMBER 6...SUPPLEMENTARY NOTES None 14. ABSTRACT Breast cancer brain metastasis (BCBM) is devastating and increasing in frequency, however, BCBM mechanisms are

  11. Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages.

    PubMed

    Frankenberger, Casey; Rabe, Daniel; Bainer, Russell; Sankarasharma, Devipriya; Chada, Kiran; Krausz, Thomas; Gilad, Yoav; Becker, Lev; Rosner, Marsha Rich

    2015-10-01

    Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf kinase inhibitory protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment and the importance of such regulation to metastasis suppression are incompletely understood. Here, we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating tumor-associated macrophages (TAM). TAMs isolated from nonmetastatic RKIP(+) tumors, relative to metastatic RKIP(-) tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of prometastatic factors, including PRGN, and shed TNFR2. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP(+) tumors restores recruitment of prometastatic TAMs and intravasation, whereas treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and prometastatic TAM factors strikingly separates TNBC patients based on survival outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis-suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage

  12. Tumor metastasis: molecular insights and evolving paradigms.

    PubMed

    Valastyan, Scott; Weinberg, Robert A

    2011-10-14

    Metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and/or epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. Recent advances provide provocative insights into these cell-biological and molecular changes, which have implications regarding the steps of the invasion-metastasis cascade that appear amenable to therapeutic targeting.

  13. Metastasis and Circulating Tumor Cells

    PubMed Central

    van Dalum, Guus; Holland, Linda

    2012-01-01

    Cancer is a prominent cause of death worldwide. In most cases, it is not the primary tumor which causes death, but the metastases. Metastatic tumors are spread over the entire human body and are more difficult to remove or treat than the primary tumor. In a patient with metastatic disease, circulating tumor cells (CTCs) can be found in venous blood. These circulating tumor cells are part of the metastatic cascade. Clinical studies have shown that these cells can be used to predict treatment response and their presence is strongly associated with poor survival prospects. Enumeration and characterization of CTCs is important as this can help clinicians make more informed decisions when choosing or evaluating treatment. CTC counts are being included in an increasing number of studies and thus are becoming a bigger part of disease diagnosis and therapy management. We present an overview of the most prominent CTC enumeration and characterization methods and discuss the assumptions made about the CTC phenotype. Extensive CTC characterization of for example the DNA, RNA and antigen expression may lead to more understanding of the metastatic process. PMID:27683421

  14. WAVE3 is a Biomarker for Breast Cancer Progression and Metastasis

    DTIC Science & Technology

    2012-04-01

    SUBJECT TERMS Breast cancer, Circulating Tumor Cells, WAVE3, Immunostaining, Metastasis 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF...of patients with metastatic breast cancer. (A) Semi-quantitative RT-PCR from total RNA extracted from a mix of 5 million cells of EBV -lin (a PBMC...and MDA-MB-231 (a highly metastatic breast cancer cell line), at the indicated ratios. MDA-MB-231 cells and EBV -Lin cells were used alone as a

  15. HER2 expression is a strong independent predictor of nodal metastasis in breast cancer.

    PubMed

    Ahmed, Ahmed R H

    2016-12-01

    Identification of metastatic potential of breast cancer cells is necessary for proper management of this disease. This work aimed to estimate likelihood of axillary lymph node (ALN) involvement in breast cancer patients based on human epidermal growth factor receptor 2 (HER2) expression. Primary tumors of 317 breast cancer patients were evaluated for estrogen receptor (ER), progesterone receptor (PR) and HER2 expression by immunohistochemistry. The validity of these molecules to predict ALN metastasis was measured statistically and compared to predictive effect of other clinicopathological parameters. ER, PR and HER2 expression was detected in 75.7%, 73.2% and 19.9% of tumors, respectively. Although increased tumor size and grade, ER and PR negativity and HER2 positivity were strong indicators of ALN metastasis on univariate analyses, only tumor size and HER2 expression were independent predictors of ALN involvement on multivariate analysis. ROC curve showed a strong validity of the model using these two parameters to predict ALN status (AUC 0.86; p<0001). HER2-rich, luminal B and triple negative tumors had 6.87, 6.32 and 3.58 times increased risk of metastasis compared to luminal A tumors; respectively. HER2 expression in pT1 and pT2 tumors raised the risk of ALN metastasis by 7.7 and 7.6 times, respectively and grade 1 and 2 tumors that expressed HER2 were 16.0 and 7.8 times more likely to have ALN metastasis, respectively. To conclude, HER2 expression is associated with a significant rise of metastatic potential of breast cancer cells and could be a strong indicator of regional and distant metastasis of breast cancer.

  16. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain.

    PubMed

    Chen, Jinyu; Lee, Ho-Jeong; Wu, Xuefeng; Huo, Lei; Kim, Sun-Jin; Xu, Lei; Wang, Yan; He, Junqing; Bollu, Lakshmi R; Gao, Guang; Su, Fei; Briggs, James; Liu, Xiaojing; Melman, Tamar; Asara, John M; Fidler, Isaiah J; Cantley, Lewis C; Locasale, Jason W; Weihua, Zhang

    2015-02-01

    Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells, but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the nonoxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBP) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients.

  17. Procollagen Lysyl Hydroxylase 2 is Essential for Hypoxia-Induced Breast Cancer Metastasis

    PubMed Central

    Gilkes, Daniele; Bajpai, Saumendra; Wong, Carmen Chak-Lui; Chaturvedi, Pallavi; Hubbi, Maimon E.; Wirtz, Denis; Semenza, Gregg L.

    2013-01-01

    Metastasis is the leading cause of death among patients who have breast cancer. Understanding the role of the extracellular matrix in the metastatic process may lead to the development of improved therapies to treat cancer patients. Intratumoral hypoxia, found in the majority of breast cancers, is associated with an increased risk of metastasis and mortality. We found that in hypoxic breast cancer cells, HIF-1 activates transcription of the PLOD1 and PLOD2 genes encoding procollagen lysyl hydroxylases that are required for the biogenesis of collagen, which is a major constituent of the extracellular matrix. High PLOD2 expression in breast cancer biopsies is associated with increased risk of mortality. We demonstrate that PLOD2 is critical for fibrillar collagen formation by breast cancer cells, increases tumor stiffness, and is required for metastasis to lymph nodes and lungs. PMID:23378577

  18. Osteocytic Connexin Hemichannels Suppress Breast Cancer Growth and Bone Metastasis

    PubMed Central

    Zhou, Jade Z.; Riquelme, Manuel A.; Gu, Sumin; Kar, Rekha; Gao, Xiaoli; Sun, LuZhe; Jiang, Jean X.

    2016-01-01

    Although the skeleton is one of predominant sites for breast cancer metastasis, why breast cancer cells often become dormant after homing to bone is not well understood. Here, we reported an intrinsic self-defense mechanism of bone cells against breast cancer cells: a critical role of connexin (Cx) 43 hemichannels in osteocytes in the suppression of breast cancer bone metastasis. Cx43 hemichannels allow passage of small molecules between the intracellular and extracellular environments. The treatment of bisphosphonate drugs, either alendronate (ALN) or zoledronic acid (ZOL), opened Cx43 hemichannels in osteocytes. Conditioned media (CM) collected from MLO-Y4 osteocyte cells treated with bisphosphonates inhibited the anchorage-independent growth, migration and invasion of MDA-MB-231 human breast cancer cells and Py8119 mouse mammary carcinoma cells and this inhibitory effect was attenuated with Cx43(E2), a specific hemichannel blocking antibody. The opening of osteocytic Cx43 hemichannels by mechanical stimulation had similar inhibitory effects on breast cancer cells and this inhibition was attenuated by Cx43(E2) antibody as well. These inhibitory effects on cancer cells were mediated by ATP released from osteocyte Cx43 hemichannels. Furthermore, both Cx43 osteocyte-specific knockout mice and osteocyte-specific Δ130–136 transgenic mice with impaired Cx43 gap junctions and hemichannels showed significantly increased tumor growth and attenuated the inhibitory effect of ZOL. However, R76W transgenic mice with functional hemichannels but not gap junctions in osteocytes did not display a significant difference. Together, our studies establish the specific inhibitory role of osteocytic Cx43 hemichannels, and exploiting the activity of this channel could serve as a de novo therapeutic strategy. PMID:27041582

  19. Isolated mucinous adrenal metastasis in a breast cancer patient.

    PubMed

    Demirci, Umut; Buyukberber, Suleyman; Cakir, Tansel; Poyraz, Aylar; Baykara, Meltem; Karakus, Esra; Tufan, Gulnihal; Benekli, Mustafa; Coskun, Ugur

    2011-12-01

    Mucinous breast carcinoma (MBC) is a rare histological type of breast cancer and rarely associated with advanced disease. We report a case that had MBC with an isolated adrenal metastasis which was removed by laparoscopic adrenelectomy. This case is unique due to the unexpected metastasis of pure mucinous carcinoma developed after 4 years of hormone therapy.

  20. NSG Mice Provide a Better Spontaneous Model of Breast Cancer Metastasis than Athymic (Nude) Mice

    PubMed Central

    Puchalapalli, Madhavi; Zeng, Xianke; Mu, Liang; Anderson, Aubree; Hix Glickman, Laura; Zhang, Ming; Sayyad, Megan R.; Mosticone Wangensteen, Sierra; Clevenger, Charles V.; Koblinski, Jennifer E.

    2016-01-01

    Metastasis is the most common cause of mortality in breast cancer patients worldwide. To identify improved mouse models for breast cancer growth and spontaneous metastasis, we examined growth and metastasis of both estrogen receptor positive (T47D) and negative (MDA-MB-231, SUM1315, and CN34BrM) human breast cancer cells in nude and NSG mice. Both primary tumor growth and spontaneous metastases were increased in NSG mice compared to nude mice. In addition, a pattern of metastasis similar to that observed in human breast cancer patients (metastases to the lungs, liver, bones, brain, and lymph nodes) was found in NSG mice. Furthermore, there was an increase in the metastatic burden in NSG compared to nude mice that were injected with MDA-MB-231 breast cancer cells in an intracardiac experimental metastasis model. This data demonstrates that NSG mice provide a better model for studying human breast cancer metastasis compared to the current nude mouse model. PMID:27662655

  1. Targeting Phosphatidylserince for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2014-10-01

    Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis 5b. GRANT NUMBER W81XWH-12-1-0316 5c. PROGRAM ELEMENT NUMBER 6...SUPPLEMENTARY NOTES 14. ABSTRACT Brain metastasis occurs in ~30% of metastatic breast cancer patients. The prognosis is extremely poor, with a...Introduction Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, with a median survival of 4-6 months even

  2. MMP-8: A Breast Cancer Bone Metastasis Suppressor Gene

    DTIC Science & Technology

    2005-08-01

    embedded in paraffin and stained with Gomori trichrome. (A) distal femur , control mouse. (B) distal femur , mouse with osteolytic metastasis . Note...A AD_______ Award Number: W81XWH-04-1-0687 TITLE: MMP-8: A Breast Cancer Bone Metastasis Suppressor Gene PRINCIPAL INVESTIGATOR: Nagarajan...CONTRACT NUMBER MMP-8: A Breast Cancer Bone Metastasis Suppressor Gene 5b. GRANT NUMBER W81 XWH-04-1-0687 6c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d

  3. 14-3-3ζ turns TGF-β’s function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2

    PubMed Central

    Xu, Jia; Acharya, Sunil; Sahin, Ozgur; Zhang, Qingling; Saito, Yohei; Yao, Jun; Wang, Hai; Li, Ping; Zhang, Lin; Lowery, Frank J; Kuo, Wen-Ling; Xiao, Yi; Ensor, Joe; Sahin, Aysegul A; Zhang, Xiang H.-F.; Hung, Mien-Chie; Zhang, Jitao David; Yu, Dihua

    2015-01-01

    Summary Transforming growth factor-β (TGF-β) functions as a tumor suppressor in pre-malignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF-β are proposed to be dictated by different partners of its downstream effectors Smads. However, the mechanism for the contextual changes of Smad partners remained undefined. Here, we demonstrate that 14-3-3ζ destabilizes p53, a Smad partner in pre-malignant mammary epithelial cells, by downregulating 14-3-3σ, thus turning off TGF-β’s tumor suppression function. Conversely, 14-3-3ζ stabilizes Gli2 in breast cancer cells, and Gli2 partners with Smads to activate PTHrP and promote TGF-β-induced bone metastasis. The 14-3-3ζ-driven contextual changes of Smad partners from p53 to Gli2 may serve as biomarkers and therapeutic targets of TGF-β-mediated cancer progression. PMID:25670079

  4. Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis.

    PubMed

    Ye, Tinghong; Wei, Xiawei; Yin, Tao; Xia, Yong; Li, Deliang; Shao, Bin; Song, Xuejiao; He, Sisi; Luo, Min; Gao, Xiang; He, Zhiyao; Luo, Can; Xiong, Ying; Wang, Ningyu; Zeng, Jun; Zhao, Lifeng; Shen, Guobo; Xie, Yongmei; Yu, Luoting; Wei, Yuquan

    2014-02-01

    Aberrant fibroblast growth factor (FGF) and FGF receptor (FGFR) system have been associated with breast cancer. The objectives of our study were to investigate the effects and mechanisms of FGFR inhibition on tumor growth and metastasis on breast cancer. Our studies showed that the FGFR inhibitor PD173074 decreased the viability of several human breast cancer cells, as well as 4T1 murine mammary tumor cells. Therefore, we chose 4T1 cells to study PD173074's antitumor mechanism. Flow cytometry showed that PD173074 induced 4T1 cell apoptosis in a concentration-dependent manner. Western blot demonstrated that PD173074-induced apoptosis was correlated with the inhibition of Mcl-1 and survivin. Moreover, PD173074 also significantly increased the ratio of Bax/Bcl-2. PD173074 could also block 4T1 cell migration and invasion in vitro. In 4T1 tumor-bearing mice, PD173074 significantly inhibited tumor growth without obvious side effects. Meanwhile, PD173074 functionally reduced microvessel density and proliferation index and induced tumor apoptosis. Importantly, we found that FGFR inhibition by PD173074 reduced myeloid-derived suppressor cells (MDSCs) in the blood, spleens and tumors, accompanied by the increased infiltration of CD4(+) and CD8(+) T cells in the spleens and tumors. Furthermore, PD173074 significantly inhibited breast tumor metastasis to the lung of inoculated 4T1 breast cancer cells, which was accompanied by a reduction in MDSCs. Our findings suggested that FGFR inhibition could delay breast tumor progression, impair lung metastasis and break immunosuppression by effecting on tumor microenvironment, which may provide a promising therapeutic approach for breast cancer patient.

  5. Pathogenesis and Blood-Brain Barrier Heterogeneity of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2005-07-01

    diagnosis and treatment and improve our understanding of the role of BBB in chemotherapy of brain tumors. 15. SUBJECT TERMS Breast Cancer, Brain...of the pathobiology of brain metastasis may lead to novel targeted treatment paradigms and a better prognosis for patients with brain metastatic...metastasis (Fenner and Possinger, 2002; Walsh, 1996) may be incorrect. The development of rational therapeutic strategies for the treatment of brain

  6. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis

    PubMed Central

    Zhang, Hui; Li, Jiufeng; He, Tianfang; Yeo, Eun-Jin; Soong, Daniel Y.H.; Carragher, Neil O.; Munro, Alison; Chang, Alvin; Bresnick, Anne R.; Lang, Richard A.

    2015-01-01

    Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease. PMID:26261265

  7. Inhibition of breast cancer metastasis with microRNA-302a by downregulation of CXCR4 expression.

    PubMed

    Liang, Zhongxing; Bian, Xuehai; Shim, Hyunsuk

    2014-08-01

    Metastasis remains a main cause of mortality from breast cancer and an unresolved issue. The purpose of this study is to investigate the role of miR-302a in the development of breast cancer metastasis mediated by CXCR4, a critical regulator of metastasis, and to identify miR-302a as an effective therapeutic agent for therapy and prevention of breast cancer metastasis. Our studies show that miR-302a expression levels were downregulated in metastatic breast cancer cells and tumor tissues. Additionally, the expression levels of miR-302a were inversely correlated with CXCR4 levels. More promisingly, miR-302a inhibited the invasion and metastasis of breast cancer cells in vitro and in vivo and reduced the expression of CXCR4. Our findings demonstrated that the repression of miR-302a levels contributes to breast cancer metastasis and restoration of miR-302a baseline expression inhibits the invasion and metastasis of breast cancer cells. These data suggest that miR-302a mimics are potential therapeutic agents for breast cancer metastasis.

  8. Diagnosis of breast tumors after breast reduction.

    PubMed

    Beer, G M; Kompatscher, P; Hergan, K

    1996-01-01

    We conducted a retrospective study to evaluate the diagnosability of breast tumors after breast reductions as this is a frequent surgical procedure. The data should shed light on the hypothesis that routine screening methods concerning the diagnosis of breast tumors prove more difficult after breast operations. All women who had undergone breast reduction at our department between January 1989 and December 1994 were examined. During this period we counted 166 patients; the majority of them (n = 144) had undergone a bilateral breast reduction and the rest of them (n = 22) a unilateral breast reduction for various reasons. After the operation, all patients were checked in standardized intervals. Those who developed any kind of breast mass (n = 6) were recorded and examined by ultrasound and mammography, and occasionally by an additional fine-needle biopsy. In case any doubt about the dignity had remained, an excisional biopsy was carried out. In none of our patients was it possible to get a precise diagnosis of an ill-defined mass with ultrasound. With mammography, some of the existing masses, which were really scars, mimicked different kinds of tumors, and once a carcinoma was initially interpreted as scar tissue with oil cysts. The diagnosis of breast masses after breast reductions with routinely used screening methods has proved to be more difficult as breast reductions lead to architectural alterations of the remaining breast parenchyma. Such alterations can and should be documented shortly after the operation so that later occurring tumors are distinguished more easily. Therefore, a basic mammography 3 months after each breast reduction has to be claimed in order to facilitate further breast tumor diagnosis.

  9. Cerebellar metastases of recurrent phyllodes tumor breast; a rare phenomenon reflecting the unpredictable outcome.

    PubMed

    Singh, Jyotsna; Majumdar, Kaushik; Gupta, Rahul; Batra, Vineeta Vijay

    2015-01-01

    Carcinomas of lung, breast, colon, kidney, and malignant melanomas are the most common malignancies that metastasize to the central nervous system (CNS). Phyllodes tumor is a rare fibroepithelial tumor of the breast, often having unpredictable recurrences, with increasing histological grade and distant metastasis. Malignant forms exist, which may develop distant metastases usually to the lung, pleura, bone, and liver. CNS metastasis of phyllodes tumor is rare and associated with a poor prognosis, with resistance to chemotherapy and radiation. We present a rare case of cerebellar metastasis in recurrent phyllodes tumor breast with subsequent rapid downhill course.

  10. Lx2-32c–loaded polymeric micelles with small size for intravenous drug delivery and their inhibitory effect on tumor growth and metastasis in clinically associated 4T1 murine breast cancer

    PubMed Central

    Chen, Li-qing; Huang, Wei; Gao, Zhong-gao; Fang, Wei-shuo; Jin, Ming-ji

    2016-01-01

    Lx2-32c is a novel taxane derivative with a strong antitumor activity. In this study, we developed Lx2-32c–loaded polymeric micelles (Lx2-32c-PMs) with small size and investigated their antitumor efficacy against tumor growth and metastasis on 4T1 murine breast cancer cell line with Cremophor EL–based Lx2-32c solution as the control. In this study, copolymer monomethoxy polyethylene glycol2000–polylactide1300 was used to prepare Lx2-32c-PMs by film hydration method, and their physicochemical properties were characterized as well, according to morphology, particle size, zeta potential, in vitro drug release, and reconstitution stability. Under confocal laser scanning microscopy, it was observed that Lx2-32c-PMs could be effectively taken up by 4T1 cells in a time-dependent manner. Cell Counting Kit-8 assay showed that the IC50 of Lx2-32c-PMs was 0.3827 nM. Meanwhile, Lx2-32c-PMs had better ability to promote apoptosis and induce G2/M cycle block and polyploidy formation, compared with Lx2-32c solution. More importantly, in vivo animal studies showed that compared to Lx2-32c solution, Lx2-32c-PMs possessed better ability not only to effectively inhibit the tumor growth, but also to significantly suppress spontaneous and postoperative metastasis to distant organs in 4T1 orthotopic tumor-bearing mice. Consequently, Lx2-32c-PMs have significantly prolonged the survival lifetime of tumor-bearing mice. Thus, our study reveals that Lx2-32c-PMs had favorable antitumor activity and exhibited a good prospect for application in the field of antitumor therapy. PMID:27799769

  11. RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation.

    PubMed

    Morales, Mònica; Arenas, Enrique J; Urosevic, Jelena; Guiu, Marc; Fernández, Esther; Planet, Evarist; Fenwick, Robert Bryn; Fernández-Ruiz, Sonia; Salvatella, Xavier; Reverter, David; Carracedo, Arkaitz; Massagué, Joan; Gomis, Roger R

    2014-07-01

    In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme.

  12. RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation

    PubMed Central

    Morales, Mònica; Arenas, Enrique J; Urosevic, Jelena; Guiu, Marc; Fernández, Esther; Planet, Evarist; Fenwick, Robert Bryn; Fernández-Ruiz, Sonia; Salvatella, Xavier; Reverter, David; Carracedo, Arkaitz; Massagué, Joan; Gomis, Roger R

    2014-01-01

    In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme. PMID:24867881

  13. KLF17 is a negative regulator of epithelial-mesenchymal transition and metastasis in breast cancer

    PubMed Central

    Gumireddy, Kiranmai; Li, Anping; Gimotty, Phyllis A.; Klein-Szanto, Andres J.; Showe, Louise C.; Katsaros, Dionyssios; Coukos, George; Zhang, Lin; Huang, Qihong

    2009-01-01

    Metastasis is a complex multi-step process requiring the concerted action of many genes and is the primary cause of cancer deaths. Pathways that regulate metastasis enhancement and suppression both contribute to tumor dissemination process. In order to identify novel metastasis suppressors, we set up a forward genetic screen in a mouse model. We transduced a genome-wide RNAi library into the non-metastatic 168FARN breast cancer cell line, orthotopically transplanted the cells into mouse mammary fat pads, and then selected for cells that could metastasize to the lung and identified an RNAi for the KLF17 gene. Conversely, we demonstrate that ectopic expression of KLF17 in highly metastatic 4T1 breast cancer cell line inhibited their ability to metastasize from the mammary fat pad to the lung. We also show that suppression of KLF17 expression promotes breast cancer cell invasion and epithelial-mesenchymal transition (EMT) and that KLF17 functions by directly binding to the promoter of Id-1, a key metastasis regulator in breast cancer, to inhibit its transcription. Finally, we demonstrate that KLF17 expression is significantly down-regulated in primary human breast cancer samples and that the combined expression patterns of KLF17 and Id-1 can serve as a potential biomarker for lymph node metastasis in breast cancer. PMID:19801974

  14. Identification of brain- and bone-specific breast cancer metastasis genes.

    PubMed

    Klein, Andreas; Olendrowitz, Christian; Schmutzler, Rita; Hampl, Juergen; Schlag, Peter M; Maass, Nicolai; Arnold, Norbert; Wessel, Ralf; Ramser, Juliane; Meindl, Alfons; Scherneck, Siegfried; Seitz, Susanne

    2009-04-18

    In breast cancer, metastases are relatively widely distributed, with the most common sites being bone, regional lymph nodes, lung, liver, and brain. The detailed mechanism of organ-specific metastasis is poorly understood. In this study, we initiated a search for genes that are implicated in brain or bone metastasis of primary human breast cancer. We generated gene expression profiles of 18 brain and eight bone metastases derived from primary breast tumors. We identified 73 genes differentially expressed between brain and bone metastases. Visualization of the differential gene expression profiles by correspondence and cluster analyses shows that the metastases clearly separate into two distinct groups as an exact reflection of their site of metastasis. Moreover, the analysis of this gene set in primary breast tumors relapsing to either bone or brain allowed accurate categorization of the tumors according to their metastatic site. The identified genes may prove to be excellent markers to predict the site of metastasis in breast cancer patients and could lead to tailor-made therapy to an individual patient.

  15. A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer

    PubMed Central

    Goddard, Erica T.; Fischer, Jacob; Schedin, Pepper

    2016-01-01

    Breast cancer is the leading cause of cancer-related mortality in women worldwide. Liver metastasis is involved in upwards of 30% of cases with breast cancer metastasis, and results in poor outcomes with median survival rates of only 4.8 - 15 months. Current rodent models of breast cancer metastasis, including primary tumor cell xenograft and spontaneous tumor models, rarely metastasize to the liver. Intracardiac and intrasplenic injection models do result in liver metastases, however these models can be confounded by concomitant secondary-site metastasis, or by compromised immunity due to removal of the spleen to avoid tumor growth at the injection site. To address the need for improved liver metastasis models, a murine portal vein injection method that delivers tumor cells firstly and directly to the liver was developed. This model delivers tumor cells to the liver without complications of concurrent metastases in other organs or removal of the spleen. The optimized portal vein protocol employs small injection volumes of 5 - 10 μl, ≥ 32 gauge needles, and hemostatic gauze at the injection site to control for blood loss. The portal vein injection approach in Balb/c female mice using three syngeneic mammary tumor lines of varying metastatic potential was tested; high-metastatic 4T1 cells, moderate-metastatic D2A1 cells, and low-metastatic D2.OR cells. Concentrations of ≤ 10,000 cells/injection results in a latency of ~ 20 - 40 days for development of liver metastases with the higher metastatic 4T1 and D2A1 lines, and > 55 days for the less aggressive D2.OR line. This model represents an important tool to study breast cancer metastasis to the liver, and may be applicable to other cancers that frequently metastasize to the liver including colorectal and pancreatic adenocarcinomas. PMID:28060292

  16. SATB1 tethers multiple gene loci to reprogram expression profiledriving breast cancer metastasis

    SciTech Connect

    Han, Hye-Jung; Kohwi, Yoshinori; Kohwi-Shigematsu, Terumi

    2006-07-13

    Global changes in gene expression occur during tumor progression, as indicated by expression profiling of metastatic tumors. How this occurs is poorly understood. SATB1 functions as a genome organizer by folding chromatin via tethering multiple genomic loci and recruiting chromatin remodeling enzymes to regulate chromatin structure and expression of a large number of genes. Here we show that SATB1 is expressed at high levels in aggressive breast cancer cells, and is undetectable in non-malignant breast epithelial cells. Importantly, RNAi-mediated removal of SATB1 from highly-aggressive MDA-MB-231 cells altered the expression levels of over 1200 genes, restored breast-like acinar polarity in three-dimensional cultures, and prevented the metastastic phenotype in vivo. Conversely, overexpression of SATB1 in the less-aggressive breast cancer cell line Hs578T altered the gene expression profile and increased metastasis dramatically in vivo. Thus, SATB1 is a global regulator of gene expression in breast cancer cells, directly regulating crucial metastasis-associated genes, including ERRB2 (HER2/NEU), TGF-{beta}1, matrix metalloproteinase 3, and metastasin. The identification of SATB1 as a protein that re-programs chromatin organization and transcription profiles to promote breast cancer metastasis suggests a new model for metastasis and may provide means of therapeutic intervention.

  17. Eribulin Mesylate Combined with Local Treatment for Brain Metastasis from Breast Cancer: Two Case Reports.

    PubMed

    Byun, Kyung-Do; Ahn, Sung Gwe; Baik, Hyung Joo; Lee, Anbok; Bae, Ki Beom; An, Min Sung; Kim, Kwang Hee; Shin, Jae Ho; Park, Ha Kyoung; Cho, Heunglae; Jeong, Joon; Kim, Tae Hyun

    2016-06-01

    The prognosis associated with brain metastasis arising from breast cancer is very poor. Eribulin is a microtubule dynamic inhibitor synthesized from halichondrin B, a natural marine product. In a phase III study (EMBRACE), eribulin improved overall survival in patients with heavily pretreated metastatic breast cancers. However, these studies included few patients with brain metastases. Metastatic brain tumors (MBT) were detected during first-line palliative chemotherapy in a 43-year-old woman with breast cancer metastasis to the lung and mediastinal nodes; the genetic subtype was luminal B-like human epidermal growth factor receptor 2 (HER2)-negative. Whole brain radiotherapy (WBRT) followed by eribulin treatment continuously decreased the size, and induced regression, of the MBT with systemic disease stability for 12 months. Another 48-year-old woman with metastatic breast cancer (HER2+ subtype) presented with MBT. Following surgical resection of the tumor, eribulin with concurrent WBRT showed regression of the MBT without systemic progression for 18 months.

  18. An in vitro 3D model using collagen coated gelatin nanofibers for studying breast cancer metastasis.

    PubMed

    Janani, G; Pillai, Mamatha M; Selvakumar, R; Bhattacharyya, Amitava; Sabarinath, C

    2017-02-07

    The study of breast cancer metastasis is limited due to poor knowledge of molecular progression of breast tumor and varied heterogeneity. For a better understanding of tumor metastasis, a reliable 3D in vitro model bridging the gap between 2D cultures and in vivo animal model studies is essential. Our study is focused on two key points: (i) designing a 3D microenvironment for studying metastasis and (ii) simulating the metastasis milieu by inducing epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET). An electrospun gelatin nanofiber matrix (EGNF) was fabricated using electrospinning and further dip coated with different concentrations of collagen to obtain surface complexity and mechanical properties, similar to connective tissues. Nanofiber matrices were physically characterized by Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and field-emission scanning electron microscopy (FESEM). The FTIR, AFM, and FESEM results indicated the crosslinking and confirmed the presence of pores in the nanofiber matrices. Comparative studies on biocompatibility, cell attachment, and the proliferation of MCF-7 cells on EGNF and collagen coated gelatin nanofibrous matrix (CCGM) revealed higher cellular attachment and proliferation in CCGM. CCGM with human metastatic breast cancer cell line (MCF-7) was taken to study breast cancer metastasis using estrogen (induces EMT) and progesterone (induces MET) hormones for 24 h. Quantitative real-time PCR was used for quantifying the expression of metastasis related genes, and fluorescence microscopy for verifying the invasion of cells to the matrices. The expression of E-cadherin and matrix metalloproteinase 2 (MMP 2) confirmed the occurrence of EMT and MET. Live cell imaging and cellular attachment showed significant increase of cellular invasion in crosslinked 0.15% CCGM that serves as a suitable non-toxic, biocompatible, and affordable scaffold for studying breast cancer

  19. G Protein Coupled Receptor Kinase 3 Regulates Breast Cancer Migration, Invasion, and Metastasis

    PubMed Central

    Billard, Matthew J.; Fitzhugh, David J.; Parker, Joel S.; Brozowski, Jaime M.; McGinnis, Marcus W.; Timoshchenko, Roman G.; Serafin, D. Stephen; Lininger, Ruth; Klauber-Demore, Nancy; Sahagian, Gary; Truong, Young K.; Sassano, Maria F.; Serody, Jonathan S.; Tarrant, Teresa K.

    2016-01-01

    Triple negative breast cancer (TNBC) is a heterogeneous disease that has a poor prognosis and limited treatment options. Chemokine receptor interactions are important modulators of breast cancer metastasis; however, it is now recognized that quantitative surface expression of one important chemokine receptor, CXCR4, may not directly correlate with metastasis and that its functional activity in breast cancer may better inform tumor pathogenicity. G protein coupled receptor kinase 3 (GRK3) is a negative regulator of CXCR4 activity, and we show that GRK expression correlates with tumorigenicity, molecular subtype, and metastatic potential in human tumor microarray analysis. Using established human breast cancer cell lines and an immunocompetent in vivo mouse model, we further demonstrate that alterations in GRK3 expression levels in tumor cells directly affect migration and invasion in vitro and the establishment of distant metastasis in vivo. The effects of GRK3 modulation appear to be specific to chemokine-mediated migration behaviors without influencing tumor cell proliferation or survival. These data demonstrate that GRK3 dysregulation may play an important part in TNBC metastasis. PMID:27049755

  20. Vascular targeting of a gold nanoparticle to breast cancer metastasis

    PubMed Central

    Peiris, Pubudu M.; Deb, Partha; Doolittle, Elizabeth; Doron, Gilad; Goldberg, Amy; Govender, Priya; Shah, Shruti; Rao, Swetha; Carbone, Sarah; Cotey, Thomas; Sylvestre, Meilyn; Singh, Sohaj; Schiemann, William P.; Lee, Zhenghong; Karathanasis, Efstathios

    2015-01-01

    The vast majority of breast cancer deaths are due to metastatic disease. While deep tissue targeting of nanoparticles is suitable for some primary tumors, vascular targeting may be a more attractive strategy for micrometastasis. This study combined a vascular targeting strategy with the enhanced targeting capabilities of a nanoparticle to evaluate the ability of a gold nanoparticle to specifically target the early spread of metastatic disease. As a ligand for the vascular targeting strategy, we utilized a peptide targeting alpha(v) beta(3) integrin, which is functionally linked to the development of micrometastases at a distal site. By employing a straightforward radiolabeling method to incorporate Technetium-99m into the gold nanoparticles, we used the high sensitivity of radionuclide imaging to monitor the longitudinal accumulation of the nanoparticles in metastatic sites. Animal and histological studies showed that vascular targeting of the nanoparticle facilitated highly accurate targeting of micrometastasis in the 4T1 mouse model of breast cancer metastasis using radionuclide imaging and a low dose of the nanoparticle. Due to the efficient targeting scheme, 14% of the injected AuNP deposited at metastatic sites in the lungs within 60 min after injection, indicating that the vascular bed of metastasis is a viable target site for nanoparticles. PMID:26036431

  1. Silencing of atp6v1c1 prevents breast cancer growth and bone metastasis.

    PubMed

    Feng, Shengmei; Zhu, Guochun; McConnell, Matthew; Deng, Lianfu; Zhao, Qiang; Wu, Mengrui; Zhou, Qi; Wang, Jinshen; Qi, Jin; Li, Yi-Ping; Chen, Wei

    2013-01-01

    Previous studies have shown that Atp6v1c1, a regulator of the assembly of the V0 and V1 domains of the V-ATPase complex, is up-regulated in metastatic oral tumors. Despite these studies, the function of Atp6v1c1 in tumor growth and metastasis is still unknown. Atp6v1c1's expression in metastatic oral squamous cell carcinoma indicates that Atp6v1c1 has an important function in cancer growth and metastasis. We hypothesized that elevated expression of Atp6v1c1 is essential to cancer growth and metastasis and that Atp6v1c1 promotes cancer growth and metastasis through activation of V-ATPase activity. To test this hypothesis, a Lentivirus-mediated RNAi knockdown approach was used to study the function of Atp6v1c1 in mouse 4T1 mammary tumor cell proliferation and migration in vitro and cancer growth and metastasis in vivo. Our data revealed that silencing of Atp6v1c1 in 4T1 cancer cells inhibited lysosomal acidification and severely impaired 4T1 cell growth, migration, and invasion through Matrigel in vitro. We also show that Atp6v1c1 knockdown with Lenti-c1s3, a lentivirus targeting Atp6v1c1 for shRNA mediated knockdown, can significantly inhibit 4T1 xenograft tumor growth, metastasis, and osteolytic lesions in vivo. Our study demonstrates that Atp6v1c1 may promote breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity, indicating that Atp6v1c1 may be a viable target for breast cancer therapy and silencing of Atp6v1c1 may be an innovative therapeutic approach for the treatment and prevention of breast cancer growth and metastasis.

  2. Huge malignant phyllodes breast tumor: a real entity in a new era of early breast cancer.

    PubMed

    Testori, Alberto; Meroni, Stefano; Errico, Valentina; Travaglini, Roberto; Voulaz, Emanuele; Alloisio, Marco

    2015-02-27

    Phyllodes tumor is an extremely rare tumor of the breast. It occurs in females in the third and fourth decades. The difficulty in distinguishing between phyllodes tumors and benign fibroadenoma may lead to misdiagnosis. Lymph node involvement is rarely described in phyllodes tumors; for this reason, sentinel node biopsy may be warranted. We present a case of a 33-year-old woman affected by huge tumor of the right breast with ulceration in the skin with a rapid tumor growth and with omolateral axillary metastasis.

  3. Role of Runx2 in breast cancer-mediated bone metastasis.

    PubMed

    Vishal, M; Swetha, R; Thejaswini, G; Arumugam, B; Selvamurugan, N

    2017-06-01

    Breast cancer is one of the most prevalent forms of cancer in women. The currently available treatment for breast cancer is mostly curative except when it becomes metastatic. One of the major sites for metastasis of breast cancer is the bone. Homing of the circulating tumor cells is tightly regulated including a number of factors present in the cells and their microenvironment. Runx2, a transcription factor plays an important role in osteogenesis and breast cancer mediated bone metastases. One of the recent advances in molecular therapy includes the discovery of the small, non-coding microRNAs (miRNAs) and they target specific genes to reduce their expression at the post-transcriptional level. This review provides an outline of breast cancer mediated bone metastasis and summarizes the recent development on the regulation of Runx2 expression by miRNAs which can lead to novel molecular therapeutics for the same.

  4. Inhibition of heregulin expression blocks tumorigenicity and metastasis of breast cancer

    SciTech Connect

    Tsai, Miaw-Sheue; Shamon-Taylor, Lisa A.; Mehmi, Inderjit; Tang, Careen K.; Cardillo, Marina; Lupu, Ruth

    2001-12-20

    The growth factor Heregulin (HRG) is expressed in 30% of breast cancer tumors. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether blockage of HRG reduces the aggressiveness of breast cancer cells demonstrated that transfection of MDA-MB-231 with an HRG antisense cDNA suppressed proliferation, tumorigenicity, and metastasis. Blockage of the aggressive phenotype is mediated possibly through inactivation of the erbB signaling pathways and a decrease in MMP-9 activity. Our study is the first to report that HRG is a key promoter of breast cancer progression and should be deemed as a potential target in developing therapies for the treatment of breast carcinomas.

  5. Docosahexaenoic acid suppresses breast cancer cell metastasis by targeting matrix-metalloproteinases

    PubMed Central

    Shin, Soyeon; Kim, Soyeon; Heo, Jun-Young; Kweon, Gi-Ryang; Wu, Tong; Park, Jong-Il; Lim, Kyu

    2016-01-01

    Breast cancer is one of the most prevalent cancers in women, and nearly half of breast cancer patients develop distant metastatic disease after therapy. Despite the significant advances that have been achieved in understanding breast cancer metastasis in the past decades, metastatic cancer is still hard to cure. Here, we demonstrated an anti-cancer mechanism of docosahexaenoic acid (DHA) that suppressed lung metastasis in breast cancer. DHA could inhibit proliferation and invasion of breast cancer cells in vitro, and this was mainly through blocking Cox-2-PGE2-NF-κB-MMPs cascades. DHA treatment significantly decreased Cox-2 and NF-κB expression as well as nuclear translocation of NF-κB in MDA-MB-231 cells. In addition, DHA also reduced NF-κB binding to DNA which may lead to inactivation of MMPs. Moreover, in vivo studies using Fat-1 transgenic mice showed remarkable decrease of tumor growth and metastasis to EO771 cells to lung in DHA-rich environment. In conclusion, DHA attenuated breast cancer progression and lung metastasis in part through suppressing MMPs, and these findings suggest chemoprevention and potential therapeutic strategy to overcome malignant breast cancer. PMID:27363023

  6. Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis

    PubMed Central

    Das Roy, Lopamudra; Pathangey, Latha B; Tinder, Teresa L; Schettini, Jorge L; Gruber, Helen E; Mukherjee, Pinku

    2009-01-01

    Introduction Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis. Methods To determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice. Results We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor

  7. Hypoxia-inducible factor 1 and breast cancer metastasis*

    PubMed Central

    Liu, Zhao-ji; Semenza, Gregg L.; Zhang, Hua-feng

    2015-01-01

    Accumulating evidence has shown that the hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating breast cancer progression and metastasis. The effects of hypoxia-inducible factor 1 (HIF-1), a master regulator of the hypoxic response, have been extensively studied during these processes. In this review, we focus on the roles of HIF-1 in regulating breast cancer cell metastasis, specifically its effects on multiple key steps of metastasis, such as epithelial-mesenchymal transition (EMT), invasion, extravasation, and metastatic niche formation. We also discuss the roles of HIF-1-regulated non-coding RNAs in breast cancer metastasis, and therapeutic opportunities for breast cancer through targeting the HIF-1 pathway. PMID:25559953

  8. Left adrenal gland metastasis of breast invasive ductal carcinoma: A case report.

    PubMed

    He, Tao; Liu, Jiaju; Li, Yifan; Jin, L U; Sun, Shuolei; Ni, Liangchao; Mao, Xiangming; Yang, Shangqi; Lai, Yongqing

    2016-05-01

    The majority of the metastatic lesions of the adrenal gland normally originate from lung cancer, colon malignant tumor, renal cell carcinoma and melanoma. However, adrenal gland metastasis that metastasize from breast invasive ductal carcinoma are extremely rare. The present study reported a rare case of left adrenal gland metastasis in a 35-year-old female who was diagnosed as breast carcinoma 5 years ago with a mass located on the left adrenal gland, which was detected during a routine examination. The patient was asymptomatic and adrenal gland computed tomography revealed a mass in the left adrenal gland. Definitive preoperative diagnosis failed to be established. Left adrenal gland laparoscopic adrenalectomy was performed and the diagnosis of adrenal gland metastasis of breast invasive ductal carcinoma was confirmed by pathological and immunohistochemical examination. The patient remained in good condition by the time of writing.

  9. The Role of Megakaryocytes in Breast Cancer Metastasis to Bone

    DTIC Science & Technology

    2011-05-01

    and TPO -/- mice, and femurs collected over time. Bone cytokines also will be assessed. 15. SUBJECT TERMS Megakaryocytes, breast cancer, bone...conditions of metastasis or non-metastasis. Thrombopoietin ( TPO -/-) knockout mice will be used to test metastasis in mice with a megakaryocyte deficiency...1. Begin the process of creating TPO -/-mice on a Balb/c background. We had received permission from Genentech to obtain frozen embryos of TPO

  10. Comparison of Monofractal, Multifractal and gray level Co-occurrence matrix algorithms in analysis of Breast tumor microscopic images for prognosis of distant metastasis risk.

    PubMed

    Rajković, Nemanja; Kolarević, Daniela; Kanjer, Ksenija; Milošević, Nebojša T; Nikolić-Vukosavljević, Dragica; Radulovic, Marko

    2016-10-01

    Breast cancer prognosis is a subject undergoing intense study due to its high clinical relevance for effective therapeutic management and a great patient interest in disease progression. Prognostic value of fractal and gray level co-occurrence matrix texture analysis algorithms has been previously established on tumour histology images, but without any direct performance comparison. Therefore, this study was designed to compare the prognostic power of the monofractal, multifractal and co-occurrence algorithms on the same set of images. The investigation was retrospective, with 51 patients selected on account of non-metastatic IBC diagnosis, stage IIIB. Image analysis was performed on digital images of primary tumour tissue sections stained with haematoxylin/eosin. Bootstrap-corrected Cox proportional hazards regression P-values indicated a significant association with metastasis outcome of at least one of the features within each group. AUC values were far better for co-occurrence (0.66-0.77) then for fractal features (0.60-0.64). Correction by the split-sample cross-validation likewise indicated the generalizability only for the co-occurrence features, with their classification accuracies ranging between 67 and 72 %, while accuracies of monofractal and multifractal features were reduced to nearly random 52-55 %. These findings indicate for the first time that the prognostic value of texture analysis of tumour histology is less dependent on the morphological complexity of the image as measured by fractal analysis, but predominantly on the spatial distribution of the gray pixel intensities as calculated by the co-occurrence features.

  11. Site of metastasis and breast cancer mortality: a Danish nationwide registry-based cohort study.

    PubMed

    Ording, Anne Gulbech; Heide-Jørgensen, Uffe; Christiansen, Christian Fynbo; Nørgaard, Mette; Acquavella, John; Sørensen, Henrik Toft

    2017-01-01

    Survival among patients with metastatic breast cancer may vary according to the site of metastasis and receptor status. We used Danish nationwide medical registries to establish a cohort of patients with metastatic breast cancer (870 with de novo metastatic disease and 3518 with recurrent disease with distant metastasis) diagnosed during 1997-2011. We examined 1-year and >1 to 5-year mortality associated with first site of metastasis and receptor expression status of the primary tumor. Cox proportional regression was used to compute confounder-adjusted mortality rate ratios (MRRs) associated with site of metastasis, stratified by receptor status. Overall 1-year and >1 to 5-year mortality risks were 36 and 69 %, respectively. Risk of death within 1 year was highest for brain-only (62 %) and liver-only (43 %) involvement and nearly the same for patients with lung-only (32 %), bone-only (32 %) involvement, and other/combination of sites (34 %). Using bone-only metastasis as reference, women with brain-only metastasis had more than two-fold increased risk of dying. The adjusted MRR for women with liver-only metastasis also was increased, though less pronounced. Patients with lung-only [adjusted MRR 0.9 (95 % confidence interval (CI) 0.8, 1.1)] or other metastases [adjusted MRR 1.0 (95 % CI 0.9, 1.2)] had similar mortality as patients with bone-only metastasis. Positive hormonal receptor status was a favorable prognostic factor. Metastatic breast cancer has a serious prognosis. Patients with brain-only metastasis had the highest mortality. Positive hormonal receptor status on the primary tumor was a favorable prognostic factor for all metastatic sites.

  12. Transcription factor ATF3 links host adaptive response to breast cancer metastasis

    PubMed Central

    Wolford, Chris C.; McConoughey, Stephen J.; Jalgaonkar, Swati P.; Leon, Marino; Merchant, Anand S.; Dominick, Johnna L.; Yin, Xin; Chang, Yiseok; Zmuda, Erik J.; O’Toole, Sandra A.; Millar, Ewan K.A.; Roller, Stephanie L.; Shapiro, Charles L.; Ostrowski, Michael C.; Sutherland, Robert L.; Hai, Tsonwin

    2013-01-01

    Host response to cancer signals has emerged as a key factor in cancer development; however, the underlying molecular mechanism is not well understood. In this report, we demonstrate that activating transcription factor 3 (ATF3), a hub of the cellular adaptive response network, plays an important role in host cells to enhance breast cancer metastasis. Immunohistochemical analysis of patient tumor samples revealed that expression of ATF3 in stromal mononuclear cells, but not cancer epithelial cells, is correlated with worse clinical outcomes and is an independent predictor for breast cancer death. This finding was corroborated by data from mouse models showing less efficient breast cancer metastasis in Atf3-deficient mice than in WT mice. Further, mice with myeloid cell–selective KO of Atf3 showed fewer lung metastases, indicating that host ATF3 facilitates metastasis, at least in part, by its function in macrophage/myeloid cells. Gene profiling analyses of macrophages from mouse tumors identified an ATF3-regulated gene signature that could distinguish human tumor stroma from distant stroma and could predict clinical outcomes, lending credence to our mouse models. In conclusion, we identified ATF3 as a regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes. PMID:23921126

  13. Breast cancer and metastasis: on the way toward individualized therapy.

    PubMed

    Trapé, Adriana Priscila; Gonzalez-Angulo, Ana Maria

    2012-01-01

    Breast cancer (BC) remains the most common cancer type diagnosed in women. Although targeted therapies have improved patient survival for advanced BC, these tumors frequently relapse due to drug resistance mechanisms. A systems biology approach integrates DNA, RNA and protein alterations generated from multidimensional platforms to better understand the mechanisms that regulate the metastatic process. Downstream functional analyses in pre-clinical studies might integrate the role of these aberrations into the cell, leading to discovery of new therapeutic targets. In the present report, we review relevant findings associated with genomic, transcriptomic and proteomic analyses and the contribution of the systems biology concept to the interpretation of these data in the metastatic context. Also, we highlight the importance of re-designing clinical trials towards metastasis prevention for improvement of personalized care.

  14. Monitoring Metastasis and Cachexia in a Patient with Breast Cancer: A Case Study

    PubMed Central

    Consul, Nikita; Guo, Xiaotao; Coker, Courtney; Lopez-Pintado, Sara; Hibshoosh, Hanina; Zhao, Binsheng; Kalinsky, Kevin; Acharyya, Swarnali

    2016-01-01

    Cachexia, a wasting syndrome associated with advanced cancer and metastasis, is rarely documented in breast cancer patients. However, the incidence of cachexia in breast cancer is now thought to be largely underestimated. In our case report of a breast cancer patient with bone metastasis monitored during the course of her treatment, we document the development of cachexia by image analysis in relation to her metastatic burden. Elucidation of the link between metastatic burden and cachexia could unveil a highly specific screening process for metastasis, by assessing true muscle mass loss. Our patient was a 49-year-old premenopausal woman, with metastatic invasive ductal breast carcinoma in the vertebral and iliac bones on presentation, which progressed with new metastases to her hips, thigh bones, and vertebrae. In the two-year period, that is between her diagnosis and death, she lost >10% of her baseline weight. During these two years, we retrospectively identified a decrease in paraspinal muscle (PM) at the third lumbar vertebra followed by a sharp decline in weight. The increased tumor burden over time in metastatic sites was accompanied by a decrease in abdominal muscle and visceral and subcutaneous fat and was followed by the patient’s demise. The increasing tumor burden in the patient was correlated with the mass of other tissues to determine the tissue that could best serve as a surrogate marker to cachexia and tumor burden. We noted a strong negative correlation between PM area and metastatic tumor area at the third lumbar vertebral level, with PM loss correlating to increasing tumor burden. The monitoring of PM wasting may serve as a marker, and therefore a prognostic factor, for both cachexia and extent of metastatic disease, especially in breast cancer, where metastasis to bone is frequent. Based on our data and review of the literature in this case study, longitudinal monitoring of cachexia in the selected muscle groups can give clinicians early

  15. [Breast metastasis of a squamous cell carcinoma of the uterine cervix. A case report].

    PubMed

    Yordanov, Y; Dimitrova, P

    2015-01-01

    The breast is an extremely rare target organ for metastasis of extramammary neoplasms. The occurence varies between 1.7% to 6.6% in autopsies; between 1.2% and 2% in clinical cases; and around 2.7% in sputum series. In accordance with the primary tumor localization, it is more common to find metastases of lymphoma, melanoma, rhabdomyosarcoma, tumors of the lung and ovarian tumors. Breast metastasis of the uterine cervix is a very seldomly found. According to the published literature so far there have been around 30 documented cases with such pathology. This study presents the case of a 48-year-old female with a squamous cell carcinoma of the uterine cervix, which was histologically verified in 2010. Three years after the initial tumor diagnosis, radiotherapy and chemotherapy, the patient was found to have a cystic tumor formation in one of her breasts. The formation was painful to pressure. Quadrantectomy with an open bisopsy was performed to the patient. Histological and immunohistochemical diagnosis rejected primary squamous cell carcinoma of the breast. The differential diagnosis of metastatic lesions in the breast is problematic and requires careful clinical history, immunohistochemical study and multidisciplinary approach in the management. Mammary metastases are a bad predictor and they serve as an indicator of generalized dissemination of the primary tumor process.

  16. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and T regulatory cells

    PubMed Central

    Olkhanud, Purevdorj B.; Baatar, Dolgor; Bodogai, Monica; Hakim, Fran; Gress, Ronald; Anderson, Robin L.; Deng, Jie; Xu, Mai; Briest, Susanne; Biragyn, Arya

    2009-01-01

    Cancer metastasis is a leading cause of cancer morbidity and mortality. More needs to be learned about mechanisms that control this process. In particular, the role of chemokine receptors in metastasis remains controversial. Here, using a highly metastatic breast cancer (4T1) model, we demonstrate that lung metastasis is a feature of only a proportion of the tumor cells that express CCR4. Moreover, the primary tumor growing in mammary pads activates remotely the expression of TARC/CCL17 and MDC/CCL22 in the lungs. These chemokines acting through CCR4 attract both tumor and immune cells. However, CCR4 mediated chemotaxis was not sufficient to produce metastasis, as tumor cells in the lung were efficiently eliminated by NK cells. Lung metastasis required CCR4+ Tregs which directly killed NK cells utilizing beta-galactoside-binding protein. Thus, strategies that abrogate any part of this process should improve the outcome through activation of effector cells and prevention of tumor cell migration. We confirm this prediction by killing CCR4+ cells through delivery of TARC-fused toxins or depleting Tregs and preventing lung metastasis. PMID:19567680

  17. E3 ubiquitin ligase UBR5 drives the growth and metastasis of triple negative breast cancer.

    PubMed

    Liao, Liqiu; Song, Mei; Li, Xin; Tang, Lili; Zhang, Tuo; Zhang, Lixing; Pan, Yihang; Chouchane, Lotfi; Ma, Xiaojing

    2017-03-22

    Patients with triple negative breast cancers (TNBC) are at high risk for recurrence and metastasis at an early time despite standard treatment, underscoring the need for novel therapeutic modalities. Here we report for the first time a distinctive and profound role of the E3 ubiquitin ligase UBR5 in the growth and metastasis of TNBC. An analysis of primary TNBC specimen by whole exon sequencing revealed strong gene amplifications of UBR5 associated with the disease. UBR5 overexpression in TNBC tissues was confirmed at mRNA and protein levels. CRISPR/Cas9-mediated deletion of ubr5 in an experimental murine mammary carcinoma model of TNBC dramatically abrogated tumor growth and metastasis in vivo, which could be reversed completely via reconstitution with wild type UBR5 but not a catalytically inactive mutant. Loss of UBR5 caused an impairment in angiogenesis within the tumor, associated with increased apoptosis, necrosis, and growth arrest. Absence of UBR5 in the tumor triggered aberrant epithelial to mesenchymal transition (EMT), principally via abrogated expression of E-cadherin, which resulted in severely reduced tumor metastasis to secondary organs. Use of NOD/SCID mice revealed that tumor-derived UBR5 facilitated tumor growth in a manner completely dependent upon immune cells in the microenvironment, whereas it promoted metastasis in a tumor cell-autonomous fashion. Our findings unveil UBR5 as a novel and critical regulator of tumor growth, metastasis, and immune response, and highlight the potential for UBR5 as an effective therapeutic target for the treatment of highly aggressive breast and ovarian cancers that fail conventional therapy.

  18. Patrolling Monocytes Control Tumor Metastasis to the Lung

    PubMed Central

    Hanna, Richard N.; Cekic, Caglar; Sag, Duygu; Tacke, Robert; Thomas, Graham D.; Nowyhed, Heba; Herrley, Erica; Rasquinha, Nicole; McArdle, Sara; Wu, Runpei; Peluso, Esther; Metzger, Daniel; Ichinose, Hiroshi; Shaked, Iftach; Chodaczek, Grzegorz; Biswas, Subhra K.; Hedrick, Catherine C.

    2016-01-01

    The immune system plays an important role in regulating tumor growth and metastasis. For example, classical monocytes promote tumorigenesis and cancer metastasis; however, how nonclassical “patrolling” monocytes interact with tumors is unknown. Here we show that patrolling monocytes are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack patrolling monocytes, showed increased lung metastasis in vivo. Transfer of Nr4a1-proficient patrolling monocytes into Nr4a1-deficient mice prevented tumor invasion in lung. Patrolling monocytes established early interactions with metastasizing tumor cells, scavenged tumor material from the lung vasculature and promoted natural killer cell recruitment and activation. Thus, patrolling monocytes contribute to cancer immunosurveillance and may be targets for cancer immunotherapy. PMID:26494174

  19. Inhibition of tumor growth and metastasis by photoimmunotherapy targeting tumor-associated macrophage in a sorafenib-resistant tumor model.

    PubMed

    Zhang, Chenran; Gao, Liquan; Cai, Yuehong; Liu, Hao; Gao, Duo; Lai, Jianhao; Jia, Bing; Wang, Fan; Liu, Zhaofei

    2016-04-01

    Tumor-associated macrophages (TAMs) play essential roles in tumor invasion and metastasis, and contribute to drug resistance. Clinical evidence suggests that TAM levels are correlated with local tumor relapse, distant metastasis, and poor prognosis in patients. In this study, we synthesized a TAM-targeted probe (IRD-αCD206) by conjugating a monoclonal anti-CD206 antibody with a near-infrared phthalocyanine dye. We then investigated the potential application of the IRD-αCD206 probe to near-infrared fluorescence (NIRF) imaging and photoimmunotherapy (PIT) of tumors resistant to treatment with the kinase inhibitor sorafenib. Sorafenib treatment had no effect on tumor growth in a 4T1 mouse model of breast cancer, but induced M2 macrophage polarization in tumors. M2 macrophage recruitment by sorafenib-treated 4T1 tumors was noninvasively visualized by in vivo NIRF imaging of IRD-αCD206. Small-animal single-photon emission computed tomography (SPECT)/CT and intratumoral microdistribution analysis indicated TAM-specific localization of the IRD-αCD206 probe in 4T1 tumors after several rounds of sorafenib treatment. Upon light irradiation, IRD-αCD206 suppressed the growth of sorafenib-resistant tumors. In vivo CT imaging and ex vivo histological analysis confirmed the inhibition of lung metastasis in mice by IRD-αCD206 PIT. These results demonstrate the utility of the IRD-αCD206 probe for TAM-targeted diagnostic imaging and treatment of tumors that are resistant to conventional therapeutics.

  20. Therapy of leptomeningeal metastasis in solid tumors.

    PubMed

    Mack, F; Baumert, B G; Schäfer, N; Hattingen, E; Scheffler, B; Herrlinger, U; Glas, M

    2016-02-01

    Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.

  1. MicroRNA-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis.

    PubMed

    Cai, Junchao; Guan, Hongyu; Fang, Lishan; Yang, Yi; Zhu, Xun; Yuan, Jie; Wu, Jueheng; Li, Mengfeng

    2013-02-01

    Tumor metastasis involves a series of biological steps during which the tumor cells acquire the ability to invade surrounding tissues and survive outside the original tumor site. During the early stages, the cancer cells undergo an epithelial-mesenchymal transition (EMT). Wnt/β-catenin signaling is known to drive EMT and metastasis. Here we report that Wnt/β-catenin signaling is hyperactivated in metastatic breast cancer cells that express microRNA 374a (miR-374a). In breast cancer cell lines, ectopic overexpression of miR-374a promoted EMT and metastasis both in vitro and in vivo. Furthermore, miR-374a directly targeted and suppressed multiple negative regulators of the Wnt/β-catenin signaling cascade, including WIF1, PTEN, and WNT5A. Notably, miR-374a was markedly upregulated in primary tumor samples from patients with distant metastases and was associated with poor metastasis-free survival. These results demonstrate that miR-374a maintains constitutively activated Wnt/β-catenin signaling and may represent a therapeutic target for early metastatic breast cancer.

  2. In Vivo Evidence for the Role of CD44s in Promoting Breast Cancer Metastasis to the Liver

    PubMed Central

    Ouhtit, Allal; Abd Elmageed, Zakaria Y.; Abdraboh, Mohamed E.; Lioe, Tong F.; Raj, Madhwa H.G.

    2007-01-01

    The hyaluronan receptor CD44 plays an important role in facilitating invasion and metastasis of a variety of tumors, including breast carcinomas. CD44 functions as a bioactive signaling transmitter. Although a number of studies have implicated CD44 in breast tumor invasion, the evidence is still circumstantial. We have developed a tetracycline-regulated CD44s (standard form) system in the weakly metastatic breast cancer cell MCF7, which exhibits low endogenous expression of CD44 and generated a new cell line, MCF7F-B5. Induction of CD44s alone affected the growth characteristics of MCF7F-B5 cells by increasing their abilities to proliferate, migrate, and invade in vitro. In addition, we have identified and validated cortactin as a novel transcriptional target of hyaluronan/CD44s signaling in underpinning breast tumor invasion. To test these observations in vivo, we developed a doxycycline (DOX)-regulated CD44s breast cancer xenograft model. Induction of CD44s did not affect the growth rate or local invasion of the primary tumor. However, although no mice from the +DOX group developed metastasis, 8 of 11 mice from the −DOX group developed secondary tumors to the liver only. Interestingly, metastatic breast tumors expressed high levels of CD44. This study provides in vivo evidence for the role of the standard form of CD44 in promoting breast tumor invasion and metastasis to the liver. PMID:17991717

  3. In vivo evidence for the role of CD44s in promoting breast cancer metastasis to the liver.

    PubMed

    Ouhtit, Allal; Abd Elmageed, Zakaria Y; Abdraboh, Mohamed E; Lioe, Tong F; Raj, Madhwa H G

    2007-12-01

    The hyaluronan receptor CD44 plays an important role in facilitating invasion and metastasis of a variety of tumors, including breast carcinomas. CD44 functions as a bioactive signaling transmitter. Although a number of studies have implicated CD44 in breast tumor invasion, the evidence is still circumstantial. We have developed a tetracycline-regulated CD44s (standard form) system in the weakly metastatic breast cancer cell MCF7, which exhibits low endogenous expression of CD44 and generated a new cell line, MCF7F-B5. Induction of CD44s alone affected the growth characteristics of MCF7F-B5 cells by increasing their abilities to proliferate, migrate, and invade in vitro. In addition, we have identified and validated cortactin as a novel transcriptional target of hyaluronan/CD44s signaling in underpinning breast tumor invasion. To test these observations in vivo, we developed a doxycycline (DOX)-regulated CD44s breast cancer xenograft model. Induction of CD44s did not affect the growth rate or local invasion of the primary tumor. However, although no mice from the +DOX group developed metastasis, 8 of 11 mice from the -DOX group developed secondary tumors to the liver only. Interestingly, metastatic breast tumors expressed high levels of CD44. This study provides in vivo evidence for the role of the standard form of CD44 in promoting breast tumor invasion and metastasis to the liver.

  4. Axillary metastasis as first symptom of occult breast cancer: a case report.

    PubMed

    Frattaroli, Fabrizio Maria; Carrara, Alessandro; Conte, Anna Maria; Pappalardo, Giuseppe

    2002-01-01

    Axillary lymph node metastasis from an occult breast carcinoma is a rare occurrence. We report this condition in a 59-year-old woman who presented with a swelling in the right axilla. No breast mass was clinically evident. Mammography, ultrasonography and multiple random fine-needle breast biopsies yielded no pathological findings. No extramammary primary lesions were present. Axillary sampling was performed and histological examination revealed the presence of metastatic adenocarcinoma in three of the 12 dissected lymph nodes. Estrogen receptors were positive and immunohistochemistry pointed to a breast origin. All these data were suggestive of occult breast cancer. The patient refused any further treatment but accepted clinical and radiological follow-up. Eight years later mammography revealed in the same breast a 10-mm nodule containing microcalcifications, which was not evident at physical examination. The patient underwent a lumpectomy. Intraoperative histology was positive for breast carcinoma and complete axillary clearance was performed. Histological examination revealed a lobular invasive breast carcinoma and the presence of micrometastasis in one of the 23 removed lymph nodes. The patient was given radiotherapy to the breast and axilla and tamoxifen. At present, one year after the appearance of the primary tumor, she is free of disease. Based on this case report we suggest an eclectic approach in the management of patients with axillary metastasis from occult breast cancer, depending on the clinical, pathological and biological findings.

  5. Platelet aggregation in the formation of tumor metastasis

    PubMed Central

    Tsuruo, Takashi; Fujita, Naoya

    2008-01-01

    Metastasis is the major cause of death from cancer, yet the optimal strategy against it remains uncertain. The pathogenesis of hematogenous metastasis is dynamic and consists of the following steps: 1) detachment of tumor cells from the primary site, 2) invasion into the host’s blood vessels, 3) migration in the host’s blood stream, 4) transport along the circulation, 5) arrest in or adhesion to the capillary in a distant organ, 6) extravasation, and 7) proliferation within the foreign tissues. A key to successful hematogenous metastasis is tumor survival in the bloodstream because most circulating tumor cells are rapidly destroyed by the shear forces or are attacked by the immune system. Less than 0.01% of these cells result in metastasis. Tumor cell–induced platelet aggregation has been reported to facilitate hematogenous metastasis by increasing the arrest of tumor cell emboli in the microcirculation. Platelet aggregation is also believed to protect tumor cells from immunological assault in the circulation. We have identified Aggrus as a platelet–aggregating factor expressed on a number of human cancers. Because hematogenous metastasis is reduced when neutralizing antibodies or eliminating carbohydrates attenuates Aggrus function, Aggrus’s main contribution to hematogenous metastasis of Aggrus–expressing cells, then, is by promoting platelet aggregation. Aggrus could serve as an ideal target for drug development to block metastasis. PMID:18941298

  6. Targeting Master Regulators of the Breast Cancer Metastasis Transcriptome

    DTIC Science & Technology

    2014-07-01

    dependence of breast cancer metastasis on our candidates in both hormone positive and negative breast cancers. We will study the physiologic basis of how...Andreoli MA, di Loreto C et al. HPV16 oncoproteins induce MMPs/RECK-TIMP-2 imbalance in primary keratino- cytes: possible implications in cervical

  7. The anthraquinone derivative Emodin inhibits angiogenesis and metastasis through downregulating Runx2 activity in breast cancer.

    PubMed

    Ma, Junchao; Lu, Hong; Wang, Shan; Chen, Bin; Liu, Zhaojie; Ke, Xiaoqin; Liu, Ting; Fu, Jianjiang

    2015-04-01

    Emodin (EMD) is an anthraquinone derivative extracted from the root and rhizome of Rheum palmatum L. which exhibits a range of activities, including anti-bacterial, antitumor, diuretic and vasorelaxant effects. The ability to inhibit metastasis and angiogenesis was shown in previous pharmacological studies, but clear information to address EMD affecting angiogenesis and metastasis in human breast cancer is still lacking. In the present study, we evaluated a possible role for EMD in angiogenesis and metastasis induced by breast cancer cells. It was revealed here that EMD attenuated tumor cell-induced metastasis and angiogenesis both in vitro and in vivo. Furthermore, it was found that these inhibitory effects were caused by MMPs and VEGFR-2 inhibition in metastatic breast cancer cells and endothelial cells, respectively. Western blot analysis showed reduction of Runx2 activation in the EMD-treated cells. ELISA based Runx2 transcription factor assay showed that the interaction between Runx2 and target sequences was inhibited by EMD. Our findings suggested that the inhibitory effects of EMD on tumor-induced metastasis and angiogenesis were caused by MMPs and VEGFR-2 inhibition, which may be associated with the downregulation of Runx2 transcriptional activity.

  8. Hydrogen-bonded and reduction-responsive micelles loading atorvastatin for therapy of breast cancer metastasis.

    PubMed

    Xu, Pengfei; Yu, Haijun; Zhang, Zhiwen; Meng, Qingshuo; Sun, Huiping; Chen, Xianzhi; Yin, Qi; Li, Yaping

    2014-08-01

    Metastasis is one of the major obstacles for the successful therapy of breast cancer. Although increased candidate drugs targeting cancer metastasis are tested, their clinical translation is limited by either serve toxicity or low efficacy. In present work, a nano-drug delivery system loading atorvastatin calcium (Ator) was developed for the efficient suppression of the metastasis of breast cancer. The nano-drug delivery system was constructed by a amphiphilic copolymer of methoxy polyethylene glycol-s-s-vitamin E succinate (mPEG-s-s-VES, PSV), which was consisted of a hydrophilic mPEG1k segment and a hydrophobic VES head, which were conjugated with a linker bearing amide and disulfide groups simultaneously. Self-assembly of PSV and Ator formed Ator-loaded PSV micelles (ASM) with good colloidal stability, high drug loading content (up to 50%) and great encapsulation efficiency (99.09 ± 0.28%). In cellular level, it was found that the ASM could efficiently release the Ator payload into cytosol due to detachment of PEG shell at high intracellular glutathione condition. ASM could significantly inhibit the migration and invasion of 4T1 breast cancer cells with inhibitory rates of 79.2% and 88.5%, respectively. In a 4T1 orthotropic mammary tumor metastatic cancer model, it was demonstrated that ASM could completely blocked the lung and liver metastasis of breast cancer with minimal toxicity owing to enhanced Ator accumulation in tumor and lung as compared with that of free Ator. The down-regulations of metastasis-promoting MMP-9, Twist and uPA proteins were demonstrated as the main underlying mechanism. As a result, ASM could be a promising drug delivery system for the efficient therapy of breast cancer metastasis.

  9. cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction

    SciTech Connect

    Son, Jieun; Lee, Jong-Ho; Kim, Ha-Neui; Ha, Hyunil Lee, Zang Hee

    2010-07-23

    Research highlights: {yields} CREB is highly expressed in advanced breast cancer cells. {yields} Tumor-related factors such as TGF-{beta} further elevate CREB expression. {yields} CREB upregulation stimulates metastatic potential of breast cancer cells. {yields} CREB signaling is required for breast cancer-induced bone destruction. -- Abstract: cAMP-response-element-binding protein (CREB) signaling has been reported to be associated with cancer development and poor clinical outcome in various types of cancer. However, it remains to be elucidated whether CREB is involved in breast cancer development and osteotropism. Here, we found that metastatic MDA-MB-231 breast cancer cells exhibited higher CREB expression than did non-metastatic MCF-7 cells and that CREB expression was further increased by several soluble factors linked to cancer progression, such as IL-1, IGF-1, and TGF-{beta}. Using wild-type CREB and a dominant-negative form (K-CREB), we found that CREB signaling positively regulated the proliferation, migration, and invasion of MDA-MB-231 cells. In addition, K-CREB prevented MDA-MB-231 cell-induced osteolytic lesions in a mouse model of cancer metastasis. Furthermore, CREB signaling in cancer cells regulated the gene expression of PTHrP, MMPs, and OPG, which are closely involved in cancer metastasis and bone destruction. These results indicate that breast cancer cells acquire CREB overexpression during their development and that this CREB upregulation plays an important role in multiple steps of breast cancer bone metastasis.

  10. Host B7x promotes pulmonary metastasis of breast cancer

    PubMed Central

    Abadi, Yael M.; Jeon, Hyungjun; Ohaegbulam, Kim C.; Scandiuzzi, Lisa; Ghosh, Kaya; Hofmeyer, Kimberly A.; Lee, Jun Sik; Ray, Anjana; Gravekamp, Claudia; Zang, Xingxing

    2013-01-01

    B7x (B7-H4 or B7S1) is an inhibitory member of the B7 family of T cell costimulation. It is expressed in low levels in healthy peripheral tissues such as the lung epithelium, but over-expressed in a variety of human cancers with negative clinical associations including metastasis. However, the function of B7x in the cancer context, whether expressed on cancer cells or on surrounding “host” tissues, has not been elucidated in vivo. We utilized the 4T1 metastatic breast cancer model and B7x knockout (B7x−/−) mice to investigate the effect of host tissue-expressed B7x on cancer. We found that 4T1 cells were B7x negative in vitro and in vivo and B7x−/− mice had significantly fewer lung 4T1 tumor nodules than wildtype mice. Furthermore, B7x−/− mice showed significantly enhanced survival and a memory response to tumor rechallenge. Mechanistic studies revealed that the presence of B7x correlated with reduced general and tumor-specific T cell cytokine responses, as well as with an increased infiltration of immunosuppressive cells, including tumor associated neutrophils (TANs), macrophages, and regulatory T cells into tumor-bearing lungs. Importantly, the TANs strongly bound B7x protein and inhibited proliferation of both CD4 and CD8 T cells. These results suggest that host B7x may enable metastasizing cancer cells to escape local anti-tumor immune responses through interactions with the innate as well as the adaptive immune systems. Targeting the B7x pathway thus holds much promise for improving the efficacy of immunotherapy for metastatic cancer. PMID:23455497

  11. Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer.

    PubMed

    Wu, Kerui; Fukuda, Koji; Xing, Fei; Zhang, Yingyu; Sharma, Sambad; Liu, Yin; Chan, Michael D; Zhou, Xiaobo; Qasem, Shadi A; Pochampally, Radhika; Mo, Yin-Yuan; Watabe, Kounosuke

    2015-04-10

    Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis.

  12. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages

    PubMed Central

    Kitamura, Takanori; Qian, Bin-Zhi; Soong, Daniel; Cassetta, Luca; Noy, Roy; Sugano, Gaël; Kato, Yu; Li, Jiufeng

    2015-01-01

    Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM–cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets. PMID:26056232

  13. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.

    PubMed

    Kitamura, Takanori; Qian, Bin-Zhi; Soong, Daniel; Cassetta, Luca; Noy, Roy; Sugano, Gaël; Kato, Yu; Li, Jiufeng; Pollard, Jeffrey W

    2015-06-29

    Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM-cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets.

  14. Breast metastasis from a pulmonary adenocarcinoma: Case report and review of the literature

    PubMed Central

    SANGUINETTI, ALESSANDRO; PUMA, FRANCESCO; LUCCHINI, ROBERTA; SANTOPRETE, STEFANO; CIROCCHI, ROBERTO; CORSI, ALESSIA; TRIOLA, ROBERTA; AVENIA, NICOLA

    2013-01-01

    Breast metastasis from extra-mammary malignancy is rare. An incidence of 0.4–1.3% has been reported in the literature. The primary malignancies most commonly metastasizing to the breast are leukemia, lymphoma and malignant melanoma. We present a case of metastasis to the breast from a pulmonary adenocarcinoma, diagnosed concomitantly with the primary tumor. A 43-year-old female presented with dyspnea and a dry cough of 3 weeks’ duration. A subsequent chest radiograph revealed a massive pleural effusion. Additionally, on physical examination, a poorly defined mass was noted in the upper outer quadrant of the right breast. The patient underwent bronchoscopy, simple right mastectomy and medical thoracoscopy. Following cytology, histology and immunohistochemistry, primary lung adenocarcinoma with metastasis to the breast and parietal pleura was diagnosed. Histologically, both the primary and metastatic anatomic sites demonstrated a micropapillary component, which has recently been recognized as an important prognostic factor. Although the patient received chemotherapy, she succumbed to her condition within 8 months. Accurate differentiation of metastasis from primary carcinoma is very important as the treatment and prognosis of the two differ significantly. PMID:23255943

  15. Breast metastasis from a pulmonary adenocarcinoma: Case report and review of the literature.

    PubMed

    Sanguinetti, Alessandro; Puma, Francesco; Lucchini, Roberta; Santoprete, Stefano; Cirocchi, Roberto; Corsi, Alessia; Triola, Roberta; Avenia, Nicola

    2013-01-01

    Breast metastasis from extra-mammary malignancy is rare. An incidence of 0.4-1.3% has been reported in the literature. The primary malignancies most commonly metastasizing to the breast are leukemia, lymphoma and malignant melanoma. We present a case of metastasis to the breast from a pulmonary adenocarcinoma, diagnosed concomitantly with the primary tumor. A 43-year-old female presented with dyspnea and a dry cough of 3 weeks' duration. A subsequent chest radiograph revealed a massive pleural effusion. Additionally, on physical examination, a poorly defined mass was noted in the upper outer quadrant of the right breast. The patient underwent bronchoscopy, simple right mastectomy and medical thoracoscopy. Following cytology, histology and immunohistochemistry, primary lung adenocarcinoma with metastasis to the breast and parietal pleura was diagnosed. Histologically, both the primary and metastatic anatomic sites demonstrated a micropapillary component, which has recently been recognized as an important prognostic factor. Although the patient received chemotherapy, she succumbed to her condition within 8 months. Accurate differentiation of metastasis from primary carcinoma is very important as the treatment and prognosis of the two differ significantly.

  16. The application of surgical navigation system using optical molecular imaging technology in orthotopic breast cancer and metastasis studies

    NASA Astrophysics Data System (ADS)

    Chi, Chongwei; Zhang, Qian; Kou, Deqiang; Ye, Jinzuo; Mao, Yamin; Qiu, Jingdan; Wang, Jiandong; Yang, Xin; Du, Yang; Tian, Jie

    2014-02-01

    Currently, it has been an international focus on intraoperative precise positioning and accurate resection of tumor and metastases. The methods such as X-rays, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have played an important role in preoperative accurate diagnosis. However, most of them are inapplicable for intraoperative surgery. We have proposed a surgical navigation system based on optical molecular imaging technology for intraoperative detection of tumors and metastasis. This system collects images from two CCD cameras for real-time fluorescent and color imaging. For image processing, the template matching algorithm is used for multispectral image fusion. For the application of tumor detection, the mouse breast cancer cell line 4T1-luc, which shows highly metastasis, was used for tumor model establishment and a model of matrix metalloproteinase (MMP) expressing breast cancer. The tumor-bearing nude mice were given tail vein injection of MMP 750FAST (PerkinElmer, Inc. USA) probe and imaged with both bioluminescence and fluorescence to assess in vivo binding of the probe to the tumor and metastases sites. Hematoxylin and eosin (H&E) staining was performed to confirm the presence of tumor and metastasis. As a result, one tumor can be observed visually in vivo. However liver metastasis has been detected under surgical navigation system and all were confirmed by histology. This approach helps surgeons to find orthotopic tumors and metastasis during intraoperative resection and visualize tumor borders for precise positioning. Further investigation is needed for future application in clinics.

  17. Protocadherin-7 induces bone metastasis of breast cancer

    SciTech Connect

    Li, Ai-Min; Tian, Ai-Xian; Zhang, Rui-Xue; Ge, Jie; Sun, Xuan; Cao, Xu-Chen

    2013-07-05

    Highlights: •PCDH7 is overexpression in high bone metastatic MDA-MB-231 cells. •PCDH7 is up-regulation in bone metastatic breast cancer tissues. •Suppression of PCDH7 inhibits cell proliferation, migration, and invasion in vitro. •PCDH7 induces breast cancer bone metastasis in vivo. -- Abstract: Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bone metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer.

  18. Gene expression in local stroma reflects breast tumor states and predicts patient outcome

    PubMed Central

    Bainer, Russell; Frankenberger, Casey; Rabe, Daniel; An, Gary; Gilad, Yoav; Rosner, Marsha Rich

    2016-01-01

    The surrounding microenvironment has been implicated in the progression of breast tumors to metastasis. However, the degree to which metastatic breast tumors locally reprogram stromal cells as they disrupt tissue boundaries is not well understood. We used species-specific RNA sequencing in a mouse xenograft model to determine how the metastasis suppressor RKIP influences transcription in a panel of paired tumor and stroma tissues. We find that gene expression in metastatic breast tumors is pervasively correlated with gene expression in local stroma of both mouse xenografts and human patients. Changes in stromal gene expression elicited by tumors better predicts subtype and patient survival than tumor gene expression, and genes with coordinated expression in both tissues predict metastasis-free survival. These observations support the use of stroma-based strategies for the diagnosis and prognosis of breast cancer. PMID:27982086

  19. A New Mouse Model for the Study of Human Breast Cancer Metastasis

    PubMed Central

    Iorns, Elizabeth; Drews-Elger, Katherine; Ward, Toby M.; Dean, Sonja; Clarke, Jennifer; Berry, Deborah; Ashry, Dorraya El; Lippman, Marc

    2012-01-01

    Breast cancer is the most common cancer in women, and this prevalence has a major impact on health worldwide. Localized breast cancer has an excellent prognosis, with a 5-year relative survival rate of 85%. However, the survival rate drops to only 23% for women with distant metastases. To date, the study of breast cancer metastasis has been hampered by a lack of reliable metastatic models. Here we describe a novel in vivo model using human breast cancer xenografts in NOD scid gamma (NSG) mice; in this model human breast cancer cells reliably metastasize to distant organs from primary tumors grown within the mammary fat pad. This model enables the study of the entire metastatic process from the proper anatomical site, providing an important new approach to examine the mechanisms underlying breast cancer metastasis. We used this model to identify gene expression changes that occur at metastatic sites relative to the primary mammary fat pad tumor. By comparing multiple metastatic sites and independent cell lines, we have identified several gene expression changes that may be important for tumor growth at distant sites. PMID:23118918

  20. Minimal residual disease and circulating tumor cells in breast cancer

    PubMed Central

    2011-01-01

    Tumor cell dissemination in bone marrow or other organs is thought to represent an important step in the metastatic process. The detection of bone marrow disseminated tumor cells is associated with worse outcome in early breast cancer. Moreover, the detection of peripheral blood circulating tumor cells is an adverse prognostic factor in metastatic breast cancer, and emerging data suggest that this is also true for early disease. Beyond enumeration, the characterization of these cells has the potential to improve risk assessment, treatment selection and monitoring, and the development of novel therapeutic agents, and to advance our understanding of the biology of metastasis. PMID:22078011

  1. Minimal residual disease and circulating tumor cells in breast cancer.

    PubMed

    Ignatiadis, Michail; Reinholz, Monica

    2011-10-25

    Tumor cell dissemination in bone marrow or other organs is thought to represent an important step in the metastatic process. The detection of bone marrow disseminated tumor cells is associated with worse outcome in early breast cancer. Moreover, the detection of peripheral blood circulating tumor cells is an adverse prognostic factor in metastatic breast cancer, and emerging data suggest that this is also true for early disease. Beyond enumeration, the characterization of these cells has the potential to improve risk assessment, treatment selection and monitoring, and the development of novel therapeutic agents, and to advance our understanding of the biology of metastasis.

  2. Association of EP2 receptor and SLC19A3 in regulating breast cancer metastasis

    PubMed Central

    Cheuk, Isabella W; Shin, Vivian Y; Siu, Man T; Tsang, Julia Y; Ho, John C; Chen, Jiawei; Tse, Gary M; Wang, Xian; Kwong, Ava

    2015-01-01

    Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer patients have higher metastatic rate than patients with other breast cancer subtypes. Distant metastasis is one of the causes leading to the high mortality rates. Cyclooxygenase-2 (COX2) is associated with breast cancer metastasis and the downstream prostaglandin E2 (PGE2) exerted its effect through EP receptors (EP1-EP4). However, the exact molecular events of EP receptors in breast cancer metastasis remain undefined. Expressions of EP receptors were determined during cancer development in NOD-SCID mice inoculated with MB-231 and MB-231-EP2 clone. EP2 overexpressing stable clone was constructed to investigate the proliferation and invasion potentials in vivo and in vitro. Drug transporter array was used to identify EP2 receptor-associated drug transported genes in breast cancer metastasis. Localization of EP2 receptor in primary tissues and xenografts were examined by immunostaining. Stable EP2-expression cells formed larger tumors than parental cells in mice model and was highly expressed in both primary and metastatic tissues. Silencing of EP2 receptor by siRNA and antagonist (AH 6809) significantly decreased cell proliferation and invasion, concomitant with reduced MMP-2 and MMP-9 expressions. Results from array data showed that expression of SLC19A3 was markedly increased in EP2 siRNA transfected cells. Ectopic expression of SLC19A3 retarded cell proliferation, invasion and MMPs expressions. Notably, SLC19A3 had a lower expression in primary tissues and was negatively correlated with EP2 receptor expression. Our novel finding revealed that EP2 receptor regulated metastasis through downregulation of SLC19A3. Thus, targeting EP2-SLC19A3 signaling is a potential therapeutic therapy for treating metastatic breast cancer. PMID:26807319

  3. Activation of vagus nerve by semapimod alters substance P levels and decreases breast cancer metastasis.

    PubMed

    Erin, Nuray; Duymuş, Ozlem; Oztürk, Saffet; Demir, Necdet

    2012-11-10

    Chronic inflammation is involved in initiation as well as in progression of cancer. Semapimod, a tetravalent guanylhydrazon and formerly known as CNI-1493, inhibits the release of inflammatory cytokines from activated macrophages and this effect is partly mediated by the vagus nerve. Our previous findings demonstrated that inactivation of vagus nerve activity as well sensory neurons enhanced visceral metastasis of 4THM breast carcinoma. Hence semapimod by activating vagus nerve may inhibit breast cancer metastasis. Here, effects of semapimod on breast cancer metastasis, the role of vagal sensory neurons on this effect and changes in mediators of the neuroimmune connection, such as substance P (SP) as well as neprilysin-like activity, were examined. Vagotomy was performed on half of the control animals that were treated with semapimod following orthotopic injection of 4THM breast carcinoma cells. Semapimod decreased lung and liver metastases in control but not in vagotomized animals with an associated increased SP levels in sensory nerve endings. Semapimod also increased neprilysin-like activity in lung tissue of control animals but not in tumor-bearing animals. This is the first report demonstrating that semapimod enhances vagal sensory nerve activity and may have anti-tumoral effects under in-vivo conditions. Further studies, however, are required to elucidate the conditions and the mechanisms involved in anti-tumoral effects of semapimod.

  4. Vascular normalization induced by sinomenine hydrochloride results in suppressed mammary tumor growth and metastasis.

    PubMed

    Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

    2015-03-09

    Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage.

  5. Vascular Normalization Induced by Sinomenine Hydrochloride Results in Suppressed Mammary Tumor Growth and Metastasis

    PubMed Central

    Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

    2015-01-01

    Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage. PMID:25749075

  6. Friend leukemia virus integration 1 activates the Rho GTPase pathway and is associated with metastasis in breast cancer.

    PubMed

    Song, Wei; Li, Wei; Li, Lingyu; Zhang, Shilin; Yan, Xu; Wen, Xue; Zhang, Xiaoying; Tian, Huimin; Li, Ailing; Hu, Ji-Fan; Cui, Jiuwei

    2015-09-15

    Breast cancer is the most prevalent malignant disease in women worldwide. In patients with breast cancer, metastasis to distant sites directly determines the survival outcome. However, the molecular mechanism underlying metastasis in breast cancer remains to be defined. In this report, we found that Friend leukemia virus integration 1 (FLI1) proto-oncogene was differentially expressed between the aggressive MDA-MB231 and the non-aggressive MCF-7 breast cancer cells. Congruently, immunohistochemical staining of clinical samples revealed that FLI1 was overexpressed in breast cancers as compared with the adjacent tissues. The abundance of FLI1 protein was strongly correlated with the advanced stage, poor differentiation, and lymph node metastasis in breast cancer patients. Knockdown of FLI1 with small interfering RNAs significantly attenuated the potential of migration and invasion in highly metastatic human breast cancer cells. FLI1 oncoprotein activated the Rho GTPase pathway that is known to play a role in tumor metastasis. This study for the first time identifies FLI1 as a clinically and functionally important target gene of metastasis, providing a rationale for developing FLI1 inhibitors in the treatment of breast cancer.

  7. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

    PubMed

    Wang, Hui; Liu, Xiufei; Long, Min; Huang, Yi; Zhang, Linlin; Zhang, Rui; Zheng, Yi; Liao, Xiaoyu; Wang, Yuren; Liao, Qian; Li, Wenjie; Tang, Zili; Tong, Qiang; Wang, Xiaocui; Fang, Fang; Rojo de la Vega, Montserrat; Ouyang, Qin; Zhang, Donna D; Yu, Shicang; Zheng, Hongting

    2016-04-13

    Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.

  8. Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by accelerating Twist1 degradation.

    PubMed

    Ma, Gang; He, Jianjun; Yu, Yang; Xu, Yixiang; Yu, Xiaobin; Martinez, Jarrod; Lonard, David M; Xu, Jianming

    2015-01-01

    Twist1 is a transcription factor driving epithelial-mesenchymal transition, invasion and metastasis of breast cancer cells. Mice with germ-line Twist1 knockout are embryonic lethal, while adult mice with inducible Twist1 knockout have no obvious health problems, suggesting that Twist1 is a viable therapeutic target for the inhibition of invasion and metastasis of breast cancer in adult patients. In this study, we expressed a luciferase protein or a Twist1-luciferase fusion protein in HeLa cells as part of a high throughput system to screen 1280 compounds in the Library of Pharmacologically Active Compounds (LOPAC) from Sigma-Aldrich for their effects on Twist1 protein expression. One of the most interesting compounds identified is tamoxifen, a selective estrogen receptor (ER) modulator used to treat ER-positive breast cancer. Tamoxifen treatment significantly accelerated Twist1 degradation in multiple cell lines including HEK293 human kidney cells, 4T1 and 168FARN mouse mammary tumor cells with either ectopically or endogenously expressed Twist1. Tamoxifen-induced Twist1 degradation could be blocked by the MG132 proteasome inhibitor, suggesting that tamoxifen induces Twist1 degradation through the ubiquitination-proteasome pathway. However, tamoxifen-induced Twist1 degradation was independent of Twist1 mRNA expression, estrogen signaling and MAPK-mediated Twist1 phosphorylation in these cells. Importantly, tamoxifen also significantly inhibited invasive behavior in Matrigel and lung metastasis in SCID-bg mice of ER-negative 4T1 mammary tumor cells, which depend on endogenous Twist1 to invade and metastasize. These results indicate that tamoxifen can significantly accelerate Twist1 degradation to suppress cancer cell invasion and metastasis, suggesting that tamoxifen can be used not only to treat ER-positive breast cancers but also to reduce Twist1-mediated invasion and metastasis in ER-negative breast cancers.

  9. pH-Responsive Wormlike Micelles with Sequential Metastasis Targeting Inhibit Lung Metastasis of Breast Cancer.

    PubMed

    He, Xinyu; Yu, Haijun; Bao, Xiaoyue; Cao, Haiqiang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2016-02-18

    Cancer metastasis is the main cause for the high mortality in breast cancer patients. Herein, we first report succinobucol-loaded pH-responsive wormlike micelles (PWMs) with sequential targeting capability to inhibit lung metastasis of breast cancer. PWMs can in a first step be delivered specifically to the sites of metastases in the lungs and then enable the intracellular pH-stimulus responsive drug release in cancer cells to improve the anti-metastatic effect. PWMs are identified as nanofibrillar assemblies with a diameter of 19.9 ± 1.9 nm and a length within the 50-200 nm range, and exhibited pH-sensitive drug release behavior in response to acidic intracellular environments. Moreover, PWMs can obviously inhibit the migration and invasion abilities of metastatic 4T1 breast cancer cells, and reduce the expression of the metastasis-associated vascular cell adhesion molecule-1 (VCAM-1) at 400 ng mL(-1) of succinobucol. In particular, PWMs can induce a higher specific accumulation in lung and be specifically delivered to the sites of metastases in lung, thereby leading to an 86.6% inhibition on lung metastasis of breast cancer. Therefore, the use of sequentially targeting PWMs can become an encouraging strategy for specific targeting and effective treatment of cancer metastasis.

  10. Systemic siRNA Delivery with a Dual pH-Responsive and Tumor-targeted Nanovector for Inhibiting Tumor Growth and Spontaneous Metastasis in Orthotopic Murine Model of Breast Carcinoma

    PubMed Central

    Fan, Bo; Kang, Lin; Chen, Liqing; Sun, Ping; Jin, Mingji; Wang, Qiming; Bae, You Han; Huang, Wei; Gao, Zhonggao

    2017-01-01

    Phenylboronic acid (PBA)-mediated tumor targeting nanovector is an attractive strategy for enhancing siRNA delivery and treatment of metastatic cancers. However, its nonspecific binding with various biological membranes containing cis-diol moieties restricts its potential application by systematic administration. Herein, we constructed a novel pH-activated “sheddable” PEG-coated nanoparticle for effective treatment of primary tumors and metastases, which was based on the conjugation of catechol group modified poly(ethylene glycol) (PEG-Cat) and PBA-terminated polyethylenimine (PEI-PBA) via the borate ester formed between PBA and Cat. By virtue of the pH-dependent stability of borate ester in an aqueous medium, the PEG-shell could “shield” the PBA ligand in systemic circulation to reduce its “off-target effect”, while PEG was detached at tumor extracellular pH (~6.5) to expose intact PBA moiety. Simultaneously, the PBA ligand could bind with overexpressed sialic acid residues on cancer cells, giving rise to enhanced cellular internalization. In addition, the PBA moieties could also couple with each 3'-end ribose of double-stranded siRNA. siRNAs were used as both a payload and a pH-responsive intermolecular cross-linker, and thereby acquired sufficient stability during circulating in blood and a rapidly triggered release in response to acidic endosomal/lysosomal pH-stimuli. As a result, this dual pH-sensitive nanoparticle showed enhanced siRNA uptake, gene silencing efficacy and anti-metastatic effects in vitro. Furthermore, in vivo studies demonstrated that PBA-based nanoparticles effectively accumulated in tumor and inhibited tumor growth and metastasis in 4T1 orthotopic mammary tumor model after intravenous administration. PMID:28042340

  11. Role of Adrenomedullin in Breast Cancer Bone Metastasis and Chemoresistance

    DTIC Science & Technology

    2008-05-01

    total bone lesion area in mice by xray compared to control clones. All clones maintained expression of the shRNA vector in vivo as measured by... Bone Metastasis and Chemoresistance PRINCIPAL INVESTIGATOR: Valerie A. Siclari CONTRACTING ORGANIZATION: University of...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Role of Adrenomedullin in Breast Cancer Bone Metastasis and Chemoresistance 5b. GRANT NUMBER W81XWH-06

  12. ["Clown nose"--skin metastasis of breast cancer].

    PubMed

    Soyer, H P; Cerroni, L; Smolle, J; Kerl, H

    1990-10-01

    We report on a 74-year-old woman showing a reddish infiltration of the tip of the nose, which had appeared 3 months ago. Clinically, we considered the following differential diagnoses: sarcoidosis, rosacea, pseudolymphoma, and metastasis. Histological and immunohistological investigation proved a cutaneous metastasis of carcinoma of the breast. Our case report gives evidence of the fact that cutaneous metastases of systemic malignancies are frequently located in acral regions of the skin.

  13. Neutrophils: important contributors to tumor progression and metastasis.

    PubMed

    Swierczak, Agnieszka; Mouchemore, Kellie A; Hamilton, John A; Anderson, Robin L

    2015-12-01

    The presence of neutrophils in tumors has traditionally been considered to be indicative of a failed immune response against cancers. However, there is now evidence showing that neutrophils can promote tumor growth, and increasingly, the data support an active role for neutrophils in tumor progression to distant metastasis. Neutrophils have been implicated in promoting metastasis in cancer patients, where neutrophil numbers and neutrophil-related factors and functions have been associated with progressive disease. Nevertheless, the role of neutrophils in tumors, both at the primary and secondary sites, remains controversial, with some studies reporting their anti-tumor functions. This review will focus on the data demonstrating a role for neutrophils in both tumor growth and metastasis and will attempt to clarify the discrepancies in the literature.

  14. The Biology of Breast Cancer Metastasis

    DTIC Science & Technology

    2002-10-01

    Breast cancer is the second most common cause of brain metastases, diagnosed in 10 to 15% of breast cancer patients and found at autopsy in 20 to 30...Relatively little is known about how breast cancer cells metastasize to the brain , and what phenotypes characterize these cells. This is due in...breast cancer brain metastases, using intra-carotid artery injection of breast cancer cells into nude mice.

  15. CRP2, a new invadopodia actin bundling factor critically promotes breast cancer cell invasion and metastasis

    PubMed Central

    Dieterle, Monika; Moreau, Flora; Al Absi, Antoun; Steinmetz, André; Oudin, Anaïs; Berchem, Guy; Janji, Bassam; Thomas, Clément

    2016-01-01

    A critical process underlying cancer metastasis is the acquisition by tumor cells of an invasive phenotype. At the subcellular level, invasion is facilitated by actin-rich protrusions termed invadopodia, which direct extracellular matrix (ECM) degradation. Here, we report the identification of a new cytoskeletal component of breast cancer cell invadopodia, namely cysteine-rich protein 2 (CRP2). We found that CRP2 was not or only weakly expressed in epithelial breast cancer cells whereas it was up-regulated in mesenchymal/invasive breast cancer cells. In addition, high expression of the CRP2 encoding gene CSRP2 was associated with significantly increased risk of metastasis in basal-like breast cancer patients. CRP2 knockdown significantly reduced the invasive potential of aggressive breast cancer cells, whereas it did not impair 2D cell migration. In keeping with this, CRP2-depleted breast cancer cells exhibited a reduced capacity to promote ECM degradation, and to secrete and express MMP-9, a matrix metalloproteinase repeatedly associated with cancer progression and metastasis. In turn, ectopic expression of CRP2 in weakly invasive cells was sufficient to stimulate cell invasion. Both GFP-fused and endogenous CRP2 localized to the extended actin core of invadopodia, a structure primarily made of actin bundles. Purified recombinant CRP2 autonomously crosslinked actin filaments into thick bundles, suggesting that CRP2 contributes to the formation/maintenance of the actin core. Finally, CRP2 depletion significantly reduced the incidence of lung metastatic lesions in two xenograft mouse models of breast cancer. Collectively, our data identify CRP2 as a new cytoskeletal component of invadopodia that critically promotes breast cancer cell invasion and metastasis. PMID:26883198

  16. Type III Collagen Directs Stromal Organization and Limits Metastasis in a Murine Model of Breast Cancer.

    PubMed

    Brisson, Becky K; Mauldin, Elizabeth A; Lei, Weiwei; Vogel, Laurie K; Power, Ashley M; Lo, Albert; Dopkin, Derek; Khanna, Chand; Wells, Rebecca G; Puré, Ellen; Volk, Susan W

    2015-05-01

    Breast cancer metastasis is the leading cause of cancer-related deaths in women worldwide. Collagen in the tumor microenvironment plays a crucial role in regulating tumor progression. We have shown that type III collagen (Col3), a component of tumor stroma, regulates myofibroblast differentiation and scar formation after cutaneous injury. During the course of these wound-healing studies, we noted that tumors developed at a higher frequency in Col3(+/-) mice compared to wild-type littermate controls. We, therefore, examined the effect of Col3 deficiency on tumor behavior, using the murine mammary carcinoma cell line 4T1. Notably, tumor volume and pulmonary metastatic burden after orthotopic injection of 4T1 cells were increased in Col3(+/-) mice compared to Col3(+/+) littermates. By using murine (4T1) and human (MDA-MB-231) breast cancer cells grown in Col3-poor and Col3-enriched microenvironments in vitro, we found that several major events of the metastatic process were suppressed by Col3, including adhesion, invasion, and migration. In addition, Col3 deficiency increased proliferation and decreased apoptosis of 4T1 cells both in vitro and in primary tumors in vivo. Mechanistically, Col3 suppresses the procarcinogenic microenvironment by regulating stromal organization, including density and alignment of fibrillar collagen and myofibroblasts. We propose that Col3 plays an important role in the tumor microenvironment by suppressing metastasis-promoting characteristics of the tumor-associated stroma.

  17. Inhibition of Breast Cancer Metastasis by Pluronic Copolymers with Moderate Hydrophilic-Lipophilic Balance.

    PubMed

    Sun, Huiping; Meng, Qingshuo; Tang, Shan; Su, Jinghan; Yin, Qi; Chen, Lingli; Gu, Wangwen; Yu, Haijun; Zhang, Zhiwen; Wang, Siling; Li, Yaping

    2015-09-08

    Metastasis is the primary cause resulting in the high mortality of breast cancer. The inherent antimetastasis bioactivity of Pluronic copolymers with a wide range of hydrophilic-lipophilic balance (HLB) including Pluronic L61, P85, P123, F127, F68, and F108 was first explored on metastatic 4T1 breast cancer cells. The results indicated that P85 and P123 could strongly inhibit the migration and invasion of 4T1 cells. The effects of the polymers on cell healing, migration, and invasion exhibited bell-shaped dependencies on HLB of Pluronic copolymers, and the better antimetastasis effects of Pluronic copolymers could be achieved with the HLB between 8 and 16. P85 and P123 themselves could significantly inhibit pulmonary metastasis in 4T1 mammary tumor metastasis model in situ. In addition, a synergetic antimetastasis effect could be achieved during drug combination of doxorubicin hydrochloride (DOX) and P85 or P123 intravenously. The metastasis effects of P85 and P123 both in vitro and in vivo were partially attributed to the downregulation of matrix metalloproteinase-9 (MMP-9). Therefore, Pluronic copolymers with moderate HLB 8-16 such as P85 and P123 could be promising excipients with therapeutics in drug delivery systems to inhibit breast cancer metastasis.

  18. LCP nanoparticle for tumor and lymph node metastasis imaging

    NASA Astrophysics Data System (ADS)

    Tseng, Yu-Cheng

    A lipid/calcium/phosphate (LCP) nanoparticle formulation (particle diameter ˜25 nm) has previously been developed to delivery siRNA with superior efficiency. In this work, 111In was formulated into LCP nanoparticles to form 111In-LCP for SPECT/CT imaging. With necessary modifications and improvements of the LCP core-washing and surface-coating methods, 111In-LCP grafted with polyethylene glycol exhibited reduced uptake by the mononuclear phagocytic system. SPECT/CT imaging supported performed biodistribution studies, showing clear tumor images with accumulation of 8% or higher injected dose per gram tissue (ID/g) in subcutaneous, human-H460, lung-cancer xenograft and mouse-4T1, breast cancer metastasis models. Both the liver and the spleen accumulated ˜20% ID/g. Accumulation in the tumor was limited by the enhanced permeation and retention effect and was independent of the presence of a targeting ligand. A surprisingly high accumulation in the lymph nodes (˜70% ID/g) was observed. In the 4T1 lymph node metastasis model, the capability of intravenously injected 111In-LCP to visualize the size-enlarged and tumor-loaded sentinel lymph node was demonstrated. By analyzing the SPECT/CT images taken at different time points, the PK profiles of 111In-LCP in the blood and major organs were determined. The results indicated that the decrement of 111In-LCP blood concentration was not due to excretion, but to tissue penetration, leading to lymphatic accumulation. Larger LCP (diameter ˜65 nm) nanoparticles were also prepared for the purpose of comparison. Results indicated that larger LCP achieved slightly lower accumulation in the tumor and lymph nodes, but much higher accumulation in the liver and spleen; thus, larger nanoparticles might not be favorable for imaging purposes. We also demonstrated that LCP with a diameter of ˜25 nm were better able to penetrate into tissues, travel in the lymphatic system and preferentially accumulate in the lymph nodes due to 1) small

  19. Kindlin-3 enhances breast cancer progression and metastasis by activating Twist-mediated angiogenesis

    PubMed Central

    Sossey-Alaoui, Khalid; Pluskota, Elzbieta; Davuluri, Gangarao; Bialkowska, Katarzyna; Das, Mitali; Szpak, Dorota; Lindner, Daniel J.; Downs-Kelly, Erinn; Thompson, Cheryl L.; Plow, Edward F.

    2014-01-01

    The FERM domain containing protein Kindlin-3 has been recognized as a major regulator of integrin function in hematopoietic cells, but its role in neoplasia is totally unknown. We have examined the relationship between Kindlin-3 and breast cancer in mouse models and human tissues. Human breast tumors showed a ∼7-fold elevation in Kindlin-3 mRNA compared with nonneoplastic tissue by quantitative polymerase chain reaction. Kindlin-3 overexpression in a breast cancer cell line increased primary tumor growth and lung metastasis by 2.5- and 3-fold, respectively, when implanted into mice compared with cells expressing vector alone. Mechanistically, the Kindlin-3-overexpressing cells displayed a 2.2-fold increase in vascular endothelial growth factor (VEGF) secretion and enhanced β1 integrin activation. Increased VEGF secretion resulted from enhanced production of Twist, a transcription factor that promotes tumor angiogenesis. Knockdown of Twist diminished VEGF production, and knockdown of β1 integrins diminished Twist and VEGF production by Kindlin-3-overexpressing cells, while nontargeting small interfering RNA had no effect on expression of these gene products. Thus, Kindlin-3 influences breast cancer progression by influencing the crosstalk between β1 integrins and Twist to increase VEGF production. This signaling cascade enhances breast cancer cell invasion and tumor angiogenesis and metastasis.—Sossey-Alaoui, K., Pluskota, E., Davuluri, G., Bialkowska, K., Das, M., Szpak, D., Lindner, D. J., Downs-Kelly, E., Thompson, C. L., Plow, E. F. Kindlin-3 enhances breast cancer progression and metastasis by activating Twist-mediated angiogenesis. PMID:24469992

  20. The Role of Breast Cancer Stem Cells in Metastasis and Therapeutic Implications

    PubMed Central

    Velasco-Velázquez, Marco A.; Popov, Vladimir M.; Lisanti, Michael P.; Pestell, Richard G.

    2011-01-01

    Cancer stem cells (CSCs) possess the capacity to self-renew and to generate heterogeneous lineages of cancer cells that comprise tumors. A substantial body of evidence supports a model in which CSCs play a major role in the initiation, maintenance, and clinical outcome of cancers. In contrast, analysis of the role of CSCs in metastasis has been mainly conceptual and speculative. This review summarizes recent data that support the theory of CSCs as the source of metastatic lesions in breast cancer, with a focus on the key role of the microenvironment in the stemness-metastasis link. PMID:21640330

  1. Pericyte–fibroblast transition promotes tumor growth and metastasis

    PubMed Central

    Hosaka, Kayoko; Yang, Yunlong; Seki, Takahiro; Fischer, Carina; Dubey, Olivier; Fredlund, Erik; Hartman, Johan; Religa, Piotr; Ishii, Yoko; Sasahara, Masakiyo; Larsson, Ola; Cossu, Giulio; Cao, Renhai; Lim, Sharon; Cao, Yihai

    2016-01-01

    Vascular pericytes, an important cellular component in the tumor microenvironment, are often associated with tumor vasculatures, and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte–fibroblast transition (PFT), which significantly contributes to tumor invasion and metastasis. Gain- and loss-of-function experiments demonstrate that PDGF-BB-PDGFRβ signaling promotes PFT both in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB–activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFRβ ablate the PDGF-BB–induced PFT. Genetic tracing of pericytes with two independent mouse strains, TN-AP-CreERT2:R26R-tdTomato and NG2-CreERT2:R26R-tdTomato, shows that PFT cells gain stromal fibroblast and myofibroblast markers in tumors. Importantly, coimplantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells and metastasis. Our findings reveal a mechanism of vascular pericytes in PDGF-BB–promoted cancer invasion and metastasis by inducing PFT, and thus targeting PFT may offer a new treatment option of cancer metastasis. PMID:27608497

  2. Intramedullary spinal metastasis of a carcinoid tumor.

    PubMed

    Kumar, Jay I; Yanamadala, Vijay; Shin, John H

    2015-12-01

    We report an intramedullary spinal cord metastasis from a bronchial carcinoid, and discuss its mechanisms and management. Intramedullary spinal cord metastases from any cancer are rare, and bronchial carcinoids account for only a small fraction of lung cancers. To our knowledge, an intramedullary spinal cord metastasis from a bronchial carcinoid has been described only once previously.

  3. A Rare Case of Phyllodes Tumor Metastasis to the Stomach Presenting as Anemia.

    PubMed

    Choi, Do Il; Chi, Ho Seok; Lee, Sang Ho; Kwon, Youngmee; Park, Seog Yun; Sim, Sung Hoon; Park, In Hae; Lee, Keun Seok

    2016-09-01

    Metastasis of a phyllodes tumor to the stomach is an extremely rare condition with important clinical implications. A 44-year-old woman was initially diagnosed with a phyllodes tumor in her right breast in 2008, and subsequently presented to an out-patient clinic with dizziness on December 16, 2013. We found that she had severe anemia (hemoglobin levels: 6.7 g/dL), and we quickly performed esophagogastroduodenoscopy to identify the cause. This procedure revealed large ulcerofungating masses with active bleeding in the stomach. Histopathological examination revealed that the masses were consistent with phyllodes tumor metastases. In patients with a metastatic phyllodes tumor presenting as anemia, gastric metastasis should be considered as one of the differential diagnoses because overlooking the possibility might have dire consequences if cytotoxic chemotherapy were administered.

  4. Involvement of chemokine receptors in breast cancer metastasis

    NASA Astrophysics Data System (ADS)

    Müller, Anja; Homey, Bernhard; Soto, Hortensia; Ge, Nianfeng; Catron, Daniel; Buchanan, Matthew E.; McClanahan, Terri; Murphy, Erin; Yuan, Wei; Wagner, Stephan N.; Barrera, Jose Luis; Mohar, Alejandro; Verástegui, Emma; Zlotnik, Albert

    2001-03-01

    Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

  5. Gasdermin-B Promotes Invasion and Metastasis in Breast Cancer Cells

    PubMed Central

    Hergueta-Redondo, Marta; Sarrió, David; Molina-Crespo, Ángela; Megias, Diego; Mota, Alba; Rojo-Sebastian, Alejandro; García-Sanz, Pablo; Morales, Saleta; Abril, Sandra; Cano, Amparo; Peinado, Héctor; Moreno-Bueno, Gema

    2014-01-01

    Gasdermin B (GSDMB) belongs to the Gasdermin protein family that comprises four members (GSDMA-D). Gasdermin B expression has been detected in some tumor types such as hepatocarcinomas, gastric and cervix cancers; and its over-expression has been related to tumor progression. At least four splicing isoforms of GSDMB have been identified, which may play differential roles in cancer. However, the implication of GSDMB in carcinogenesis and tumor progression is not well understood. Here, we uncover for the first time the functional implication of GSDMB in breast cancer. Our data shows that high levels of GSDMB expression is correlated with reduced survival and increased metastasis in breast cancer patients included in an expression dataset (>1,000 cases). We demonstrate that GSDMB is upregulated in breast carcinomas compared to normal breast tissue, being the isoform 2 (GSDMB-2) the most differentially expressed. In order to evaluate the functional role of GSDMB in breast cancer two GSDMB isoforms were studied (GSDMB-1 and GSDMB-2). The overexpression of both isoforms in the MCF7 breast carcinoma cell line promotes cell motility and invasion, while its silencing in HCC1954 breast carcinoma cells decreases the migratory and invasive phenotype. Importantly, we demonstrate that both isoforms have a differential role on the activation of Rac-1 and Cdc-42 Rho-GTPases. Moreover, our data support that GSMDB-2 induces a pro-tumorigenic and pro-metastatic behavior in mouse xenograft models as compared to GSDMB-1. Finally, we observed that although both GSDMB isoforms interact in vitro with the chaperone Hsp90, only the GSDMB-2 isoform relies on this chaperone for its stability. Taken together, our results provide for the first time evidences that GSDMB-2 induces invasion, tumor progression and metastasis in MCF7 cells and that GSDMB can be considered as a new potential prognostic marker in breast cancer. PMID:24675552

  6. Hydroxyapatite nanoparticle-containing scaffolds for the study of breast cancer bone metastasis.

    PubMed

    Pathi, Siddharth P; Lin, Debra D W; Dorvee, Jason R; Estroff, Lara A; Fischbach, Claudia

    2011-08-01

    Breast cancer frequently metastasizes to bone, where it leads to secondary tumor growth, osteolytic bone degradation, and poor clinical prognosis. Hydroxyapatite Ca(10)(PO(4))(6)(OH)(2) (HA), a mineral closely related to the inorganic component of bone, may be implicated in these processes. However, it is currently unclear how the nanoscale materials properties of bone mineral, such as particle size and crystallinity, which change as a result of osteolytic bone remodeling, affect metastatic breast cancer. We have developed a two-step hydrothermal synthesis method to obtain HA nanoparticles with narrow size distributions and varying crystallinity. These nanoparticles were incorporated into gas-foamed/particulate leached poly(lactide-co-glycolide) scaffolds, which were seeded with metastatic breast cancer cells to create mineral-containing scaffolds for the study of breast cancer bone metastasis. Our results suggest that smaller, poorly-crystalline HA nanoparticles promote greater adsorption of adhesive serum proteins and enhance breast tumor cell adhesion and growth relative to larger, more crystalline nanoparticles. Conversely, the larger, more crystalline HA nanoparticles stimulate enhanced expression of the osteolytic factor interleukin-8 (IL-8). Our data suggest an important role for nanoscale HA properties in the vicious cycle of bone metastasis and indicate that mineral-containing tumor models may be excellent tools to study cancer biology and to define design parameters for non-tumorigenic mineral-containing or mineralized matrices for bone regeneration.

  7. Selection of brain metastasis-initiating breast cancer cells determined by growth on hard agar.

    PubMed

    Guo, Lixia; Fan, Dominic; Zhang, Fahao; Price, Janet E; Lee, Ju-Seog; Marchetti, Dario; Fidler, Isaiah J; Langley, Robert R

    2011-05-01

    An approach that facilitates rapid isolation and characterization of tumor cells with enhanced metastatic potential is highly desirable. Here, we demonstrate that plating GI-101A human breast cancer cells on hard (0.9%) agar selects for the subpopulation of metastasis-initiating cells. The agar-selected cells, designated GI-AGR, were homogeneous for CD44(+) and CD133(+) and five times more invasive than the parental GI-101A cells. Moreover, mice injected with GI-AGR cells had significantly more experimental brain metastases and shorter overall survival than did mice injected with GI-101A cells. Comparative gene expression analysis revealed that GI-AGR cells were markedly distinct from the parental cells but shared an overlapping pattern of gene expression with the GI-101A subline GI-BRN, which was generated by repeated in vivo recycling of GI-101A cells in an experimental brain metastasis model. Data mining on 216 genes shared between GI-AGR and GI-BRN breast cancer cells suggested that the molecular phenotype of these cells is consistent with that of cancer stem cells and the aggressive basal subtype of breast cancer. Collectively, these results demonstrate that analysis of cell growth in a hard agar assay is a powerful tool for selecting metastasis-initiating cells in a heterogeneous population of breast cancer cells, and that such selected cells have properties similar to those of tumor cells that are selected based on their potential to form metastases in mice.

  8. Effects of vascular targeting photodynamic therapy on lymphatic tumor metastasis

    NASA Astrophysics Data System (ADS)

    Fateye, B.; He, C.; Chen, B.

    2009-06-01

    Vascular targeting photodynamic therapy (vPDT) is currently in clinical trial for prostate cancer (PCa) treatment. In order to study the effect of vPDT on tumor metastasis, GFP-PC3 or PC-3 xenografts were treated with verteporfin (BPD) PDT. Vascular function was assessed by ultrasound imaging; lymph node and lung metastasis were assessed by fluorescence imaging. vPDT significantly reduced tumor blood flow within 30minutes to 2 hours of treatment. Sub-curative treatment resulted in re-perfusion within 2 weeks of treatment and increased lymph node metastasis. With curative doses, no metastasis was observed. In order to identify cellular or matrix factors and cytokines implicated, conditioned medium from BPD PDTtreated endothelial cells was incubated with PC3 cells in vitro. Tumor cell proliferation and migration was assessed. By immunoblotting, we evaluated the change in mediators of intracellular signaling or that may determine changes in tumor phenotype. Low sub-curative dose (200ng/ml BPD) of endothelial cells was associated with ~15% greater migration in PC3 cells when compared with control. This dose was also associated with sustained activation of Akt at Ser 473, an upstream effector in the Akt/ mTOR pathway that has been correlated with Gleason scores in PCa and with survival and metastasis in vitro and in vivo. In conclusion, the study implicates efficacy of PDT of endothelial cells as an important determinant of its consequences on adjacent tumor proliferation and metastasis.

  9. Potential Role of CD68 in Breast Cancer Bone Metastasis

    DTIC Science & Technology

    2012-01-01

    reliable data. b. Quantify and compare CD68 expression levels in normal mammary epithelial cells, breast cancer tissues from primary sites and breast...cancer tissues from bone metastasis (Months 2-24). I have applied for and obtained the Institutional review board (IRB) approval to proceed with...this portion of the research. I am currently awaiting the normal and diseased tissues from our official collaborator Dr. Hue Luu in the Department of

  10. The incidence of bone metastasis after early-stage breast cancer in Canada.

    PubMed

    Liede, Alexander; Jerzak, Katarzyna J; Hernandez, Rohini K; Wade, Sally W; Sun, Ping; Narod, Steven A

    2016-04-01

    Current information on the incidence and prevalence of bone metastases in women with breast cancer is scarce. This study examined the occurrence and predictors of bone metastases, as well as post-metastasis survival in a prospective cohort of Canadian women with breast cancer. We included women treated for early-stage (stage I, II, or III) breast cancer at the Henrietta Banting Breast Centre (HBBC) in Toronto, Canada between 1987 and 2000. Data were abstracted from medical records and pathology reports in the HBBC database; follow-up extended to end of data availability or August 31, 2015. Actuarial survival analyses provided cumulative incidence of bone metastases at 5, 10, and 15 years after breast cancer diagnosis. Kaplan-Meier curves describe breast cancer mortality. Regression models assessed patient, tumor, and treatment characteristics as predictors of bone metastases with all-cause mortality as a competing risk. Among 2097 women studied, the 5-, 10-, and 15-year probability of bone metastasis was 6.5, 10.3, and 11.3 % for the first recurrence, and 8.4, 12.5, and 13.6 % for any bone recurrence. At median follow-up (12.5 years), 13.2 % of patients had bone metastases. Median survival was 1.6 years following bone metastasis, and shorter if both bone and visceral metastases occurred. Advanced age and adjuvant treatment with tamoxifen were protective against bone metastasis. In this representative cohort of women diagnosed with early-stage breast cancer in Ontario, Canada, with long follow-up, the incidence of bone metastases was consistent with longitudinal studies from the United Kingdom, Denmark, and the US.

  11. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain

    PubMed Central

    Chen, Jinyu; Lee, Ho-Jeong; Wu, Xuefeng; Huo, Lei; Kim, Sun-Jin; Xu, Lei; Wang, Yan; He, Junqing; Bollu, Lakshmi Reddy; Gao, Guang; Su, Fei; Briggs, James; Liu, Xiaojing; Melman, Tamar; Asara, John M.; Fidler, Isaiah J.; Cantley, Lewis C.; Locasale, Jason W.; Weihua, Zhang

    2014-01-01

    Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain-metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the non-oxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBPs) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis, and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients. PMID:25511375

  12. Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing.

    PubMed

    Xu, Yilin; Gao, Xin D; Lee, Jae-Hyung; Huang, Huilin; Tan, Haiyan; Ahn, Jaegyoon; Reinke, Lauren M; Peter, Marcus E; Feng, Yue; Gius, David; Siziopikou, Kalliopi P; Peng, Junmin; Xiao, Xinshu; Cheng, Chonghui

    2014-06-01

    Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein heterogeneous nuclear ribonucleoprotein M (hnRNPM) promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFβ signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFβ-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44 standard (CD44s) splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial splicing regulator that binds to the same cis-regulatory RNA elements as hnRNPM and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.

  13. MicroRNA-421 inhibits breast cancer metastasis by targeting metastasis associated 1.

    PubMed

    Pan, Yongqin; Jiao, Genlong; Wang, Cunchuan; Yang, Jingge; Yang, Wah

    2016-10-01

    Dysregulation of microRNAs is involved in the initiation and progression of several human cancers, including breast cancer, as strong evidence of miRNAs acting as oncogenes or tumour suppressor genes has been found. This study was performed to investigate the biological functions of microRNA-421 (miR-421) in breast cancer and the underlying mechanisms. The expression level of miR-421 was detected in 50 pairs of surgical specimens and human breast cancer cell lines. The results showed that miR-421 is downregulated in breast cancer tissues and metastatic cell lines. In addition, the decrease in miR-421 levels was significantly associated with lymph node metastasis, recurrence/metastasis, or pTNM stage. Functions of miR-421 in cell migration and invasion were assessed through its silencing and overexpression. The results showed that miR-421 knockdown promotes invasion and metastasis in MCF-7 cells and its overexpression suppresses invasion and metastasis in MDA-MB-231 cells. The specific target genes of miR-421 were predicted by TargetScan algorithm and determined by dual luciferase reporter assay, quantitative reverse transcriptase PCR, and western blot analysis. miR-421 could suppress luciferase activity of the reporter containing 3'-untranslated region of metastasis associated 1 (MTA1), a potent oncogene. miR-421 overexpression or knockdown had no effect on the mRNA expression of MTA1, but it could modulate MTA1 protein level. Furthermore, MTA1 knockdown receded the effect of miR-421 inhibitor on invasion and metastasis of MCF-7 cells, and its overexpression receded the effect of miR-421 on invasion and metastasis of MDA-MB-231 cells. Our findings clearly demonstrate that miR-421 suppresses breast cancer metastasis by directly inhibiting MTA1 expression. The present study provides a new insight into the tumour suppressor roles of miR-421 and suggests that miR-421/MTA1 pathway is a putative therapeutic target in breast cancer.

  14. C-type lectins facilitate tumor metastasis

    PubMed Central

    Ding, Dongbing; Yao, Yao; Zhang, Songbai; Su, Chunjie; Zhang, Yonglian

    2017-01-01

    Metastasis, a life-threatening complication of cancer, leads to the majority of cases of cancer-associated mortality. Unfortunately, the underlying molecular and cellular mechanisms of cancer metastasis remain to be fully elucidated. C-type lectins are a large group of proteins, which share structurally homologous carbohydrate-recognition domains (CRDs) and possess diverse physiological functions, including inflammation and antimicrobial immunity. Accumulating evidence has demonstrated the contribution of C-type lectins in different steps of the metastatic spread of cancer. Notably, a substantial proportion of C-type lectins, including selectins, mannose receptor (MR) and liver and lymph node sinusoidal endothelial cell C-type lectin, are important molecular targets for the formation of metastases in vitro and in vivo. The present review summarizes what has been found regarding C-type lectins in the lymphatic and hematogenous metastasis of cancer. An improved understanding the role of C-type lectins in cancer metastasis provides a comprehensive perspective for further clarifying the molecular mechanisms of cancer metastasis and supports the development of novel C-type lectins-based therapies the for prevention of metastasis in certain types of cancer. PMID:28123516

  15. C-type lectins facilitate tumor metastasis.

    PubMed

    Ding, Dongbing; Yao, Yao; Zhang, Songbai; Su, Chunjie; Zhang, Yonglian

    2017-01-01

    Metastasis, a life-threatening complication of cancer, leads to the majority of cases of cancer-associated mortality. Unfortunately, the underlying molecular and cellular mechanisms of cancer metastasis remain to be fully elucidated. C-type lectins are a large group of proteins, which share structurally homologous carbohydrate-recognition domains (CRDs) and possess diverse physiological functions, including inflammation and antimicrobial immunity. Accumulating evidence has demonstrated the contribution of C-type lectins in different steps of the metastatic spread of cancer. Notably, a substantial proportion of C-type lectins, including selectins, mannose receptor (MR) and liver and lymph node sinusoidal endothelial cell C-type lectin, are important molecular targets for the formation of metastases in vitro and in vivo. The present review summarizes what has been found regarding C-type lectins in the lymphatic and hematogenous metastasis of cancer. An improved understanding the role of C-type lectins in cancer metastasis provides a comprehensive perspective for further clarifying the molecular mechanisms of cancer metastasis and supports the development of novel C-type lectins-based therapies the for prevention of metastasis in certain types of cancer.

  16. Nanomolar concentration of blood-soluble drag-reducing polymer inhibits experimental metastasis of human breast cancer cells

    PubMed Central

    Ding, Zhijie; Joy, Marion; Kameneva, Marina V; Roy, Partha

    2017-01-01

    Metastasis is the leading cause of cancer mortality. Extravasation of cancer cells is a critical step of metastasis. We report a novel proof-of-concept study that investigated whether non-toxic blood-soluble chemical agents capable of rheological modification of the near-vessel-wall blood flow can reduce extravasation of tumor cells and subsequent development of metastasis. Using an experimental metastasis model, we demonstrated that systemic administration of nanomolar concentrations of so-called drag-reducing polymer dramatically impeded extravasation and development of pulmonary metastasis of breast cancer cells in mice. This is the first proof-of-principle study to directly demonstrate physical/rheological, as opposed to chemical, way to prevent cancer cells from extravasation and developing metastasis and, thus, it opens the possibility of a new direction of adjuvant interventional approach in cancer. PMID:28280386

  17. Phyllodes tumor of the breast

    PubMed Central

    Herazo, Fernando; Gil, Monica; Echeverri, Carolina; Ángel, Gonzalo; Borrero, Mauricio; Madrid, Jorge; Jaramillo, Ricardo

    2015-01-01

    Introduction: Breast Phyllodes tumors are rare breast tumors present in less than 1% of new cases of breast cancer, usually occurring among middle-aged women (40-50 yrs). Objective: This study shows diagnostic experience, surgical management and follows up of patients with this disease during a period of ten years in a oncology referral center. Methods: Retrospectively, breast cancer registries at the institution were reviewed, identifying 77 patients with Phyllodes tumors between 2002 and 2012, who had been operated on at the Instituto de Cancerología - Clínica Las Américas, in Medellín (Colombia). Clinical and histopathological data belonging to these cases was captured and analyzed and descriptive statistics were used. Results: The follow up median was 22.5 months (IQR: 10.5-60.0), average age was 47.2 yrs (SD: 12.4), mean tumor size was 3.6 cm (SD: 4.6), 88.3% of the patients (68 cases) presented negative margins and none of them received adjuvant chemotherapy. Of the patients with Phyllodes tumors; 33.8% had benign, 31.2% had borderline and 35.0% had malignant tumor. Disease-free survival was 85.8% and overall survival was 94.5%. Discussion: Reported data in this article is in accordance with what has been reported in worldwide literature. In our cohort even the high mean size of the tumors, the risk of local relapse and metastatic disease is low than previously reported in literature. Trials with longer follow up and molecular trials in Phyllodes tumors are necessary to understand the behavior of these tumors in Hispanics population. PMID:26600624

  18. The perivascular niche regulates breast tumor dormancy

    PubMed Central

    Peinado, Héctor; Mori, Hidetoshi; Matei, Irina R.; Evason, Kimberley J.; Brazier, Hélène; Almeida, Dena; Koller, Antonius; Hajjar, Katherine A.; Stainier, Didier Y.R.; Chen, Emily I.; Lyden, David

    2013-01-01

    In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant, and what ‘wakes them up’, are fundamental problems in tumor biology. To address these questions, we utilized metastasis assays in mice to show that dormant DTCs reside upon microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumor-promoting, endothelial tip cell-derived factors. Our work reveals that stable microvasculature constitutes a ‘dormant niche,’ whereas sprouting neovasculature sparks micrometastatic outgrowth. PMID:23728425

  19. Gastric perforation secondary to metastasis from breast cancer.

    PubMed

    Wong, Chee Siong; Gumber, Ashutosh; Kiruparan, Pasupathy; Blackmore, Alexander

    2016-07-18

    Gastric perforation secondary to metastasis from breast cancer occurs infrequently. We present the case of a 72-year-old postmenopausal female patient with a known history of lobular carcinoma of the breast who presented to a district general hospital with a clinical diagnosis of an acute abdomen. Further contrast-enhanced CT scan demonstrated free gas and fluid in the abdomen. She underwent emergency exploratory laparotomy and onlay Graham's omentopexy patch due to 1×1 cm prepyloric gastric perforation. Final histopathology proved the presence of metastatic malignant cells in the breast origin. We discuss the issues involved in postoperative investigation and management.

  20. Pure mucinous carcinoma with axillary lymph node metastasis in a male breast.

    PubMed

    Dragoumis, Dimitrios M; Assimaki, Anthoula S; Tsiftsoglou, Aris P

    2012-10-01

    Pure mucinous carcinoma of the male breast is an extremely uncommon malignant breast neoplasm and usually occurs at advanced age. It is characterized by a higher degree of mucus production, a more benign behavior, a lower incidence of metastatic nodal involvement, and a subsequent higher survival rate. We describe such a case of a 59-year-old male, who displayed a gradually growing retroareolar tumor of the right breast. The tumor was well demarcated and had a soft consistency with a gelatinous appearance. Based on the preoperative clinical identification of right axillary lymphadenopathy, the patient eventually underwent right modified radical mastectomy and right axillary nodal dissection. Regarding histological findings, the neoplasm corresponded to a pure mucinous carcinoma with axillary lymph node metastasis. Although lymph node metastasis of pure mucinous carcinoma of the breast is rare, it is essential to perform careful clinical examination when the primary breast mass is suspicious for mucinous carcinoma, because the presence of axillary lymphadenopathy will subsequently define the proper choice of therapeutic strategy.

  1. Is tail vein injection a relevant breast cancer lung metastasis model?

    PubMed Central

    Rashid, Omar M.; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine I.; Schaum, Julia C.; Yamada, Akimitsu; Aoyagi, Tomoyoshi; Milstien, Sheldon; Spiegel, Sarah

    2013-01-01

    Background Two most commonly used animal models for studying breast cancer lung metastasis are: lung metastasis after orthotopic implantation of cells into the mammary gland, and lung implantations produced after tail vein (TV) injection of cells. Tail vein injection can produce lung lesions faster, but little has been studied regarding the differences between these tumors, thus, we examined their morphology and gene expression profiles. Methods Syngeneic murine mammary adenocarcinoma, 4T1-luc2 cells, were implanted either subcutaneously (Sq), orthotopically (OS), or injected via TV in Balb/c mice. Genome-wide microarray analyses of cultured 4T1 cells, Sq tumor, OS tumor, lung metastases after OS (LMet), and lung tumors after TV (TVt) were performed 10 days after implantation. Results Bioluminescence analysis demonstrated different morphology of metastases between LMet and TVt, confirmed by histology. Gene expression profile of cells were significantly different from tumors, OS, Sq, TVt or LMet (10,350 probe sets; FDR≤1%; P<0.0001). Sq tumors were significantly different than OS tumors (700 probe sets; FDR≤15%; P<0.01), and both tumor types (Sq and OS) were significantly different than LMet (1,247 probe sets; >1.5-fold-change; P<0.01), with no significant difference between TVt and LMet. Conclusions There were significant differences between the gene profiles of cells in culture and OS versus LMet, but there were no differences between LMet versus TVt. Therefore, the lung tumor generated by TVt can be considered genetically similar to those produced after OS, and thus TVt is a relevant model for breast cancer lung metastasis. PMID:23991292

  2. Dietary linoleate-enhanced metastasis of 4526 murine mammary tumors

    SciTech Connect

    Hubbard, N.E.

    1987-01-01

    The influence of quantitative differences in dietary linoleic acid (18:2) and of the cyclooxygenase inhibitor, indomethacin (IM), on the metastasis of line 4526 mammary tumors was investigated. All mice were fed high fat (20%, w/w), semipurified diets that were prepared using different mixtures of coconut (primarily saturated) and safflower (mostly 18:2) oil and thus contained either 1, 2, 4, 8, or 12% 18:2 (w/w). The spontaneous metastasis of 4526 tumor cells from primary sites, was increased 2-4 fold in mice that were fed diets containing higher levels of 18:2 (8 and 12%). Chronic treatment of mice with a relatively low dosage of IM reduced the growth rate of primary 4526 tumors, slightly reduced metastasis in mice fed 1 and 4% 18:2, and completely inhibited the increased metastasis observed in mice fed 12% 18:2. Treatment with a higher dosage of IM reduced metastasis even further compared to controls, but did not decrease growth rate compared to the low dosage of IM. The level of 18:2 in the diet did not appear to affect the incorporation of {sup 3}H-thymidine into tumor cells of metastatic lung nodules. The effect of 18:2 may be through a modulation of arachidonic acid metabolism. This modulation, in turn, may affect particular steps in the metastatic cascade such as lodgement and survival of tumor cells.

  3. Regulation of hematogenous tumor metastasis by acid sphingomyelinase

    PubMed Central

    Carpinteiro, Alexander; Becker, Katrin Anne; Japtok, Lukasz; Hessler, Gabriele; Keitsch, Simone; Požgajovà, Miroslava; Schmid, Kurt W; Adams, Constantin; Müller, Stefan; Kleuser, Burkhard; Edwards, Michael J; Grassmé, Heike; Helfrich, Iris; Gulbins, Erich

    2015-01-01

    Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1−/− mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of α5β1 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing β1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis. PMID:25851537

  4. Genes that mediate breast cancer metastasis to the brain.

    PubMed

    Bos, Paula D; Zhang, Xiang H-F; Nadal, Cristina; Shu, Weiping; Gomis, Roger R; Nguyen, Don X; Minn, Andy J; van de Vijver, Marc J; Gerald, William L; Foekens, John A; Massagué, Joan

    2009-06-18

    The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.

  5. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer

    PubMed Central

    Yang, Ying-Hua; Buhamrah, Asma; Schneider, Abraham; Lin, Yi-Ling; Zhou, Hua; Bugshan, Amr; Basile, John R.

    2016-01-01

    Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects. PMID:26910109

  6. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer.

    PubMed

    Yang, Ying-Hua; Buhamrah, Asma; Schneider, Abraham; Lin, Yi-Ling; Zhou, Hua; Bugshan, Amr; Basile, John R

    2016-01-01

    Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects.

  7. Rectal metastasis from Breast cancer: A rare entity

    PubMed Central

    Ng, Cho Ee; Wright, Lucie; Pieri, Andrew; Belhasan, Anas; Fasih, Tarannum

    2015-01-01

    Introduction Breast cancer metastases occurs in around 50% of all presentation. It is the second most common type of cancer to metastasise to the GI tract but this only occurs in less than 1% of cases. Presentation of case We report a case that underwent treatment for invasive lobular cancer (ILC) of the breast and 5 years later was found to have rectal and peritoneal metastasis. She is currently receiving palliative management including chemotherapy in the form of weekly Paclitaxel (Taxol®) and stenting to relieve obstruction. Conclusion There should be high clinical suspicion of bowel metastasis in patients presenting with positive faecal occult blood with or without bowel symptoms even if the incidence is less <1% of metastases, particularly in cases where the initial breast tumour was large, with positive axillary nodes. PMID:26188979

  8. Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis

    PubMed Central

    Minami, Kazumasa; Liu, Shengzhi; Liu, Yang; Chen, Andy; Wan, Qiaoqiao; Na, Sungsoo; Li, Bai-Yan; Matsuura, Nariaki; Koizumi, Masahiko; Yin, Yukun; Gan, Liangying; Xu, Aihua; Li, Jiliang; Nakshatri, Harikrishna; Yokota, Hiroki

    2017-01-01

    Dopaminergic signaling plays a critical role in the nervous system, but little is known about its potential role in breast cancer and bone metabolism. A screening of ~1,000 biologically active compounds revealed that a selective agonist of dopamine receptor D1 (DRD1), A77636, inhibited proliferation of 4T1.2 mammary tumor cells as well as MDA-MB-231 breast cancer cells. Herein, we examined the effect of A77636 on bone quality using a mouse model of bone metastasis from mammary tumor. A77636 inhibited migration of cancer cells in a DRD1-dependent fashion and suppressed development of bone-resorbing osteoclasts by downregulating NFATc1 through the elevation of phosphorylation of eIF2α. In the mouse model of bone metastasis, A77636 reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Collectively, we expect that dopaminergic signaling might provide a novel therapeutic target for breast cancer and bone metastasis. PMID:28374823

  9. Bilateral desmoid tumor of the breast: case seriesand literature review

    PubMed Central

    Wongmaneerung, Phanchaporn; Somwangprasert, Areewan; Watcharachan, Kirati; Ditsatham, Chagkrit

    2016-01-01

    Background Desmoid tumor of the breast is very rare and locally aggressive but has no distant metastasis. Bilateral lesions are extremely rare, found in only 4% of patients. Two cases of bilateral desmoid tumor of the breast are reported. The clinical presentation, diagnosis, imaging, treatment, and follow-up outcomes of recurrence as well as a brief literature review are provided. Case reports Case 1 is a 31-year-old woman who presented with nipple retraction. An ultrasound revealed BIRAD V in both breasts. She underwent a bilateral excisional biopsy under ultrasound mark with the pathology result of extra-abdominal desmoid tumor in both breasts. The patient had a bilateral mastectomy with silicone implantation due to the involved margins by excision. She remained tumor free after 7-year follow-up. Case 2 is a 28-year-old woman who presented with a lump on her right breast that she had discovered ~2 months earlier. An ultrasound showed a spiculated mass in the right breast and some circumscribed hypoechoic masses in both breasts. A bilateral breast excision was done. The pathology result was an extra-abdominal desmoid tumor. She had recurrence on both sides and underwent a mastectomy and silicone implantation. The tumor has not recurred after 1-year follow-up. Conclusion Imaging cannot distinguish between benign breast lesions and malignancy. Pathology results are helpful in making a definitive diagnosis. Given that the desmoid tumor is locally aggressive, a local excision with clear margins is recommended. Chemotherapy and hormonal treatment are controversial. PMID:27578999

  10. Detection of cellular senescence within human invasive breast carcinomas distinguishes different breast tumor subtypes

    PubMed Central

    Cotarelo, Cristina L.; Schad, Arno; Kirkpatrick, Charles James; Sleeman, Jonathan P.; Springer, Erik; Schmidt, Marcus; Thaler, Sonja

    2016-01-01

    Oncogene-induced senescence is thought to act as a barrier to tumorigenesis by arresting cells at risk of malignant transformation. Nevertheless, numerous findings suggest that senescent cells may conversely promote tumor progression through the development of the senescence-associated secretome they produce. It is likely that the composition and the physiological consequences mediated by the senescence secretome are dependent on the oncogenes that trigger the senescence program. Breast cancer represents a heterogenous disease that can be divided into breast cancer subtypes due to different subsets of genetic and epigenetic abnormalities. As tumor initiation and progression of these breast cancer subtypes is triggered by diverse oncogenic stimuli, differences in the senescence secretomes within breast tumors might be responsible for tumor initiation, progression, metastasis and therapeutic response. Many studies have addressed the role of senescence as a barrier to tumor progression using murine xenograft models. However, few investigations have been performed to elucidate the degree to which senescent tumor cells are present within untreated human tumors, and if present, whether these senescent tumor cells may play a role in disease progression. In the present study we analysed the appearance of senescent cells within invasive breast cancers. Detection of cellular senescence by the use of SAβ-galactosidase (SAβ-gal) staining within invasive breast carcinoms from 129 untreated patients revealed differences in the amount of SAβ-gal+ tumor cells between breast cancer subtypes. The highest percentages of SAβ-gal+ tumor cells were found in HER2-positive and luminal A breast carcinomas whereas triple negative tumors showed either little or no positivity. PMID:27713152

  11. Neural Regulation of Breast Cancer Metastasis

    DTIC Science & Technology

    2009-10-01

    and F. Entschladen, The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta ... blockers . Int J Cancer, 2006. 118(11): p. 2744-9. 8. Draoui, A, B. Vandewalle, L. Hornez, F. Revillion, and J. Lefebvre, Beta-adrenergic receptors in

  12. ERα Mediates Estrogen-Induced Expression of the Breast Cancer Metastasis Suppressor Gene BRMS1

    PubMed Central

    Ma, Hongtao; Gollahon, Lauren S.

    2016-01-01

    Recently, estrogen has been reported as putatively inhibiting cancer cell invasion and motility. This information is in direct contrast to the paradigm of estrogen as a tumor promoter. However, data suggests that the effects of estrogen are modulated by the receptor isoform with which it interacts. In order to gain a clearer understanding of the role of estrogen in potentially suppressing breast cancer metastasis, we investigated the regulation of estrogen and its receptor on the downstream target gene, breast cancer metastasis suppressor 1 (BRMS1) in MCF-7, SKBR3, TTU-1 and MDA-MB-231 breast cancer cells. Our results showed that estrogen increased the transcription and expression of BRMS1 in the ERα positive breast cancer cell line, MCF-7. Additionally, the ERα specific agonist PPT also induced the transcription and expression of BRMS1. However, the two remaining estrogen receptor (ER) subtype agonists had no effect on BRMS1 expression. In order to further examine the influence of ERα on BRMS1 expression, ERα expression was knocked down using siRNA (siERα). Western blot analysis showed that siERα reduced estrogen-induced and PPT-induced BRMS1 expression. In summary, this study demonstrates estrogen, via its α receptor, positively regulates the expression of BRMS1, providing new insight into a potential inhibitory effect of estrogen on metastasis suppression. PMID:26821020

  13. Modulating mammary tumor growth, metastasis and immunosuppression by siRNA-induced MIF reduction in tumor microenvironment.

    PubMed

    Zhang, M; Yan, L; Kim, J A

    2015-10-01

    Macrophage migration inhibitory factor (MIF) has been identified as a major gene product upregulated in breast cancer cells-tissues upon the accumulation of macrophages. However, regulatory role of MIF in tumor microenvironment is not well understood. Previously, we have developed small interfering RNA (siRNA)-loaded nanoparticle system to effectively reduce MIF expression in both breast cancer cells and macrophages. Using this nanoparticle system, in this study we demonstrated that the siRNA-induced MIF reduction in murine mammary cancer line 4T1 and human breast cancer line MDA-MB-231 resulted in significant reduction of cell proliferation and increase of apoptosis; the siRNA-induced MIF reduction in tumor-associated macrophages resulted in a significant reduction of surface expression of CD74 and CD206 and a significant increase of surface expression of major histocompatibility complex II, as well as intracellular expression of tumor necrosis factor-α and interleukin-2. A direct injection of the MIF-siRNA-loaded nanoparticles into 4T1 tumor in mice resulted in effective reduction of intratumoral MIF. This led to a reduction of tumor growth and metastasis. This also resulted in a reduction of circulating myeloid-derived suppressive cells both in number and in suppressive function. CD4 T-cell infiltration to tumor was increased. More importantly, this not only slowed the growth of treated 4T1 tumor, but also delayed the growth and metastasis of a contralateral untreated 4T1-luc tumor, suggesting the development of systemic antitumor responses. This study demonstrates for the first time that the siRNA-mediated intratumoral MIF reduction can induce antitumoral immune response via reducing systemic immune suppression.

  14. Occult breast primary malignancy presenting as isolated axillary lymph node metastasis - early detection of primary site by 18F-FDG PET/CT.

    PubMed

    Soundararajan, Ramya; Naswa, Niraj; Karunanithi, Sellam; Walia, Ritika; Kumar, Rakesh; Bal, Chandrasekhar

    2016-01-01

    Breast cancer patients rarely present with isolated axillary lymph node metastasis without any clinical or radiological evidence of primary tumor. Identification of the primary site of tumor helps in planning appropriate patient management which has definite impact on patient's survival. We present here a case of 30-year-old female who presented with isolated right axillary lymph node metastasis with no evidence of primary tumor clinically. Conventional imaging modalities were negative for primary site. She underwent whole body 18F-Flurodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and it contributed significantly in early detection of occult primary tumor in right breast.

  15. γ knife radiosurgery of brain metastasis from breast cancer.

    PubMed

    Padovani, Laetitia; Muracciole, Xavier; Régis, Jean

    2012-01-01

    The incidence of brain metastasis in patients with metastatic breast cancer ranges from 14 to 16%.Age, number of metastatic sites, short disease-free survival and molecular subtypes are associated with the occurrence of brain metastasis. Patients classified in the triple-negative group more frequently presented brain metastasis as the first site (26%) than those in the human epidermal growth factor receptor 2 (HER2)-positive (6%) or luminal (12%) subtypes. Whole brain radiation therapy (WBRT) is still the standard treatment for breast cancer patients with brain metastasis. The 1- and 2-year survival rates of patients with brain metastasis were 25 and 10%, respectively, with a median survival of 6 months. In selected patients with single brain metastasis, majority of lung cancer, three randomized controlled trials underlined the significant survival benefit in adding local treatment such as surgery or stereotactic radio surgery to WBRT. Similarly, the upfront stereotactic radiosurgery (SRS) alone did not affect survival rate in three other randomized studies and represents an alternative treatment for patients with stage 1-4. Metastatic breast cancer patients with Karnofsky Performance Scale ≥70, single or oligometastatic brain metastases and well-controlled extracranial disease or favorable disease-specific graded prognostic assessment group presented a median overall survival of 16 months. Delaying WBRT could spare patients of neurocognitive toxicity due to full-dose whole brain irradiation. Nevertheless, the real WBRT neurocognitive impact is still unclear. These patients should be followed with serial magnetic resonance image every 3 months and treated with WBRT or additional SRS at recurrence to control brain disease.

  16. LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice.

    PubMed

    Li, Rong; Doherty, Judy; Antonipillai, Juliana; Chen, Sheng; Devlin, Mark; Visser, Kathryn; Baell, Jonathan; Street, Ian; Anderson, Robin L; Bernard, Ora

    2013-04-01

    Metastasis is the major cause of morbidity and mortality in cancer patients. An understanding of the genes that regulate metastasis and development of therapies to target these genes is needed urgently. Since members of the LIM kinase (LIMK) family are key regulators of the actin cytoskeleton and are involved in cell motility and invasion, LIMK is considered to be a good therapeutic target for metastatic disease. Here we investigated the consequences of LIMK inhibition on growth and metastasis of human and mouse mammary tumors. LIMK activity was reduced in tumor cells by expression of dominant-negative LIMK1, by RNA interference or with a selective LIMK inhibitor. The extent of phosphorylation of the LIMK substrate, cofilin, of proliferation and invasion in 2D and 3D culture and of tumor growth and metastasis in mice were assessed. Inhibition of LIMK activity efficiently reduced the pro-invasive properties of tumor cells in vitro. Tumors expressing dominant-negative LIMK1 grew more slowly and were less metastatic in mice. However, systemic administration of a LIMK inhibitor did not reduce either primary tumor growth or spontaneous metastasis. Surprisingly, metastasis to the liver was increased after administration of the inhibitor. These data raise a concern about the use of systemic LIMK inhibitors for the treatment of metastatic breast cancer.

  17. Inhibiting metastasis of breast cancer cells in vitro using gold nanorod-siRNA delivery system

    NASA Astrophysics Data System (ADS)

    Zhang, Weiqi; Meng, Jie; Ji, Yinglu; Li, Xiaojin; Kong, Hua; Wu, Xiaochun; Xu, Haiyan

    2011-09-01

    Breast cancer is the most common malignant disease in women, and it is not the primary tumor but its metastasis kills most patients with breast cancer. Anti-metastasis therapy based on RNA interference (RNAi) is emerging as one of promising strategies in tumor therapy. However, construction of an efficient delivery system for siRNA is still one of the major challenges. In this work, siRNA against protease-activated receptor-1 (PAR-1) which is a pivotal gene involved in tumor metastasis was conjugated to gold nanorods (AuNRs) via electrostatic interaction and delivered to highly metastatic human breast cancer cells. It was demonstrated that the siRNA oligos were successfully delivered into the cancer cells and mainly located in vesicle-like structures including lysosome. After transfected with the complex of AuNRs and PAR-1 siRNA (AuNRs@PAR-1 siRNA), expression of PAR-1 at both mRNA and protein levels were efficiently down regulated, as evidenced by quantitative real time PCR and flow cytometry analysis, respectively. Transwell migration assay confirmed the decrease in metastatic ability of the cancer cells. The silencing efficiency of the complex was in-between that of TurboFect and Lipofectamine, however, the cytotoxicity of the AuNRs was lower than that of the latter two. Taken together, AuNRs with PAR-1 siRNA are suited for RNAi based anti-metastasis therapy.Breast cancer is the most common malignant disease in women, and it is not the primary tumor but its metastasis kills most patients with breast cancer. Anti-metastasis therapy based on RNA interference (RNAi) is emerging as one of promising strategies in tumor therapy. However, construction of an efficient delivery system for siRNA is still one of the major challenges. In this work, siRNA against protease-activated receptor-1 (PAR-1) which is a pivotal gene involved in tumor metastasis was conjugated to gold nanorods (AuNRs) via electrostatic interaction and delivered to highly metastatic human breast cancer

  18. LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling.

    PubMed

    Kuzmanov, Aleksandar; Hopfer, Ulrike; Marti, Patricia; Meyer-Schaller, Nathalie; Yilmaz, Mahmut; Christofori, Gerhard

    2014-03-01

    An epithelial-mesenchymal transition (EMT) is a critical process during embryonic development and the progression of epithelial tumors to metastatic cancers. Gene expression profiling has uncovered the transcription factor LIM homeobox gene 2 (Lhx2) with up-regulated expression during TGFβ-induced EMT in normal and cancerous breast epithelial cells. Loss and gain of function experiments in transgenic mouse models of breast cancer and of insulinoma in vivo and in breast cancer cells in vitro indicate that Lhx2 plays a critical role in primary tumor growth and metastasis. Notably, the transgenic expression of Lhx2 during breast carcinogenesis promotes vessel maturation, primary tumor growth, tumor cell intravasation and metastasis by directly inducing the expression of platelet-derived growth factor (PDGF)-B in tumor cells and by indirectly increasing the expression of PDGF receptor-β (PDGFRβ) on tumor cells and pericytes. Pharmacological inhibition of PDGF-B/PDGFRβ signaling reduces vessel functionality and tumor growth and Lhx2-induced cell migration and cell invasion. The data indicate a dual role of Lhx2 during EMT and tumor progression: by inducing the expression of PDGF-B, Lhx2 provokes an autocrine PDGF-B/PDGFRβ loop required for cell migration, invasion and metastatic dissemination and paracrine PDGF-B/PDGFRβ signaling to support blood vessel functionality and, thus, primary tumor growth.

  19. A novel microfluidic model can mimic organ-specific metastasis of circulating tumor cells

    PubMed Central

    Kong, Jing; Luo, Yong; Jin, Dong; An, Fan; Zhang, Wenyuan; Liu, Lilu; Li, Jiao; Fang, Shimeng; Li, Xiaojie; Yang, Xuesong; Lin, Bingcheng; Liu, Tingjiao

    2016-01-01

    A biomimetic microsystem might compensate costly and time-consuming animal metastatic models. Herein we developed a biomimetic microfluidic model to study cancer metastasis. Primary cells isolated from different organs were cultured on the microlfuidic model to represent individual organs. Breast and salivary gland cancer cells were driven to flow over primary cell culture chambers, mimicking dynamic adhesion of circulating tumor cells (CTCs) to endothelium in vivo. These flowing artificial CTCs showed different metastatic potentials to lung on the microfluidic model. The traditional nude mouse model of lung metastasis was performed to investigate the physiological similarity of the microfluidic model to animal models. It was found that the metastatic potential of different cancer cells assessed by the microfluidic model was in agreement with that assessed by the nude mouse model. Furthermore, it was demonstrated that the metastatic inhibitor AMD3100 inhibited lung metastasis effectively in both the microfluidic model and the nude mouse model. Then the microfluidic model was used to mimick liver and bone metastasis of CTCs and confirm the potential for research of multiple-organ metastasis. Thus, the metastasis of CTCs to different organs was reconstituted on the microfluidic model. It may expand the capabilities of traditional cell culture models, providing a low-cost, time-saving, and rapid alternative to animal models. PMID:27191997

  20. Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis.

    PubMed

    McCaffrey, Luke Martin; Montalbano, JoAnne; Mihai, Constantina; Macara, Ian G

    2012-11-13

    Loss of epithelial organization is a hallmark of carcinomas, but whether polarity regulates tumor growth and metastasis is poorly understood. To address this issue, we depleted the Par3 polarity gene by RNAi in combination with oncogenic Notch or Ras(61L) expression in the murine mammary gland. Par3 silencing dramatically reduced tumor latency in both models and produced invasive and metastatic tumors that retained epithelial marker expression. Par3 depletion was associated with induction of MMP9, destruction of the extracellular matrix, and invasion, all mediated by atypical PKC-dependant JAK/Stat3 activation. Importantly, Par3 expression is significantly reduced in human breast cancers, which correlates with active aPKC and Stat3. These data identify Par3 as a regulator of signaling pathways relevant to invasive breast cancer.

  1. Phase transitions in tumor growth: III vascular and metastasis behavior

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, J. A.; Cocho, G.; Mansilla, R.; Nieto-Villar, José Manuel

    2016-11-01

    We propose a mechanism for avascular, vascular and metastasis tumor growth based on a chemical network model. Vascular growth and metastasis, appear as a hard phase transition type, as "first order", through a supercritical Andronov-Hopf bifurcation, emergence of limit cycle and then through a cascade of bifurcations type saddle-foci Shilnikov's bifurcation. Finally, the thermodynamics framework developed shows that the entropy production rate, as a Lyapunov function, indicates the directional character and stability of the dynamical behavior of tumor growth according to this model.

  2. [Appendiceal neuroendocrine tumor with lymph node metastasis in a teenager].

    PubMed

    Kim, Keun Young; Park, Won Cheol

    2015-02-01

    Neuroendocrine tumor (NET) is a cancer-like tumor that occurs mostly in the gastrointestinal system. Within the gastrointestinal tract, NET most commonly occurs in the rectum whereas appendix is very rarely involved. In most cases of appendiceal NET, it is found at a relatively early stage compared to other NETs because appendiceal NET frequently presents with acute appendicitis because appendiceal NET frequently presents with acute appendicitis even when the size is smaller than 1 cm. Therefore, it is very rare for lymph node metastasis to occur in a young adult. Herein, we report a rare case of grade 1 appendiceal NET with lymph node metastasis which developed in a teenage male.

  3. Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo

    SciTech Connect

    Zhou, Z. N.; Sharma, V. P.; Beaty, B. T.; Roh-Johnson, M.; Peterson, E. A.; Van Rooijen, N.; Kenny, P. A.; Wiley, H. S.; Condeelis, J. S.; Segall, J. E.

    2014-10-13

    Increased expression of HBEGF in estrogen receptor-negative breast tumors is correlated with enhanced metastasis to distant organ sites and more rapid disease recurrence upon removal of the primary tumor. Our previous work has demonstrated a paracrine loop between breast cancer cells and macrophages in which the tumor cells are capable of stimulating macrophages through the secretion of colony-stimulating factor-1 while the tumor-associated macrophages (TAMs), in turn, aid in tumor cell invasion by secreting epidermal growth factor. To determine how the autocrine expression of epidermal growth factor receptor (EGFR) ligands by carcinoma cells would affect this paracrine loop mechanism, and in particular whether tumor cell invasion depends on spatial ligand gradients generated by TAMs, we generated cell lines with increased HBEGF expression. We found that autocrine HBEGF expression enhanced in vivo intravasation and metastasis and resulted in a novel phenomenon in which macrophages were no longer required for in vivo invasion of breast cancer cells. In vitro studies revealed that expression of HBEGF enhanced invadopodium formation, thus providing a mechanism for cell autonomous invasion. The increased invadopodium formation was directly dependent on EGFR signaling, as demonstrated by a rapid decrease in invadopodia upon inhibition of autocrine HBEGF/EGFR signaling as well as inhibition of signaling downstream of EGFR activation. HBEGF expression also resulted in enhanced invadopodium function via upregulation of matrix metalloprotease 2 (MMP2) and MMP9 expression levels. We conclude that high levels of HBEGF expression can short-circuit the tumor cell/macrophage paracrine invasion loop, resulting in enhanced tumor invasion that is independent of macrophage signaling.

  4. Palbociclib inhibits epithelial-mesenchymal transition and metastasis in breast cancer via c-Jun/COX-2 signaling pathway.

    PubMed

    Qin, Ge; Xu, Fei; Qin, Tao; Zheng, Qiufan; Shi, Dingbo; Xia, Wen; Tian, Yun; Tang, Yanlai; Wang, Jingshu; Xiao, Xiangshen; Deng, Wuguo; Wang, Shusen

    2015-12-08

    Palbociclib, a highly selective CDK4/6 inhibitor, has been shown to be a novel anti-tumor agent that suppresses breast cancer cell proliferation. However, its anti-metastasis activity remains controversial. In the present study, we evaluated whether palbociclib prevented breast cancer cell metastasis and revealed its regulatory mechanism. We found that palbociclib inhibited migration and invasion in the breast cancer cells MDA-MB-231 and T47D. The epithelial-mesenchymal transition (EMT) markers, vimentin and Snail, were down-regulated with palbociclib treatment. Moreover, we revealed that this inhibition was mediated by the c-Jun/COX-2 pathway. COX-2 was decreased after palbociclib treatment. The production of PGE2 was also reduced along with COX-2. Additionally, our data showed that c-Jun, a crucial transcriptional regulator of COX-2, was down-regulated by palbociclib. We found that palbociclib weakened the COX-2 promoter binding activity of c-Jun and prevented its translocation from the cytoplasm to cell nuclei. Bioluminescence imaging and tail intravenous injection were used to evaluate the anti-metastasis effect of palbociclib in vivo. The data demonstrated that palbociclib reduced breast cancer metastasis to the lung. These results therefore demonstrated that the anti-metastasis activity of palbociclib is mediated via the c-Jun/COX-2 signaling pathway by inhibiting EMT in breast cancer cells.

  5. Palbociclib inhibits epithelial-mesenchymal transition and metastasis in breast cancer via c-Jun/COX-2 signaling pathway

    PubMed Central

    Zheng, Qiufan; Shi, Dingbo; Xia, Wen; Tian, Yun; Tang, Yanlai; Wang, Jingshu; Xiao, Xiangshen; Deng, Wuguo; Wang, Shusen

    2015-01-01

    Palbociclib, a highly selective CDK4/6 inhibitor, has been shown to be a novel anti-tumor agent that suppresses breast cancer cell proliferation. However, its anti-metastasis activity remains controversial. In the present study, we evaluated whether palbociclib prevented breast cancer cell metastasis and revealed its regulatory mechanism. We found that palbociclib inhibited migration and invasion in the breast cancer cells MDA-MB-231 and T47D. The epithelial-mesenchymal transition (EMT) markers, vimentin and Snail, were down-regulated with palbociclib treatment. Moreover, we revealed that this inhibition was mediated by the c-Jun/COX-2 pathway. COX-2 was decreased after palbociclib treatment. The production of PGE2 was also reduced along with COX-2. Additionally, our data showed that c-Jun, a crucial transcriptional regulator of COX-2, was down-regulated by palbociclib. We found that palbociclib weakened the COX-2 promoter binding activity of c-Jun and prevented its translocation from the cytoplasm to cell nuclei. Bioluminescence imaging and tail intravenous injection were used to evaluate the anti-metastasis effect of palbociclib in vivo. The data demonstrated that palbociclib reduced breast cancer metastasis to the lung. These results therefore demonstrated that the anti-metastasis activity of palbociclib is mediated via the c-Jun/COX-2 signaling pathway by inhibiting EMT in breast cancer cells. PMID:26540629

  6. TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β-Catenin Pathway upon LPS Stimulation.

    PubMed

    Li, Jun; Yin, Jing; Shen, Wenzhi; Gao, Ruifang; Liu, Yanhua; Chen, Yanan; Li, Xiru; Liu, Chenghu; Xiang, Rong; Luo, Na

    2017-03-14

    Bacteria/virus-induced chronic inflammation is involved in both tumor initiation and tumor progression. Toll-like receptor 4 (TLR4) has been implicated in the development of several types of cancer. In this study, we explored the impact of TLR4 activation by lipopolysaccharide (LPS) on breast cancer metastasis and associated signaling molecules. We first examined TLR4 expression levels in breast tissue using a human breast tissue microarray and breast cell lines. We then studied the role of TLR4 activation by LPS stimulation in breast cancer metastasis using both in vitro and in vivo models. Finally, we investigated signaling molecules involved in the process using Western blotting and fluorescent immunohistochemistry staining. The results showed that TLR4 expression levels increased in breast cancer tissue compared to normal breast tissue. In addition, our results also showed that TLR4 pathway activation by LPS stimulation in MCF7 and MDA-MB-231 breast cancer cells caused the following actions: (1) promotes migration of breast cancer cells, (2) triggers the β-catenin signaling pathway via PI3K/Akt/GSK3β, and (3) promotes transcription of downstream β-catenin target genes leading to breast cancer metastasis. This study substantiates and further extends the relationship between TLR4 activation by LPS and breast cancer using both in vitro and in vivo models. The results suggest that the Akt/GSK3β/β-catenin signal transduction pathway may serve as a viable clinical treatment target in breast cancer. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc.

  7. Eribulin Mesylate Combined with Local Treatment for Brain Metastasis from Breast Cancer: Two Case Reports

    PubMed Central

    Byun, Kyung-Do; Ahn, Sung Gwe; Baik, Hyung Joo; Lee, Anbok; Bae, Ki Beom; An, Min Sung; Kim, Kwang Hee; Shin, Jae Ho; Park, Ha Kyoung; Cho, Heunglae; Jeong, Joon

    2016-01-01

    The prognosis associated with brain metastasis arising from breast cancer is very poor. Eribulin is a microtubule dynamic inhibitor synthesized from halichondrin B, a natural marine product. In a phase III study (EMBRACE), eribulin improved overall survival in patients with heavily pretreated metastatic breast cancers. However, these studies included few patients with brain metastases. Metastatic brain tumors (MBT) were detected during first-line palliative chemotherapy in a 43-year-old woman with breast cancer metastasis to the lung and mediastinal nodes; the genetic subtype was luminal B-like human epidermal growth factor receptor 2 (HER2)-negative. Whole brain radiotherapy (WBRT) followed by eribulin treatment continuously decreased the size, and induced regression, of the MBT with systemic disease stability for 12 months. Another 48-year-old woman with metastatic breast cancer (HER2+ subtype) presented with MBT. Following surgical resection of the tumor, eribulin with concurrent WBRT showed regression of the MBT without systemic progression for 18 months. PMID:27382400

  8. Apoptosis-linked gene 2 promotes breast cancer growth and metastasis by regulating the cytoskeleton.

    PubMed

    Qin, Juan; Li, Dengwen; Zhou, Yunqiang; Xie, Songbo; Du, Xin; Hao, Ziwei; Liu, Ruming; Liu, Xinqi; Liu, Min; Zhou, Jun

    2017-01-10

    Breast cancer is the most prevalent cancer in women. Although it begins as local disease, breast cancer frequently metastasizes to the lymph nodes and distant organs. Therefore, novel therapeutic targets are needed for the management of this disease. Apoptosis-linked gene 2 (ALG-2) is a calcium-binding protein crucial for diverse physiological processes and has recently been implicated in cancer development. However, it remains unclear whether this protein is involved in the pathogenesis of breast cancer. Here, we demonstrate that the expression of ALG-2 is significantly upregulated in breast cancer tissues and is correlated with clinicopathological characteristics indicative of tumor malignancy. Our data further show that ALG-2 stimulates breast cancer growth and metastasis in mice. ALG-2 also promotes breast cancer cell proliferation, survival, and motility in vitro. Mechanistic data reveal that ALG-2 disrupts the localization of centrosome proteins, resulting in spindle multipolarity and chromosome missegregation. In addition, ALG-2 drives the polarization and migration of breast cancer cells by facilitating the rearrangement of microtubules and microfilaments. These findings reveal a critical role for ALG-2 in the pathogenesis of breast cancer and have important implications for its diagnosis and therapy.

  9. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Gαq-p63RhoGEF-Rho GTPase pathway.

    PubMed

    Tang, Xiaolong; Jin, Rongrong; Qu, Guojun; Wang, Xiu; Li, Zhenxi; Yuan, Zengjin; Zhao, Chen; Siwko, Stefan; Shi, Tieliu; Wang, Ping; Xiao, Jianru; Liu, Mingyao; Luo, Jian

    2013-10-15

    Adhesion G-protein-coupled receptors (GPCR), which contain adhesion domains in their extracellular region, have been found to play important roles in cell adhesion, motility, embryonic development, and immune response. Because most adhesion molecules with adhesion domains have vital roles in cancer metastasis, we speculated that adhesion GPCRs are potentially involved in cancer metastasis. In this study, we identified GPR116 as a novel regulator of breast cancer metastasis through expression and functional screening of the adhesion GPCR family. We found that knockdown of GPR116 in highly metastatic (MDA-MB-231) breast cancer cells suppressed cell migration and invasion. Conversely, ectopic GPR116 expression in poorly metastatic (MCF-7 and Hs578T) cells promoted cell invasion. We further showed that knockdown of GPR116 inhibited breast cancer cell metastasis in two mammary tumor metastasis mouse models. Moreover, GPR116 modulated the formation of lamellipodia and actin stress fibers in cells in a RhoA- and Rac1-dependent manner. At a molecular level, GPR116 regulated cell motility and morphology through the Gαq-p63RhoGEF-RhoA/Rac1 pathway. The biologic significance of GPR116 in breast cancer is substantiated in human patient samples, where GPR116 expression is significantly correlated with breast tumor progression, recurrence, and poor prognosis. These findings show that GPR116 is crucial for the metastasis of breast cancer and support GPR116 as a potential prognostic marker and drug target against metastatic human breast cancer.

  10. CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis.

    PubMed

    Sun, Yanan; Mao, Xiaoyun; Fan, Chuifeng; Liu, Chong; Guo, Ayao; Guan, Shu; Jin, Quanxiu; Li, Bo; Yao, Fan; Jin, Feng

    2014-08-01

    CXCR4 and its ligand CXCL12 can promote the proliferation, survival, and invasion of cancer cells. They have been shown to play an important role in regulating metastasis of breast cancer to specific organs. High CXCR4 expression was also correlated to poor clinical outcome. Previous study also showed that tumor cells express a high level of CXCR4 and that tumor metastasis target tissues (lung, liver, and bone) express high levels of the ligand CXCL12, allowing tumor cells to directionally migrate to target organs via a CXCL12-CXCR4 chemotactic gradient. However, the exact mechanisms of how CXCR4 and CXCL12 enhance metastasis and/or tumor growth and their full implications on breast cancer progression are unknown. Yet it is likely that chemokine receptor signaling may provide more than just a migrational advantage by also helping the metastasized cells establish and survive in secondary environments. In this study, we investigated CXCR4 and CXCL12 expression in breast cancer and analyzed its association with clinicopathological factors by immunohistochemistry first. Then, we detected the mRNA and protein expression of CXCR4 and CXCL12 in breast cancer cell lines by Western blot and RT-PCR. The MDA-MB-231 has CXCR4 expression and very weak CXCL12 expression. So, we constructed the functional CXCL12 expression in MDA-MB-231 using a gene transfection technique. Further experiments were conducted to evaluate the effect of CXCL12 transfection on the biological behaviors of MDA-MB-231. The cell proliferation of MDA-MB-231-CXCL12 was accessed by MTT assay; the apoptosis was analyzed by an AnnexinV-FITC/propidium iodide double staining of flow cytometry method; and the cell invasive ability was examined by Matrigel invasion assay. Immunohistochemical analysis showed the co-expression of CXCR4 and CXCL12 correlated with lymph node metastasis and TNM stage (p < 0.01). It suggested that the chemokine CXCL12 and its sole ligand CXCR4 play important role in the malignance

  11. Molecular Markers for Breast Cancer: Prediction on Tumor Behavior

    PubMed Central

    Banin Hirata, Bruna Karina; Oda, Julie Massayo Maeda; Losi Guembarovski, Roberta; Ariza, Carolina Batista; de Oliveira, Carlos Eduardo Coral; Watanabe, Maria Angelica Ehara

    2014-01-01

    Breast cancer is one of the most common cancers with greater than 1,300,000 cases and 450,000 deaths each year worldwide. The development of breast cancer involves a progression through intermediate stages until the invasive carcinoma and finally into metastatic disease. Given the variability in clinical progression, the identification of markers that could predict the tumor behavior is particularly important in breast cancer. The determination of tumor markers is a useful tool for clinical management in cancer patients, assisting in diagnostic, staging, evaluation of therapeutic response, detection of recurrence and metastasis, and development of new treatment modalities. In this context, this review aims to discuss the main tumor markers in breast carcinogenesis. The most well-established breast molecular markers with prognostic and/or therapeutic value like hormone receptors, HER-2 oncogene, Ki-67, and p53 proteins, and the genes for hereditary breast cancer will be presented. Furthermore, this review shows the new molecular targets in breast cancer: CXCR4, caveolin, miRNA, and FOXP3, as promising candidates for future development of effective and targeted therapies, also with lower toxicity. PMID:24591761

  12. Molecular Mechanism of Lymph Node Metastasis in Breast Cancer

    DTIC Science & Technology

    2010-09-01

    modulated mammary tumor growth and spontaneous metastasis. Moreover, expression of CCR7 had no effect on primary tumor growth, but affects lymph node...express CCL21, which is not affected following treatment with hyaluronan. Together, these data suggest an important role of HAS2, LYVE1 and CCR7 in a...lym ph nodes. CCL21 is primarily expressed in LECs and functions as a ch emoattractant for CCR7 -expressi ng dendritic cells and T cells. W e

  13. The Snail-Induced Sulfonation Pathway in Breast Cancer Metastasis

    DTIC Science & Technology

    2014-09-01

    AD_________________ Award Number: W81XWH-11-1-0494   TITLE: The Snail -Induced Sulfonation... Snail -Induced Sulfonation Pathway in Breast Cancer Metastasis 5b. GRANT NUMBER W81XWH-11-1-0494 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Dr...provided funding for a 3-year project that has resulted in fundamental new insights into how the transcription factor Snail can control gene

  14. Cutaneous metastasis of primitive neuroectodermal lung tumor.

    PubMed

    Garcia Romero, Diana; Hilara Sanchez, Yolanda; Perez Alvarez, Javier; Ramirez Garcia, Jose Ramon; De Pable Martin, Maria Pilar

    2013-06-15

    Primary sarcomas of the chest are rare. Although primitive neuroectodermal tumor (PNET) usually develops in the chest wall, it has been described as a primary pulmonary tumor. We present an unusual case of PNET arising in the lung of an 89-year-old man.

  15. [Treatment of liver metastasis of endocrine tumors of the pancreas].

    PubMed

    Orozco Zepeda, H

    1997-01-01

    The aim of this review article is to analyze the diagnostic approach, presentation and therapeutic modalities in patients with liver metastasis from endocrine tumors. The paper shows the "state of the art" of therapeutic approaches with emphasis on the roll of different surgery, radio and chemotherapy, arterial embolization and other palliative procedures. The overall results of each of this modalities are also shown.

  16. Osteopontin facilitates tumor metastasis by regulating epithelial–mesenchymal plasticity

    PubMed Central

    Jia, Rongjie; Liang, Yingchao; Chen, Rui; Liu, Guoke; Wang, Hao; Tang, Min; Zhou, Xuyu; Wang, Huajing; Yang, Yang; Wei, Huafeng; Li, Bohua; Song, Yipeng; Zhao, Jian

    2016-01-01

    Tumor metastasis leads to high mortality; therefore, understanding the mechanisms that underlie tumor metastasis is crucial. Generally seen as a secretory protein, osteopontin (OPN) is involved in multifarious pathophysiological events. Here, we present a novel pro-metastatic role of OPN during metastatic colonization. Unlike secretory OPN (sOPN), which triggers the epithelial–mesenchymal transition (EMT) to initiate cancer metastasis, intracellular/nuclear OPN (iOPN) induces the mesenchymal–epithelial transition (MET) to facilitate the formation of metastases. Nuclear OPN is found to interact with HIF2α and impact the subsequent AKT1/miR-429/ZEB cascade. In vivo assays confirm that the progression of metastatic colonization is accompanied by the nuclear accumulation of OPN and the MET process. Furthermore, evidence of nuclear OPN in the lung metastases is exhibited in clinical specimens. Finally, VEGF in the microenvironment was shown to induce the translocation of OPN into the nucleus through a KDR/PLCγ/PKC-dependent pathway. Taken together, our results describe the pleiotropic roles of OPN in the tumor metastasis cascade, which indicate its potential as an effective target for both early and advanced tumors. PMID:28032860

  17. Genomic analysis of a spontaneous model of breast cancer metastasis to bone reveals a role for the extracellular matrix.

    PubMed

    Eckhardt, Bedrich L; Parker, Belinda S; van Laar, Ryan K; Restall, Christina M; Natoli, Anthony L; Tavaria, Michael D; Stanley, Kym L; Sloan, Erica K; Moseley, Jane M; Anderson, Robin L

    2005-01-01

    A clinically relevant model of spontaneous breast cancer metastasis to multiple sites, including bone, was characterized and used to identify genes involved in metastatic progression. The metastatic potential of several genetically related tumor lines was assayed using a novel real-time quantitative RT-PCR assay of tumor burden. Based on this assay, the tumor lines were categorized as nonmetastatic (67NR), weakly metastatic to lymph node (168FARN) or lung (66cl4), or highly metastatic to lymph node, lung, and bone (4T1.2 and 4T1.13). In vitro assays that mimic stages of metastasis showed that highly metastatic tumors lines were more adhesive, invasive, and migratory than the less metastatic lines. To identify metastasis-related genes in this model, each metastatic tumor was array profiled against the nonmetastatic 67NR using 15,000 mouse cDNA arrays. A significant proportion of genes relating to the extracellular matrix had elevated expression in highly metastatic tumors. The role of one of these genes, POEM, was further investigated in the model. In situ hybridization showed that POEM expression was specific to the tumor epithelium of highly metastatic tumors. Decreased POEM expression in 4T1.2 tumors significantly inhibited spontaneous metastasis to the lung, bone, and kidney. Taken together, our data support a role for the extracellular matrix in metastatic progression and describe, for the first time, a role for POEM in this process.

  18. The synergistic effects of radiofrequency ablation (RFA) with glycated chitosan for inhibiting the metastasis of breast cancer

    NASA Astrophysics Data System (ADS)

    Chiu, Hsin-Yu; Leu, Jyh-Der; Chen, Wei R.; Lee, Yi-Jang

    2016-03-01

    Breast cancer is increasing with years in Taiwan because of dietary style, life behavior and several social-physiological factors. According to the record of Bureau of Health Promotion in Taiwan, the incidence of breast cancer is top one, and the mortality of that is top one cancer type in women. Compared with USA, most of breast cancer cases found in Taiwanese women have reached to stage 2 or 3. Current therapeutic strategies for breast cancer include surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy. However, these methods used for curing the late-stage breast cancer remains rare. Because the metastasis is the major problem of late-stage breast cancer, it is of interest to investigate whether a systemic therapy can reduce the symptoms of cancer. The immunotherapy, particularly an induction of autoimmune system, is probably important for the treatment of late-stage breast cancer. Glycated chitosan (GC) is derived from chitosan, a linear polysaccharide composed of D-glucosamine and N-acetyl-D-glucosamine through β-(1-4) linkage. Several lines of evidence have shown that GC is an immunoadjuvant that can target on primary and metastatic tumors formed in animal and human patients. In our previous data, GC was demonstrated to decrease the motility and invasion of mammalian breast cancer cells in vitro and in vivo. Radiofrequency ablation (RFA) is dependent on a small generator that delivers high frequency alternating electric current directly to burn a tumor lesion. Therefore, the temperature may reach up to above 60 °C. In this study, we used 4T1 mouse breast cancer cell that is the approximately equal to stage 4 of human breast cancer. And triple modality reporter gene (3R) was delivered into the cells using transfected piggyBac, a transposable element for observation of tumor growth and metastasis in vivo. Data showed that growth and metastasis of tumors smaller than 500mm3 were entirely suppressed by RFA-GC combination treatment

  19. Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer

    PubMed Central

    Kim, Min Soo; Jeong, Joon; Seo, Jeongbeob; Kim, Hae-Suk; Kim, Seong-Jin; Jin, Wook

    2016-01-01

    Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and CSC status. We identified a new molecular and functional network present in metastasis that regulates and coordinates with TrkC. Inhibition of SOCS3-mediated JAK2 degradation by TrkC increases total JAK2/STAT3 expression, and then leads to upregulation of Twist-1 through activation of JAK2/STAT3 cascade. Also, TrkC increases secretion and expression of IL-6, suggesting that this autocrine loop generated by TrkC maintains the mesenchymal state by continued activation of the JAK2/STAT3 cascade and upregulation of Twist expression. Moreover, TrkC interacts with the c-Src/Jak2 complex, which increases Twist-1 and Twist-2 levels via regulation of JAK2/STAT3 activation and JAK2/STAT3 expression. Furthermore, TrkC enhances metastatic potential of breast cancer via induction of EMT by upregulating Twist-1 and Twist-2. Additionally, TrkC significantly enhances the ability of breast cancer cells to form pulmonary metastases and primary tumor formation. Unexpectedly, we found that TrkC expression and clinical breast tumor pathological phenotypes show significant correlation. These findings suggest that TrkC plays a central role in tumorigenicity, metastasis, and self-renewal traits of metastatic breast cancer. PMID:27654855

  20. Possible Synchronous Lung Metastasis of Breast Mass Detected Using Breast Ultrasonography: A Report of Two Cases

    PubMed Central

    Bekci, Tümay

    2015-01-01

    Ultrasonography (US), which is used for the diagnosis of breast cancer and the evaluation of its local metastasis, has proven its worth as a diagnostic method. In breast ultrasonographic examination peripherally localized metastatic lesions at the posterior of the screened breast tissue can also be detected. In this case report, two female patients whose breast ultrasonography showed lumps. Their peripheral lung metastases were screened ultrasonographically, and the patients were diagnosed in a timely manner. Ultrasonographic examination at a patient’s first appointment – and especially during routine check-ups after the primary treatment – can allow an early diagnosis of peripherally localized lung metastasis at the posterior of the screened breast tissue and make a vital contribution to the patient’s prognosis.

  1. Molecular Mechanisms in Compromised Endothelial Barrier during Breast Cancer Metastasis

    DTIC Science & Technology

    2009-03-01

    We seek to study in this project the signaling cascades in the underlying endothelium triggered by metastatic breast cancer cells during diapedesis ... diapedesis of the tumor cell triggered a marked regional activation of MLCK at the site of invasive entry – implicating a tumor-mediated biphasic Ca2

  2. Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis

    PubMed Central

    2010-01-01

    Background Toll-like receptors (TLRs) have garnered an extraordinary amount of interest in cancer research due to their role in tumor progression. By activating the production of several biological factors, TLRs induce type I interferons and other cytokines, which drive an inflammatory response and activate the adaptive immune system. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4 and 9 in breast cancer. Methods The expression levels of TLR3, TLR4 and TLR9 were analyzed on tumors from 74 patients with breast cancer. The analysis was performed by immunohistochemistry. Results Samples of carcinomas with recurrence exhibited a significant increase in the mRNA levels of TLR3, TLR4 and TLR9. Tumors showed high expression of TLRs expression levels by cancer cells, especially TLR4 and 9. Nevertheless, a significant percentage of tumors also showed TLR4 expression by mononuclear inflammatory cells (21.6%) and TLR9 expression by fibroblast-like cells (57.5%). Tumors with high TLR3 expression by tumor cell or with high TLR4 expression by mononuclear inflammatory cells were significantly associated with higher probability of metastasis. However, tumours with high TLR9 expression by fibroblast-like cells were associated with low probability of metastasis. Conclusions The expression levels of TLR3, TLR4 and TLR9 have clinical interest as indicators of tumor aggressiveness in breast cancer. TLRs may represent therapeutic targets in breast cancer. PMID:21129170

  3. Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression.

    PubMed

    Borin, Thaiz Ferraz; Arbab, Ali Syed; Gelaleti, Gabriela Bottaro; Ferreira, Lívia Carvalho; Moschetta, Marina Gobbe; Jardim-Perassi, Bruna Victorasso; Iskander, A S M; Varma, Nadimpalli Ravi S; Shankar, Adarsh; Coimbra, Verena Benedick; Fabri, Vanessa Alves; de Oliveira, Juliana Garcia; Zuccari, Debora Aparecida Pires de Campos

    2016-01-01

    The occurrence of metastasis, an important breast cancer prognostic factor, depends on cell migration/invasion mechanisms, which can be controlled by regulatory and effector molecules such as Rho-associated kinase protein (ROCK-1). Increased expression of this protein promotes tumor growth and metastasis, which can be restricted by ROCK-1 inhibitors. Melatonin has shown oncostatic, antimetastatic, and anti-angiogenic effects and can modulate ROCK-1 expression. Metastatic and nonmetastatic breast cancer cell lines were treated with melatonin as well as with specific ROCK-1 inhibitor (Y27632). Cell viability, cell migration/invasion, and ROCK-1 gene expression and protein expression were determined in vitro. In vivo lung metastasis study was performed using female athymic nude mice treated with either melatonin or Y27832 for 2 and 5 wk. The metastases were evaluated by X-ray computed tomography and single photon emission computed tomography (SPECT) and by immunohistochemistry for ROCK-1 and cytokeratin proteins. Melatonin and Y27632 treatments reduced cell viability and invasion/migration of both cell lines and decreased ROCK-1 gene expression in metastatic cells and protein expression in nonmetastatic cell line. The numbers of 'hot' spots (lung metastasis) identified by SPECT images were significantly lower in treated groups. ROCK-1 protein expression also was decreased in metastatic foci of treated groups. Melatonin has shown to be effective in controlling metastatic breast cancer in vitro and in vivo, not only via inhibition of the proliferation of tumor cells but also through direct antagonism of metastatic mechanism of cells rendered by ROCK-1 inhibition. When Y27632 was used, the effects were similar to those found with melatonin treatment.

  4. Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression

    PubMed Central

    Borin, Thaiz Ferraz; Arbab, Ali Syed; Gelaleti, Gabriela Bottaro; Ferreira, Lívia Carvalho; Moschetta, Marina Gobbe; Jardim-Perassi, Bruna Victorasso; Iskander, ASM; Varma, Nadimpalli Ravi S.; Shankar, Adarsh; Coimbra, Verena Benedick; Fabri, Vanessa Alves; de Oliveira, Juliana Garcia; de Campos Zuccari, Debora Aparecida Pires

    2016-01-01

    The occurrence of metastasis, an important breast cancer prognostic factor, depends on cell migration/invasion mechanisms, which can be controlled by regulatory and effector molecules such as Rho-associated kinase protein (ROCK-1). Increased expression of this protein promotes tumor growth and metastasis, which can be restricted by ROCK-1 inhibitors. Melatonin has shown oncostatic, antimetastatic, and anti-angiogenic effects and can modulate ROCK-1 expression. Metastatic and nonmetastatic breast cancer cell lines were treated with melatonin as well as with specific ROCK-1 inhibitor (Y27632). Cell viability, cell migration/invasion, and ROCK-1 gene expression and protein expression were determined in vitro. In vivo lung metastasis study was performed using female athymic nude mice treated with either melatonin or Y27832 for 2 and 5 wk. The metastases were evaluated by X-ray computed tomography and single photon emission computed tomography (SPECT) and by immunohistochemistry for ROCK-1 and cytokeratin proteins. Melatonin and Y27632 treatments reduced cell viability and invasion/migration of both cell lines and decreased ROCK-1 gene expression in metastatic cells and protein expression in nonmetastatic cell line. The numbers of ‘hot’ spots (lung metastasis) identified by SPECT images were significantly lower in treated groups. ROCK-1 protein expression also was decreased in metastatic foci of treated groups. Melatonin has shown to be effective in controlling metastatic breast cancer in vitro and in vivo, not only via inhibition of the proliferation of tumor cells but also through direct antagonism of metastatic mechanism of cells rendered by ROCK-1 inhibition. When Y27632 was used, the effects were similar to those found with melatonin treatment. PMID:26292662

  5. Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis.

    PubMed

    Silva, Patricio; Mendoza, Pablo; Rivas, Solange; Díaz, Jorge; Moraga, Carolina; Quest, Andrew F G; Torres, Vicente A

    2016-05-17

    Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia-driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA-targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia-induced tumor cell migration, invasion and metastasis.

  6. Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis

    PubMed Central

    Silva, Patricio; Mendoza, Pablo; Rivas, Solange; Díaz, Jorge; Moraga, Carolina; Quest, Andrew F.G.; Torres, Vicente A.

    2016-01-01

    Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia-driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA-targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia-induced tumor cell migration, invasion and metastasis. PMID:27121131

  7. Action of hexachlorobenzene on tumor growth and metastasis in different experimental models

    SciTech Connect

    Pontillo, Carolina Andrea; Rojas, Paola; Chiappini, Florencia; Sequeira, Gonzalo; Cocca, Claudia; Crocci, Máximo; Colombo, Lucas; Lanari, Claudia; and others

    2013-05-01

    Hexachlorobenzene (HCB) is a widespread organochlorine pesticide, considered a possible human carcinogen. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR). We have found that HCB activates c-Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways and cell migration, in an AhR-dependent manner in MDA-MB-231 breast cancer cells. The aim of this study was to investigate in vitro the effect of HCB (0.005, 0.05, 0.5, 5 μM) on cell invasion and metalloproteases (MMPs) 2 and 9 activation in MDA-MB-231 cells. Furthermore, we examined in vivo the effect of HCB (0.3, 3, 30 mg/kg b.w.) on tumor growth, MMP2 and MMP9 expression, and metastasis using MDA-MB-231 xenografts and two syngeneic mouse breast cancer models (spontaneous metastasis using C4-HI and lung experimental metastasis using LM3). Our results show that HCB (5 μM) enhances MMP2 expression, as well as cell invasion, through AhR, c-Src/HER1 pathway and MMPs. Moreover, HCB increases MMP9 expression, secretion and activity through a HER1 and AhR-dependent mechanism, in MDA-MB-231 cells. HCB (0.3 and 3 mg/kg b.w.) enhances subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivo models. In vivo, using MDA-MB-231 model, the pesticide (0.3, 3 and 30 mg/kg b.w.) activated c-Src, HER1, STAT5b, and ERK1/2 signaling pathways and increased MMP2 and MMP9 protein levels. Furthermore, we observed that HCB stimulated lung metastasis regardless the tumor hormone-receptor status. Our findings suggest that HCB may be a risk factor for human breast cancer progression. - Highlights: ► HCB enhances MMP2 and MMP9 expression and cell invasion in MDA-MB-231, in vitro. ► HCB-effects are mediated through AhR, HER1 and/or c-Src. ► HCB increases subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivo models. ► HCB activates c-Src/HER1 pathway and increases MMPs levels in MDA-MB-231 tumors. ► HCB stimulates lung metastasis in C4-HI and LM3 in vivo models.

  8. Breast metastasis from signet ring cell carcinoma of the urinary bladder: A case report

    PubMed Central

    CHEN, YAOMIN; WEI, HAIYAN; LI, JUN; LIU, XIAOJIAO; FU, PEIFEN

    2016-01-01

    Carcinoma of the bladder metastatic to the breast is only sporadically reported in the literature. To the best of our knowledge, the present report is the first described case of signet ring cell carcinoma of the urinary bladder metastasizing to the breast. The patient was a 43-year-old woman who underwent transurethral partial cystectomy for signet ring cell carcinoma of the urinary bladder and adjuvant chemotherapy with cisplatin and gemcitabine. At 7 months postcystectomy, the patient presented with a solitary nodule in the right breast. Following transdermic core needle puncture biopsy of the lesion and histological examination, the tumor was found to be composed of signet ring cells, which were similar to the cells in the original cystectomy specimen. The patient underwent mastectomy without further chemotherapy and has remained free from metastasis to other organs during 1 year follow-up. PMID:27330778

  9. Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice.

    PubMed

    Tang, Xiaoyun; Benesch, Matthew G K; Dewald, Jay; Zhao, Yuan Y; Patwardhan, Neeraj; Santos, Webster L; Curtis, Jonathan M; McMullen, Todd P W; Brindley, David N

    2014-11-01

    Lipid phosphate phosphatase-1 (LPP1) degrades lysophosphatidate (LPA) and attenuates receptor-mediated signaling. LPP1 expression is low in many cancer cells and tumors compared with normal tissues. It was hypothesized from studies with cultured cells that increasing LPP1 activity would decrease tumor growth and metastasis. This hypothesis has never been tested in vivo. To do this, we inducibly expressed LPP1 or a catalytically inactive mutant in cancer cells. Expressing active LPP1 increased extracellular LPA degradation by 5-fold. It also decreased the stimulation of Ca(2+) transients by LPA, a nondephosphorylatable LPA1/2 receptor agonist and a protease-activated receptor-1 peptide. The latter results demonstrate that LPP1 has effects downstream of receptor activation. Decreased Ca(2+) mobilization and Rho activation contributed to the effects of LPP1 in attenuating the LPA-induced migration of MDA-MB-231 breast cancer cells and their growth in 3D culture. Increasing LPP1 expression in breast and thyroid cancer cells decreased tumor growth and the metastasis by up to 80% compared with expression of inactive LPP1 or green fluorescent protein in syngeneic and xenograft mouse models. The present work demonstrates for the first time that increasing the LPP1 activity in three lines of aggressive cancer cells decreases their abilities to produce tumors and metastases in mice.

  10. Genomic copy number imbalances associated with bone and non-bone metastasis of early-stage breast cancer.

    PubMed

    Liu, Yanhong; Zhou, Renke; Baumbusch, Lars O; Tsavachidis, Spyros; Brewster, Abenaa M; Do, Kim-Anh; Sahin, Aysegul; Hortobagyi, Gabriel N; Taube, Joseph H; Mani, Sendurai A; Aarøe, Jørgen; Wärnberg, Fredrik; Børresen-Dale, Anne-Lise; Mills, Gordon B; Thompson, Patricia A; Bondy, Melissa L

    2014-01-01

    The aim of this study is to identify and validate copy number aberrations in early-stage primary breast tumors associated with bone or non-bone metastasis. Whole-genome molecular inversion probe arrays were used to evaluate copy number imbalances (CNIs) in breast tumors from 960 early-stage patients with information about site of metastasis. The CoxBoost algorithm was used to select metastasis site-related CNIs and to fit a Cox proportional hazards model. Gains at 1q41 and 1q42.12 and losses at 1p13.3, 8p22, and Xp11.3 were significantly associated with bone metastasis. Gains at 2p11.2, 3q21.3-22.2, 3q27.1, 10q23.1, and 14q13.2-3 and loss at 7q21.11 were associated with non-bone metastasis. To examine the joint effect of CNIs and clinical predictors, patients were stratified into three risk groups (low, intermediate, and high) based on the sum of predicted linear hazard ratios. For bone metastasis, the hazard (95 % confidence interval) for the low-risk group was 0.32 (0.11-0.92) compared to the intermediate-risk group and 2.99 (1.74-5.11) for the high-risk group. For non-bone metastasis, the hazard for the low-risk group was 0.34 (0.17-0.66) and 2.33 (1.59-3.43) for the high-risk group. The prognostic value of loss at 8p22 for bone metastasis and gains at 10q23.1 for non-bone metastasis, and gain at 11q13.5 for both bone and non-bone metastases were externally validated in 335 breast tumors pooled from four independent cohorts. Distinct CNIs are independently associated with bone and non-bone metastasis for early-stage breast cancer patients across cohorts. These data warrant consideration for tailoring surveillance and management of metastasis risk.

  11. Crosstalk between TGF-β signaling and miRNAs in breast cancer metastasis.

    PubMed

    Chen, Wei; Zhou, Siying; Mao, Ling; Zhang, Heda; Sun, Dawei; Zhang, Junying; Li, JIan; Tang, Jin-Hai

    2016-08-01

    Transforming growth factor-β (TGF-β) signaling pathway is a key regulator of various cancer biologies, including cancer cell migration, invasion, angiogenesis, proliferation, as well as apoptosis, and it is one of indispensable signaling pathways during cancer metastasis. TGF-β signaling pathway can regulate and be regulated by a series of molecular and signaling pathways where microRNAs (miRNAs) seem to play important roles. miRNAs are small non-coding RNAs that can regulate expressions of their target genes. Emerging evidence suggest that miRNAs participate in various biological and pathologic processes such as cancer cells apoptosis, proliferation, invasion, migration, and metastasis by influencing multiple signaling pathways. In this article, we focus on the interaction between miRNAs and TGF-β in breast cancer (BC) metastasis through modulating invasion-metastasis-related factors, including epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), matrix metalloproteinase (MMP), tissue inhibitors of MMPs (TIMPs), cell adhesion molecules (CAMs), and tumor microenvironment (TME). Through a clear understanding of the complicated links between TGF-β pathway and miRNAs, it may provide a novel and safer therapeutic target to prevent BC metastasis.

  12. Breast Cancer Metastasis to the Stomach That Was Diagnosed after Endoscopic Submucosal Dissection

    PubMed Central

    Kita, Masahide; Hori, Keisuke; Kawahara, Yoshiro; Taira, Naruto; Nogami, Tomohiro; Shien, Tadahiko; Tanaka, Takehiro; Doihara, Hiroyoshi; Okada, Hiroyuki

    2016-01-01

    A 52-year-old woman presented with stage IIB primary breast cancer (cT2N1M0), which was treated using neoadjuvant chemotherapy (epirubicin, cyclophosphamide, and paclitaxel). However, the tumor persisted in patchy areas; therefore, we performed modified radical mastectomy and axillary lymph node dissection. Routine endoscopy at 8 months revealed a depressed lesion on the gastric angle's greater curvature, and histology revealed signet ring cell proliferation. We performed endoscopic submucosal dissection for gastric cancer, although immunohistochemistry revealed that the tumor was positive for estrogen receptor, mammaglobin, and gross cystic disease fluid protein-15 (E-cadherin-negative). Therefore, we revised the diagnosis to gastric metastasis from the breast cancer. PMID:27957354

  13. Versican G3 Promotes Mouse Mammary Tumor Cell Growth, Migration, and Metastasis by Influencing EGF Receptor Signaling

    PubMed Central

    Du, William Weidong; Yang, Burton B.; Shatseva, Tatiana A.; Yang, Bing L.; Deng, Zhaoqun; Shan, Sze Wan; Lee, Daniel Y.; Seth, Arun; Yee, Albert J.

    2010-01-01

    Increased versican expression in breast tumors is predictive of relapse and has negative impact on survival rates. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. Here we evaluated the expression of versican in mouse mammary tumor cell lines observing that 4T1 cells expressed highest levels while 66c14 cells expressed low levels. We exogenously expressed a G3 construct in 66c14 cells and analyzed its effects on cell proliferation, migration, cell cycle progression, and EGFR signaling. Experiments in a syngeneic orthotopic animal model demonstrated that G3 promoted tumor growth and systemic metastasis in vivo. Activation of pERK correlated with high levels of G3 expression. In vitro, G3 enhanced breast cancer cell proliferation and migration by up-regulating EGFR signaling, and enhanced cell motility through chemotactic mechanisms to bone stromal cells, which was prevented by inhibitor AG 1478. G3 expressing cells demonstrated increased CDK2 and GSK-3β (S9P) expression, which were related to cell growth. The activity of G3 on mouse mammary tumor cell growth, migration and its effect on spontaneous metastasis to bone in an orthotopic model was modulated by up-regulating the EGFR-mediated signaling pathway. Taken together, EGFR-signaling appears to be an important pathway in versican G3-mediated breast cancer tumor invasiveness and metastasis. PMID:21079779

  14. Integrating structure to protein-protein interaction networks that drive metastasis to brain and lung in breast cancer.

    PubMed

    Engin, H Billur; Guney, Emre; Keskin, Ozlem; Oliva, Baldo; Gursoy, Attila

    2013-01-01

    Blocking specific protein interactions can lead to human diseases. Accordingly, protein interactions and the structural knowledge on interacting surfaces of proteins (interfaces) have an important role in predicting the genotype-phenotype relationship. We have built the phenotype specific sub-networks of protein-protein interactions (PPIs) involving the relevant genes responsible for lung and brain metastasis from primary tumor in breast cancer. First, we selected the PPIs most relevant to metastasis causing genes (seed genes), by using the "guilt-by-association" principle. Then, we modeled structures of the interactions whose complex forms are not available in Protein Databank (PDB). Finally, we mapped mutations to interface structures (real and modeled), in order to spot the interactions that might be manipulated by these mutations. Functional analyses performed on these sub-networks revealed the potential relationship between immune system-infectious diseases and lung metastasis progression, but this connection was not observed significantly in the brain metastasis. Besides, structural analyses showed that some PPI interfaces in both metastasis sub-networks are originating from microbial proteins, which in turn were mostly related with cell adhesion. Cell adhesion is a key mechanism in metastasis, therefore these PPIs may be involved in similar molecular pathways that are shared by infectious disease and metastasis. Finally, by mapping the mutations and amino acid variations on the interface regions of the proteins in the metastasis sub-networks we found evidence for some mutations to be involved in the mechanisms differentiating the type of the metastasis.

  15. Roles of glycosaminoglycans and glycanmimetics in tumor progression and metastasis.

    PubMed

    Basappa; Rangappa, Kanchugarakoppal S; Sugahara, Kazuyuki

    2014-10-01

    Various tumor cells exhibit structural alterations in the sulfated modifications to glycosaminoglycans (GAGs). The altered expression of chondroitin sulfate (CS) and heparan sulfate (HS) on the surfaces of tumor cells is known to play a key role in malignant transformation and tumor metastasis. The receptor molecule for the CS chains containing E-disaccharide units (CS-E) expressed on Lewis lung carcinoma (LLC) cells was recently revealed to be Receptor for Advanced Glycation End-products (RAGE). RAGE is also involved in the development of various pathological conditions including aging, infection, pulmonary fibrosis, diabetes, and Alzheimer's disease, by binding to a wide range of ligands. RAGE binds strongly not only to CS-E, but also to HS-expressing LLC cells. Recombinant RAGE bound CS-E and HS with high affinity. Furthermore, in a mouse model, the colonization of the lungs by LLC cells was inhibited by intravenously injected CS-E, an anti-CS-E antibody, or an anti-RAGE antibody. These findings demonstrated that RAGE is at least one of the critical receptors for CS and HS chains expressed on the tumor cell surface and is involved in experimental lung metastasis, and also that CS/HS and RAGE are potential molecular targets for the treatment of pulmonary metastasis. We, hence, reviewed these findings and also several chemically synthesized small GAGmimetics that exhibit potent anti-metastatic and/or anti-tumor activities.

  16. A 3q gene signature associated with triple negative breast cancer organ specific metastasis and response to neoadjuvant chemotherapy

    PubMed Central

    Qian, Jun; Chen, Heidi; Ji, Xiangming; Eisenberg, Rosana; Chakravarthy, A. Bapsi; Mayer, Ingrid A.; Massion, Pierre P.

    2017-01-01

    Triple negative breast cancers (TNBC) are aggressive tumors, with high rates of metastatic spread and targeted therapies are critically needed. We aimed to assess the prognostic and predictive value of a 3q 19-gene signature identified previously from lung cancer in a collection of 4,801 breast tumor gene expression data. The 3q gene signature had a strong association with features of aggressiveness such as high grade, hormone receptor negativity, presence of a basal-like or TNBC phenotype and reduced distant metastasis free survival. The 3q gene signature was strongly associated with lung metastasis only in TNBC (P < 0.0001, Hazard ratio (HR) 1.44, 95% confidence interval (CI), 1.31–1.60), significantly associated with brain but not bone metastasis regardless of TNBC status. The association of one 3q driver gene FXR1 with distant metastasis in TNBC (P = 0.01) was further validated by immunohistochemistry. In addition, the 3q gene signature was associated with better response to neoadjuvant chemotherapy in TNBC (P < 0.0001) but not in non-TNBC patients. Our study suggests that the 3q gene signature is a novel prognostic marker for lung and/or brain metastasis and a predictive marker for the response to neoadjuvant chemotherapy in TNBC, implying a potential role for 3q genes in the mechanism of organ-specific metastasis. PMID:28387221

  17. Inhibition of Growth and Metastasis of Breast Cancer in Mice by Milk Fermented With Lactobacillus casei CRL 431.

    PubMed

    Aragón, Félix; Carino, Silvia; Perdigón, Gabriela; de Moreno de LeBlanc, Alejandra

    2015-06-01

    Breast cancer is the second cause of death in women, who are especially related to uncontrolled metastasis. It was previously demonstrated that the administration of milk fermented by Lactobacillus casei CRL 431 [fermented milk (FM)] delayed the tumor growth in a murine breast cancer model. In this work we evaluated if the administration of FM to mice, starting when the tumor was measurable, can affect not only the tumor growth, but also the extravasation of tumor cells and the lung metastasis. The evaluation of immune cells-infiltrating tumors and lungs was also performed. Tumor volume was calculated. Whole blood, lungs, and liver were processed to count the number of colonies formed by tumor cells. Blood serum was obtained for monocyte chemoattractant protein-1, interleukin (IL)-10, and IL-6 determination, lung tissues for histologic observations, and tumor tissues for angiogenesis determination. Mice that received FM were compared with animals given milk or to the controls without any especial supplementation. The results showed that FM administration to mice decreased or suppressed tumor growth, with less tumor vascularity, extravasation of tumor cells, and lung metastasis. These benefits were associated to modulation of the immune response by decreasing the infiltration of macrophages in both the tumor and the lungs. FM administration maintained an increased antitumor response associated to CD8 lymphocytes, and also increased CD4 lymphocytes that can be involved in the modulation of the immune response. The future evaluation of cytokine profiles will allow knowing more about subpopulation of macrophages and lymphocytes associated to the beneficial effect of this probiotic in the breast cancer model.

  18. Cystic brain metastasis is associated with poor prognosis in patients with advanced breast cancer

    PubMed Central

    Sun, Bing; Huang, Zhou; Wu, Shikai; Ding, Lijuan; Shen, Ge; Cha, Lei; Wang, Junliang; Song, Santai

    2016-01-01

    Purpose Brain metastasis (BM) with a cystic component from breast cancer is rare and largely uncharacterized. The purpose of this study was to identify the characteristics of cystic BM in a large cohort of breast cancer patients. Results A total of 35 eligible patients with cystic BM and 255 patients with solid BM were analyzed. Three factors were significantly associated with an increased probability of developing cystic lesions: age at diagnosis ≤ 40 years, age at BM ≤ 45 years, and poor histological grade (p < 0.05). Patients with cystic metastasis were also characterized by a larger metastasis volume, a shorter progression-free survival (PFS) following their first treatment for BM, and poor overall survival after BM (p < 0.05). Multivariate analysis further demonstrated that local control of cystic BM was only potentially achieved for HER2-negative primary tumors (p = 0.084). Methods Breast cancer patients with parenchymal BM were reviewed from consecutive cases treated at our institution. Cystic BM was defined when the volume of a cystic lesion was greater than 50% of the aggregated volume of all lesions present. Clinicopathologic and radiographic variables were correlated with development of cystic lesions and with prognosis of cystic BM. Conclusions This study shows that cystic BM from breast cancer, a special morphological type of BM, had worse prognosis than the more commonly observed solid BM. Younger age and low tumor grade were associated with the development of cystic lesions. Further comprehensive research and management of cystic BM are warranted to improve its poor prognosis. PMID:27659537

  19. Extracellular Galectin-3 in Tumor Progression and Metastasis

    PubMed Central

    Fortuna-Costa, Anneliese; Gomes, Angélica M.; Kozlowski, Eliene O.; Stelling, Mariana P.; Pavão, Mauro S. G.

    2014-01-01

    Galectin-3, the only chimera galectin found in vertebrates, is one of the best-studied galectins. It is expressed in several cell types and is involved in a broad range of physiological and pathological processes, such as cell adhesion, cell activation and chemoattraction, cell cycle, apoptosis, and cell growth and differentiation. However, this molecule raises special interest due to its role in regulating cancer cell activities. Galectin-3 has high affinity for β-1,6-N-acetylglucosamine branched glycans, which are formed by the action of the β1,6-N-acetylglucosaminyltransferase V (Mgat5). Mgat5-related changes in protein/lipid glycosylation on cell surface lead to alterations in the clustering of membrane proteins through lattice formation, resulting in functional advantages for tumor cells. Galectin-3 presence enhances migration and/or invasion of many tumors. Galectin-3-dependent clustering of integrins promotes ligand-induced integrin activation, leading to cell motility. Galectin-3 binding to mucin-1 increases transendothelial invasion, decreasing metastasis-free survival in an experimental metastasis model. Galectin-3 also affects endothelial cell behavior by regulating capillary tube formation. This lectin is found in the tumor stroma, suggesting a role for microenvironmental galectin-3 in tumor progression. Galectin-3 also seems to be involved in the recruitment of tumor-associated macrophages, possibly contributing to angiogenesis and tumor growth. This lectin can be a relevant factor in turning bone marrow in a sanctuary for leukemia cells, favoring resistance to therapy. Finally, galectin-3 seems to play a relevant role in orchestrating distinct cell events in tumor microenvironment and for this reason, it can be considered a target in tumor therapies. In conclusion, this review aims to describe the processes of tumor progression and metastasis involving extracellular galectin-3 and its expression and regulation. PMID:24982845

  20. Neoadjuvant immunotherapy with chitosan and interleukin-12 to control breast cancer metastasis

    PubMed Central

    Vo, Jimmy LN; Yang, Lirong; Kurtz, Samantha L; Smith, Sean G; Koppolu, Bhanu prasanth; Ravindranathan, Sruthi; Zaharoff, David A

    2015-01-01

    Metastasis accounts for approximately 90% of breast cancer-related deaths. Therefore, novel approaches which prevent or control breast cancer metastases are of significant clinical interest. Interleukin-12 (IL-12)-based immunotherapies have shown promise in controlling metastatic disease, yet modest responses and severe toxicities due to systemic administration of IL-12 in early trials have hindered clinical application. We hypothesized that localized delivery of IL-12 co-formulated with chitosan (chitosan/IL-12) could elicit tumor-specific immunity and provide systemic protection against metastatic breast cancer while minimizing systemic toxicity. Chitosan is a biocompatible polysaccharide derived primarily from the exoskeletons of crustaceans. In a clinically relevant resection model, mice bearing spontaneously metastatic 4T1 mammary adenocarcinomas received intratumoral injections of chitosan/IL-12, or appropriate controls, prior to tumor resection. Neoadjuvant chitosan/IL-12 immunotherapy resulted in long-term tumor-free survival in 67% of mice compared to only 24% or 0% of mice treated with IL-12 alone or chitosan alone, respectively. Antitumor responses following chitosan/IL-12 treatment were durable and provided complete protection against rechallenge with 4T1, but not RENCA renal adenocarcinoma, cells. Lymphocytes from chitosan/IL-12-treated mice demonstrated robust tumor-specific lytic activity and interferon-γ production. Cell-mediated immune memory was confirmed in vivo via clinically relevant delayed-type hypersensitivity (DTH) assays. Comprehensive hematology and toxicology analyses revealed that chitosan/IL-12 induced transient, reversible leukopenia with no changes in critical organ function. Results of this study suggest that neoadjuvant chitosan/IL-12 immunotherapy prior to breast tumor resection is a promising translatable strategy capable of safely inducing to tumor-specific immunity and, in the long term, reducing breast cancer mortality due to

  1. Brain metastasis reirradiation in patients with advanced breast cancer

    PubMed Central

    Huang, Zhou; Sun, Bing; Shen, Ge; Cha, Lei; Meng, Xiangying; Wang, Junliang; Zhou, Zhenshan; Wu, Shikai

    2017-01-01

    The outcome of recurrent brain metastasis is dismal. This study aims to assess the clinical outcomes and toxicity of reirradiation as a salvage treatment for progressive brain metastasis in patients with advanced breast cancer. Between July 2005 and September 2014, the medical records of 56 patients with brain metastasis from breast cancer were retrospectively reviewed. Of these patients, 39 received whole-brain radiotherapy (WBRT) followed by stereotactic radiosurgery (SRS) reirradiation (Group 1), and 17 received SRS followed by WBRT reirradiation (Group 2). Overall survival (OS) and brain progression-free survival rates/times were calculated using the Kaplan–Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Change in neurologic function was also assessed. The median OS was 10.8 months (range, 1.3–56.8 months). In Group 1, the median PFS time (PFS-1) was 6.5 months and the OS time was 11.4 months. Multivariate analysis revealed that longer OS was significantly associated with a high Karnofsky performance score (KPS) (P = 0.004), controlled extracranial metastasis (P = 0.001) and a good response to reirradiation (P = 0.034). In Group 2, the median PFS time (PFS-2) after reirradiation was 8.5 months and the OS time was 10.8 months. Multivariate analysis revealed that longer OS was significantly associated with a high KPS (P = 0.018). The majority of the patients had improved or stable neurological function. Reirradiation is an effective and a safe treatment for patients with brain metastases from breast cancer. It might delay the progression of intracranial disease and improve neurological function. A suitable patient selection for reirradiation was suggested. PMID:27707842

  2. Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells.

    PubMed

    Cohen, Evan N; Gao, Hui; Anfossi, Simone; Mego, Michal; Reddy, Neelima G; Debeb, Bisrat; Giordano, Antonio; Tin, Sanda; Wu, Qiong; Garza, Raul J; Cristofanilli, Massimo; Mani, Sendurai A; Croix, Denise A; Ueno, Naoto T; Woodward, Wendy A; Luthra, Raja; Krishnamurthy, Savitri; Reuben, James M

    2015-01-01

    Inflammatory breast cancer (IBC) is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1), a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

  3. The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer.

    PubMed

    Sahay, Debashish; Leblanc, Raphael; Grunewald, Thomas G P; Ambatipudi, Srikant; Ribeiro, Johnny; Clézardin, Philippe; Peyruchaud, Olivier

    2015-08-21

    Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas.

  4. The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer

    PubMed Central

    Sahay, Debashish; Leblanc, Raphael; Grunewald, Thomas G. P.; Ambatipudi, Srikant; Ribeiro, Johnny; Clézardin, Philippe; Peyruchaud, Olivier

    2015-01-01

    Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1 in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas. PMID:26098771

  5. PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes

    PubMed Central

    Ponente, Manfredi; Campanini, Letizia; Cuttano, Roberto; Piunti, Andrea; Delledonne, Giacomo A.; Coltella, Nadia; Valsecchi, Roberta; Villa, Alessandra

    2017-01-01

    Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients. PMID:28239645

  6. PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes.

    PubMed

    Ponente, Manfredi; Campanini, Letizia; Cuttano, Roberto; Piunti, Andrea; Delledonne, Giacomo A; Coltella, Nadia; Valsecchi, Roberta; Villa, Alessandra; Cavallaro, Ugo; Pattini, Linda; Doglioni, Claudio; Bernardi, Rosa

    2017-02-23

    Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients.

  7. Oncostatin M Promotes Mammary Tumor Metastasis to Bone and Osteolytic Bone Degradation

    PubMed Central

    Bolin, Celeste; Tawara, Ken; Sutherland, Caleb; Redshaw, Jeff; Aranda, Patrick; Moselhy, Jim; Anderson, Robin

    2012-01-01

    Oncostatin M (OSM) is an interleukin-6 (IL-6) family cytokine that has been implicated in a number of biological processes including inflammation, hematopoiesis, immune responses, development, and bone homeostasis. Recent evidence suggests that OSM may promote breast tumor invasion and metastasis. We investigated the role of OSM in the formation of bone metastases in vivo using the 4T1.2 mouse mammary tumor model in which OSM expression was knocked down using shRNA (4T1.2-OSM). 4T1.2-OSM cells were injected orthotopically into Balb/c mice, resulting in a greater than 97% decrease in spontaneous metastasis to bone compared to control cells. Intratibial injection of these same 4T1.2-OSM cells also dramatically reduced the osteolytic destruction of trabecular bone volume compared to control cells. Furthermore, in a tumor resection model, mice bearing 4T1.2-OSM tumors showed an increase in survival by a median of 10 days. To investigate the specific cellular mechanisms important for OSM-induced osteolytic metastasis to bone, an in vitro model was developed using the RAW 264.7 preosteoclast cell line co-cultured with 4T1.2 mouse mammary tumor cells. Treatment of co-cultures with OSM resulted in a 3-fold induction of osteoclastogenesis using the TRAP assay. We identified several tumor cell–induced factors including vascular endothelial growth factor, IL-6, and a previously uncharacterized OSM-regulated bone metastasis factor, amphiregulin (AREG), which increased osteoclast differentiation by 4.5-fold. In addition, pretreatment of co-cultures with an anti-AREG neutralizing antibody completely reversed OSM-induced osteoclastogenesis. Our results suggest that one mechanism for OSM-induced osteoclast differentiation is via an AREG autocrine loop, resulting in decreased osteoprotegerin secretion by the 4T1.2 cells. These data provide evidence that OSM might be an important therapeutic target for the prevention of breast cancer metastasis to bone. PMID:23050044

  8. Breast cancer metastasis to the stomach confirmed using gastroscopy: A case report

    PubMed Central

    TAN, LINSHEN; PIAO, YING; LIU, ZHAOZHE; HAN, TAO; SONG, FULIN; GAO, FEI; HAN, YALING; XIE, XIAODONG

    2014-01-01

    Breast cancer metastasis to the stomach is relatively rare. Unlike infiltrating ductal carcinoma, invasive lobular carcinoma (ILC) has a high tendency to metastasize to the stomach. The present study reports a case of a 53-year-old female who had undergone a modified radical mastectomy of the left breast for ILC eight years previously and presented at the clinic seeking treatment for epigastric discomfort from sour regurgitation and belching that had persisted for one month. Gastroscopy revealed multiple apophysis lesions in the stomach, which were diagnosed as metastatic tumors to the stomach. The diagnosis was further established using histological and immunohistochemical analyses for gross cystic disease fluid protein-15, cytokeratin (CK) 7 and CK20. The patient was treated with systemic chemotherapy without surgery. During the treatment, two gastroscopy procedures revealed that the apophysis lesions in the gastric body had narrowed significantly. Few cases of breast cancer metastasizing to the stomach have been reported, particularly those that have been confirmed using gastroscopy. The present study reports a case of breast cancer metastasis to the stomach to raise awareness of the condition. PMID:25120688

  9. Regulation of Breast Cancer and Bone Metastasis by MicroRNAs

    PubMed Central

    Vimalraj, S.; Miranda, P. J.; Ramyakrishna, B.; Selvamurugan, N.

    2013-01-01

    Breast cancer progression including bone metastasis is a complex process involving numerous changes in gene expression and function. MicroRNAs (miRNAs) are small endogenous noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs posttranscriptionally, often affecting a number of gene targets simultaneously. Alteration in expression of miRNAs is common in human breast cancer, possessing with either oncogenic or tumor suppressive activity. The expression and the functional role of several miRNAs (miR-206, miR-31, miR-27a/b, miR-21, miR-92a, miR-205, miR-125a/b, miR-10b, miR-155, miR-146a/b, miR-335, miR-204, miR-211, miR-7, miR-22, miR-126, and miR-17) in breast cancer has been identified. In this review we summarize the experimentally validated targets of up- and downregulated miRNAs and their regulation in breast cancer and bone metastasis for diagnostic and therapeutic purposes. PMID:24191129

  10. Cadm1 is a metastasis susceptibility gene that suppresses metastasis by modifying tumor interaction with the cell-mediated immunity.

    PubMed

    Faraji, Farhoud; Pang, Yanli; Walker, Renard C; Nieves Borges, Rosan; Yang, Li; Hunter, Kent W

    2012-09-01

    Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors, including cellular immunity. We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms. However, how metastasis susceptibility genes interact with the tumor stroma is incompletely understood. Here, we employ a complex genetic screen to identify Cadm1 as a novel modifier of metastasis. We demonstrate that Cadm1 can specifically suppress metastasis without affecting primary tumor growth. Unexpectedly, Cadm1 did not alter tumor-cell-autonomous properties such as proliferation or invasion, but required the host's adaptive immune system to affect metastasis. The metastasis-suppressing effect of Cadm1 was lost in mice lacking T cell-mediated immunity, which was partially phenocopied by depleting CD8(+) T cells in immune-competent mice. Our data show a novel function for Cadm1 in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms, and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors.

  11. Motif mimetic of epsin perturbs tumor growth and metastasis

    PubMed Central

    Dong, Yunzhou; Wu, Hao; Rahman, H.N. Ashiqur; Liu, Yanjun; Pasula, Satish; Tessneer, Kandice L.; Cai, Xiaofeng; Liu, Xiaolei; Chang, Baojun; McManus, John; Hahn, Scott; Dong, Jiali; Brophy, Megan L.; Yu, Lili; Song, Kai; Silasi-Mansat, Robert; Saunders, Debra; Njoku, Charity; Song, Hoogeun; Mehta-D’Souza, Padmaja; Towner, Rheal; Lupu, Florea; McEver, Rodger P.; Xia, Lijun; Boerboom, Derek; Srinivasan, R. Sathish; Chen, Hong

    2015-01-01

    Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium–targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin–interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium–specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy. PMID:26571402

  12. Patterns of metastasis and survival in breast cancer patients: a preliminary study in an Iranian population.

    PubMed

    Ziaei, Jamal Eivazi; Pourzand, Ali; Bayat, Amrollah; Vaez, Jalil

    2012-01-01

    Due to lack of sufficient data on characteristics of breast cancer patients and risk factors for developing metastasis in Iran this study was designed to understand clinical aspects impacting on survival. A cross-sectional study on breast cancer patients was conducted in an oncology clinic of the university hospital between 1995 and 2010. Data were retrieved from medical records and included age, menopausal status, tumor diameter, number of involved nodes, histopathological type, estrogen and progesterone receptor expression, c-erbB-2, primary and secondary metastasis sites, overall survival, disease free interval and type of chemotherapy protocol. The results were analyzed with SPSS 13 software.The mean age of the patients was 49.2 (27-89) years. The primary tumors were mainly ER positive (48%) and PR negative (49.3%). The status of lymph nodes dissected and examined in these patients was unknown in 19 patients (25.3%) while 18 patients (24%) had positive lymph nodes with no report on the number of involved nodes. All of the patients had received antracyclin based chemotherapy in an adjuvant or metastatic setting. Adjuvant hormonal therapy was administered to receptor positive patients. In average, overall survival after recurrence was 30 months (95%CI 24.605-35.325) for non-skeletal versus 42 months (95%CI 31.211-52.789) for skeletal metastasis (P= 0.002). The median survival was also greater for receptor positive patients; 39 months (95%CI 33.716-44.284) for PR+ versus 26 months (95%CI 19.210-32.790) for PR- (P=0.047) and 38 months (95%CI 32.908-43.092) for ER+ versus 27 months (95%CI 18.780-35.220) for ER- patients (P=0.016). No relation was found between site of first metastasis and hormone receptor, age, tumor diameter, DFI and menopausal status. Sites of metastasis were independent of age, size of the tumor, menopausal and hormone receptor status in this study. Overall survival provided significant relations with respect to receptor status and bone

  13. The role of individual inheritance in tumor progression and metastasis.

    PubMed

    Hunter, Kent

    2015-07-01

    Metastasis, the dissemination and growth of tumor cells at secondary sites, is the primary cause of patient mortality from solid tumors. Metastasis is an extremely complex, inefficient process requiring contributions of not only the tumor cell but also local and distant environmental factors, at both the cellular and molecular level. Variation in the function of any of the steps in the metastatic cascade may therefore have profound implications for the ultimate course of the disease. In addition to the somatic and cellular heterogeneity that can affect cancer outcome, an individual's specific ancestry or genetic background can also significantly influence metastatic progression. These inherited variants not only encoded for metastatic susceptibility but also provided a window to study critical factors that are not easily accessible with current technologies. Furthermore, investigations into inherited metastatic susceptibility enable identification of important molecular and cellular processes that are not subject to mutation and are consequently not detectable by standard cancer genome sequencing strategies. Incorporation of inherited variation into metastasis research therefore provides methods to more comprehensively investigate the etiology of the lethal consequences of tumor progression.

  14. Hyperinsulinemia Promotes Metastasis to the Lung in a Mouse Model of Her2-mediated Breast Cancer

    PubMed Central

    Ferguson, Rosalyn; Gallagher, Emily; Cohen, Dara; Tobin-Hess, Aviva; Alikhani, Nyosha; Novosyadlyy, Ruslan; Haddad, Nadine; Yakar, Shoshana; LeRoith, Derek

    2014-01-01

    The Her2 oncogene is expressed in approximately 25% of human breast cancers and is associated with metastatic progression and poor outcome. Epidemiological studies report that breast cancer incidence and mortality rates are higher in women with type 2 diabetes. Here we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis. Hyperinsulinemic (MKR+/+) mice were crossed with doxycycline-inducible NeuNT (MTB/TAN) mice to produce the MTB/TAN/MKR+/+ mouse model. Both MTB/TAN and MTB/TAN/MKR+/+ mice were administered doxycycline in drinking water to induce NeuNT mammary tumor formation. In tumor tissues removed at two, four and six weeks of Neu-NT overexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor (IR)/insulin-like growth factor receptor 1 (IGF-1R), suggesting that activation of these receptors in conditions of hyperinsulinemia could contribute to the increased growth of mammary tumors. After 12 weeks on doxycycline, although no significant further increase in tumor weight was observed in MTB/TAN/MKR+/+ compared to MTB/TAN mice, the number of lung metastases was significantly higher in MTB/TAN/MKR+/+ mice compared to controls (MTB/TAN/MKR+/+ 16.41 ± 4.18 vs. MTB/TAN 5.36 ± 2.72). In tumors at the six week time-point, we observed an increase in vimentin, a cytoskeletal protein and marker of mesenchymal cells, associated with epithelial-to-mesenchymal transition and cancer associated fibroblasts. We conclude that hyperinsulinemia in MTB/TAN/MKR+/+ mice resulted in larger primary tumors, with more mesenchymal cells and therefore, more aggressive tumors with more numerous pulmonary metastases. PMID:23572162

  15. Investigating the Role of Indoleamine 2,3-dioxygenase (IDO) in Breast Cancer Metastasis

    DTIC Science & Technology

    2011-09-01

    2,3-dioxygenase (IDO) in Breast Cancer Metastasis PRINCIPAL INVESTIGATOR: Courtney Smith, Ph.D...5a. CONTRACT NUMBER Investigating the Role of Indoleamine 2,3-dioxygenase (IDO) in Breast Cancer Metastasis 5b. GRANT NUMBER W81XWH-09-1-0667...the malignant 4T1 breast carcinoma cell line exhibit metastatic spread to organs similar to that seen in human breast cancer with pulmonary metastases

  16. Unusual aggressive breast cancer: metastatic malignant phyllodes tumor.

    PubMed

    Singer, Adam; Tresley, Jonathan; Velazquez-Vega, Jose; Yepes, Monica

    2013-02-01

    For the year of 2012, it has been estimated that breast cancer will account for the greatest number of newly diagnosed cancers and the second highest proportion of cancer related deaths among women. Breast cancer, while often lumped together as one disease, represents a diverse group of malignancies with different imaging findings, histological appearances and behavior. While most invasive primary breast cancers are epithelial derived adenocarcinomas, rare neoplasms such as the phyllodes tumor may arise from mesenchymal tissue. Compared to the breast adenocarcinoma, the phyllodes tumor tends to affect a younger population, follows a different clinical course, is associated with different imaging and histological findings and is managed distinctively. There may be difficulty in differentiating the phyllodes tumor from a large fibroadenoma, but the mammographer plays a key role in reviewing the clinical and imaging data in order to arrive at the correct diagnosis. Early diagnosis with proper surgical management can often cure non-metastatic phyllodes tumors. However, in rare cases where metastasis occurs, prognosis tends to be poor. This report describes the presentation, imaging findings and management of a metastatic malignant phyllodes tumor.

  17. Myosin 1e promotes breast cancer malignancy by enhancing tumor cell proliferation and stimulating tumor cell de-differentiation

    PubMed Central

    Ouderkirk-Pecone, Jessica L.; Goreczny, Gregory J.; Chase, Sharon E.; Tatum, Arthur H.; Turner, Christopher E.; Krendel, Mira

    2016-01-01

    Despite advancing therapies, thousands of women die every year of breast cancer. Myosins, actin-dependent molecular motors, are likely to contribute to tumor formation and metastasis via their effects on cell adhesion and migration and may provide promising new targets for cancer therapies. Using the MMTV-PyMT murine model of breast cancer, we identified Myosin 1e (MYO1E) as a novel tumor promoter. Tumor latency in mice lacking MYO1E was significantly increased, and tumors formed in the absence of MYO1E displayed unusual papillary morphology, with well-differentiated layers of epithelial cells covering fibrovascular cores, rather than solid sheets of tumor cells typically observed in this cancer model. These tumors were reminiscent of papillary breast cancer in humans that is typically non-invasive and often cured by tumor excision. MYO1E-null tumors exhibited decreased expression of the markers of cell proliferation, which was recapitulated in primary tumor cells derived from MYO1E-null mice. In agreement with our findings, meta-analysis of patient survival data indicated that MYO1E expression level was associated with reduced recurrence-free survival in basal-like breast cancer. Overall, our data suggests that MYO1E contributes to breast tumor malignancy and regulates the differentiation and proliferation state of breast tumor cells. PMID:27329840

  18. GRK6 deficiency promotes angiogenesis, tumor progression and metastasis

    PubMed Central

    Raghuwanshi, Sandeep K.; Smith, Nikia; Rivers, Elizabeth, J.; Thomas, Ariel J.; Sutton, Natalie; Hu, Yuhui; Mukhopadhyay, Somnath; Chen, Xiaoxin L.; Leung, TinChung; Richardson, Ricardo M.

    2013-01-01

    G protein coupled receptor kinases (GRKs) phosphorylate the activated form of G protein coupled receptors (GPCRs) leading to receptor desensitization and down-regulation. We have recently shown that the chemokine receptor, CXCR2, couples to GRK6 to regulate cellular responses including chemotaxis, angiogenesis and wound healing. In this study, we investigate the role of GRK6 in tumorigenesis using murine models of human lung cancer. Mice deficient in GRK6 (GRK6−/−) exhibited a significant increase in Lewis lung cancer (LLC) growth and metastasis relative to control littermates (GRK6+/+). GRK6 deletion had no effect on the expression of proangiogenic chemokine or vascular endothelial growth factor (VEGF), but up-regulated matrix metalloproteinase (MMP)-2 and MMP-9 release, tumor-infiltrating PMNs and microvessel density. Since βarr2−/− mice exhibited increase LLC growth and metastasis similar to that of GRK6−/−we developed a double GRK6−/−/βarr2−/− mouse model. Surprisingly, GRK6−/−/βarr2−/− mice exhibited faster tumor growth relative to GRK6−/− or βarr2−/− mice. Treatment of the mice with anti-CXCR2 antibody inhibited tumor growth in both GRK6−/− and GRK6−/−/βarr2−/− animals. Altogether, the results indicate that CXCR2 couples to GRK6 to regulate angiogenesis, tumor progression and metastasis. Deletion of GRK6 increases the activity of the host CXCR2, resulting in greater PMN infiltration and MMP release in the tumor microenvironment thereby promoting angiogenesis and metastasis. Since GRK6−/−/βarr2−/− showed greater tumor growth relative to GRK6−/− or βarr2−/− mice, the data further suggest that CXCR2 couples to different mechanisms to mediate tumor progression and metastasis. PMID:23589623

  19. Effect of the Secretory Small GTPase Rab27B on Breast Cancer Growth, Invasion, and Metastasis

    PubMed Central

    Hendrix, An; Maynard, Dawn; Pauwels, Patrick; Braems, Geert; Denys, Hannelore; Van den Broecke, Rudy; Lambert, Jo; Van Belle, Simon; Cocquyt, Veronique; Gespach, Christian; Bracke, Marc; Seabra, Miguel C.; Gahl, William A.

    2010-01-01

    Background Secretory GTPases like Rab27B control vesicle exocytosis and deliver critical proinvasive growth regulators into the tumor microenvironment. The expression and role of Rab27B in breast cancer were unknown. Methods Expression of green fluorescent protein (GFP) fused with wild-type Rab3D, Rab27A, or Rab27B, or Rab27B point mutants defective in GTP/GDP binding or geranylgeranylation, or transient silencing RNA to the same proteins was used to study Rab27B in estrogen receptor (ER)–positive human breast cancer cell lines (MCF-7, T47D, and ZR75.1). Cell cycle progression was evaluated by flow cytometry, western blotting, and measurement of cell proliferation rates, and invasion was assessed using Matrigel and native type I collagen substrates. Orthotopic tumor growth, local invasion, and metastasis were analyzed in mouse xenograft models. Mass spectrometry identified proinvasive growth regulators that were secreted in the presence of Rab27B. Rab27B protein levels were evaluated by immunohistochemistry in 59 clinical breast cancer specimens, and Rab3D, Rab27A, and Rab27B mRNA levels were analyzed by quantitative real-time polymerase chain reaction in 20 specimens. Statistical tests were two-sided. Results Increased expression of Rab27B promoted G1 to S phase cell cycle transition, proliferation and invasiveness of cells in culture, and invasive tumor growth and hemorrhagic ascites production in a xenograft mouse model (n = 10; at 10 weeks, survival of MCF-7 GFP- vs GFP-Rab27B–injected mice was 100% vs 62.5%, hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.88, P = .03). Mass spectrometric analysis of purified Rab27B-secretory vesicles identified heat-shock protein 90α as key proinvasive growth regulator. Heat-shock protein 90α secretion was Rab27B-dependent and was required for matrix metalloproteinase-2 activation. All Rab27B-mediated functional responses were GTP- and geranylgeranyl-dependent. Presence of endogenous Rab27B mRNA and protein, but

  20. Circulating Tumor Cells in Breast Cancer Patients: An Evolving Role in Patient Prognosis and Disease Progression

    PubMed Central

    Graves, Holly; Czerniecki, Brian J.

    2011-01-01

    In this paper, we examine the role of circulating tumor cells (CTCs) in breast cancer. CTCs are tumor cells present in the peripheral blood. They are found in many different carcinomas but are not present in patients with benign disease. Recent advances in theories regarding metastasis support the role of early release of tumor cells in the neoplastic process. Furthermore, it has been found that phenotypic variation exists between the primary tumor and CTCs. Of particular interest is the incongruency found between primary tumor and CTC HER2 status in both metastatic and early breast cancer. Overall, CTCs have been shown to be a poor prognostic marker in metastatic breast cancer. CTCs in early breast cancer are not as well studied, however, several studies suggest that the presence of CTCs in early breast cancer may also suggest a poorer prognosis. Studies are currently underway looking at the use of CTC level monitoring in order to guide changes in therapy. PMID:21253472

  1. Oridonin Inhibits Tumor Growth and Metastasis through Anti-Angiogenesis by Blocking the Notch Signaling

    PubMed Central

    Li, Jingjie; Deng, Huayun; Song, Yajuan; Zhai, Dong; Peng, Yi; Lu, Xiaoling; Liu, Mingyao; Zhao, Yongxiang; Yi, Zhengfang

    2014-01-01

    While significant progress has been made in understanding the anti-inflammatory and anti-proliferative effects of the natural diterpenoid component Oridonin on tumor cells, little is known about its effect on tumor angiogenesis or metastasis and on the underlying molecular mechanisms. In this study, Oridonin significantly suppressed human umbilical vascular endothelial cells (HUVECs) proliferation, migration, and apillary-like structure formation in vitro. Using aortic ring assay and mouse corneal angiogenesis model, we found that Oridonin inhibited angiogenesis ex vivo and in vivo. In our animal experiments, Oridonin impeded tumor growth and metastasis. Immunohistochemistry analysis further revealed that the expression of CD31 and vWF protein in xenografts was remarkably decreased by the Oridonin. Furthermore, Oridonin reinforced endothelial cell-cell junction and impaired breast cancer cell transendothelial migration. Mechanistically, Oridonin not only down-regulated Jagged2 expression and Notch1 activity but also decreased the expression of their target genes. In conclusion, our results demonstrated an original role of Oridonin in inhibiting tumor angiogenesis and propose a mechanism. This study also provides new evidence supporting the central role of Notch in tumor angiogenesis and suggests that Oridonin could be a potential drug candidate for angiogenesis related diseases. PMID:25485753

  2. Cutaneous metastasis as the first manifestation of occult malignant breast neoplasia*

    PubMed Central

    Weimann, Ellem Tatiani de Souza; Botero, Erica Bruder; Mendes, Cinthia; dos Santos, Marcel Alex Soares; Stelini, Rafael Fantelli; Zelenika, Caroline Romanelli T.

    2016-01-01

    Cutaneous metastases from primary internal malignancies represent 0.7-9% of patients with cancer. We report a 65-year-old female patient referred for evaluation of normochromic papules on the trunk and upper limbs that had been present for three months. A skin biopsy revealed diffuse cutaneous infiltration by small round cell tumors. Immunohistochemistry was positive for AE1/AE3, CK7, estrogen receptor and mammaglobin. The final diagnosis was cutaneous metastasis of occult breast cancer, since the solid primary tumor was not identified. The location of the primary tumor can not be determined in 5-10% of cases. In these cases, 27% are identified before the patient’s death, 57% at autopsy, and the remaining 16% can not be located. PMID:28300911

  3. Luteolin inhibits lung metastasis, cell migration, and viability of triple-negative breast cancer cells

    PubMed Central

    Cook, Matthew T; Liang, Yayun; Besch-Williford, Cynthia; Hyder, Salman M

    2017-01-01

    Most breast cancer-related deaths from triple-negative breast cancer (TNBC) occur following metastasis of cancer cells and development of tumors at secondary sites. Because TNBCs lack the three receptors targeted by current chemotherapeutic regimens, they are typically treated with extremely aggressive and highly toxic non-targeted treatment strategies. Women with TNBC frequently develop metastatic lesions originating from drug-resistant residual cells and have poor prognosis. For this reason, novel therapeutic strategies that are safer and more effective are sought. Luteolin (LU) is a naturally occurring, non-toxic plant compound that has proven effective against several types of cancer. With this in mind, we conducted in vivo and in vitro studies to determine whether LU might suppress metastasis of TNBC. In an in vivo mouse metastasis model, LU suppressed metastasis of human MDA-MB-435 and MDA-MB-231 (4175) LM2 TNBC cells to the lungs. In in vitro assays, LU inhibited cell migration and viability of MDA-MB-435 and MDA-MB-231 (4175) LM2 cells. Further, LU induced apoptosis in MDA-MB-231 (4175) LM2 cells. Relatively low levels (10 µM) of LU significantly inhibited vascular endothelial growth factor (VEGF) secretion in MDA-MB-231 (4175) LM2 cells, suggesting that it has the ability to suppress a potent angiogenic and cell survival factor. In addition, migration of MDA-MB-231 (4175) LM2 cells was inhibited upon exposure to an antibody against the VEGF receptor, KDR, but not by exposure to a VEGF165 antibody. Collectively, these data suggest that the anti-metastatic properties of LU may, in part, be due to its ability to block VEGF production and KDR-mediated activity, thereby inhibiting tumor cell migration. These studies suggest that LU deserves further investigation as a potential treatment option for women with TNBC. PMID:28096694

  4. Exosomes in development, metastasis and drug resistance of breast cancer.

    PubMed

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-08-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system.

  5. Thyroid gland metastasis arising from breast cancer: A case report.

    PubMed

    Yang, Mei; Wang, Wei; Zhang, Chenfang

    2013-06-01

    The thyroid gland is an uncommon site for metastasis to develop and thus metastases arising from breast cancer are rarely observed. In the present study, we describe a case of a 45-year-old female with a three-year history of breast cancer who presented with a thyroid mass that was diagnosed as metastatic breast carcinoma by histopathological analysis of the subtotal thyroidectomy specimen. To ascertain the diagnosis of metastatic breast cancer, we evaluated two types of markers; those that possessed a similar expression status in the original and metastatic lesions [ER, PR and CerbB-2 (HER2/neu)], and those that are capable of differentiating between metastatic lesions and the surrounding thyroid components (TG and TTF-1). The results showed that ER, PR and CerbB-2 demonstrated a similar expression pattern in primary breast carcinoma and thyroid lesions. Meanwhile, in the thyroid lesions, the malignant cells showed negative staining for TG and TTF-1, which confirmed that lesions were not thyroid in origin. This case may prompt clinicians that although thyroid gland are uncommon metastatic site, a diagnosis of metastatic disease should be considered when new aggregates are identified in the thyroid glands and histopathological analysis may aid the diagnosis.

  6. CIP4 promotes metastasis in triple-negative breast cancer and is associated with poor patient prognosis.

    PubMed

    Cerqueira, Otto L D; Truesdell, Peter; Baldassarre, Tomas; Vilella-Arias, Santiago A; Watt, Kathleen; Meens, Jalna; Chander, Harish; Osório, Cynthia A B; Soares, Fernando A; Reis, Eduardo M; Craig, Andrew W B

    2015-04-20

    Signaling via epidermal growth factor receptor (EGFR) and Src kinase pathways promote triple-negative breast cancer (TNBC) cell invasion and tumor metastasis. Here, we address the role of Cdc42-interacting protein-4 (CIP4) in TNBC metastasis in vivo, and profile CIP4 expression in human breast cancer patients. In human TNBC cells, CIP4 knock-down (KD) led to less sustained activation of Erk kinase and impaired cell motility compared to control cells. This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies. In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model. In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease. Together, these results implicate CIP4 in promoting metastasis in TNBCs.

  7. Breast Cancer Metastasis to Bone Affects Osteoblast Differentiation

    DTIC Science & Technology

    2005-05-01

    Miele, M.E., Babu, G.R., Melly, R., Beck, L.N., Kent, J., Gilman, V.R., Sosnowski, D.M., Campo , D.A., Gay, C.V., Budgeon, L.R., Christensen, N.D...a gift from Dr. Henry Donahue, Penn State Hershey Medical Center. MDA-MB-231 cells were maintained in DMEM containing 5% fetal bovine serum (FBS) and...metastasis of breast cancer to bone, J.Orthop.Sci. 5 (2000) 75-81. [15] E. Luegmayr, F. Varga , T. Frank, et al., Effects of triiodothyronine on

  8. Breast tumor angiogenesis analysis using 3D power Doppler ultrasound

    NASA Astrophysics Data System (ADS)

    Chang, Ruey-Feng; Huang, Sheng-Fang; Lee, Yu-Hau; Chen, Dar-Ren; Moon, Woo Kyung

    2006-03-01

    Angiogenesis is the process that correlates to tumor growth, invasion, and metastasis. Breast cancer angiogenesis has been the most extensively studied and now serves as a paradigm for understanding the biology of angiogenesis and its effects on tumor outcome and patient prognosis. Most studies on characterization of angiogenesis focus on pixel/voxel counts more than morphological analysis. Nevertheless, in cancer, the blood flow is greatly affected by the morphological changes, such as the number of vessels, branching pattern, length, and diameter. This paper presents a computer-aided diagnostic (CAD) system that can quantify vascular morphology using 3-D power Doppler ultrasound (US) on breast tumors. We propose a scheme to extract the morphological information from angiography and to relate them to tumor diagnosis outcome. At first, a 3-D thinning algorithm helps narrow down the vessels into their skeletons. The measurements of vascular morphology significantly rely on the traversing of the vascular trees produced from skeletons. Our study of 3-D assessment of vascular morphological features regards vessel count, length, bifurcation, and diameter of vessels. Investigations into 221 solid breast tumors including 110 benign and 111 malignant cases, the p values using the Student's t-test for all features are less than 0.05 indicating that the proposed features are deemed statistically significant. Our scheme focuses on the vascular architecture without involving the technique of tumor segmentation. The results show that the proposed method is feasible, and have a good agreement with the diagnosis of the pathologists.

  9. Agonists and antagonists of GnRH-I and -II reduce metastasis formation by triple-negative human breast cancer cells in vivo.

    PubMed

    Schubert, Antje; Hawighorst, Thomas; Emons, Günter; Gründker, Carsten

    2011-12-01

    Metastasis to bone is a frequent problem of advanced breast cancer. Particularly breast cancers, which do not express estrogen and progesterone receptors and which have no overexpression/amplification of the HER2-neu gene, so called triple-negative breast cancers, are considered as very aggressive and possess a bad prognosis. About 60% of all human breast cancers and about 74% of triple-negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a therapeutic target. Recently, we could show that bone-directed invasion of human breast cancer cells in vitro is time- and dose-dependently reduced by GnRH analogs. In the present study, we have analyzed whether GnRH analogs are able to reduce metastases of triple-negative breast cancers in vivo. In addition, we have evaluated the effects of GnRH analogs on tumor growth. To quantify formation of metastasis by triple-negative MDA-MB-435 and MDA-MB-231 human breast cancers, we used a real-time PCR method based on detection of human-specific alu sequences measuring accurately the amount of human tumor DNA in athymic mouse organs. To analyze tumor growth, the volumes of breast cancer xenotransplants into nude mice were measured. We could demonstrate that GnRH analogs significantly reduced metastasis formation by triple-negative breast cancer in vivo. In addition, we could show that GnRH analogs significantly inhibited the growth of breast cancer into nude mice. Side effects were not detectable. In conclusion, GnRH analogs seem to be suitable drugs for an efficacious therapy for triple-negative, GnRH receptor-positive human breast cancers to prevent metastasis formation.

  10. Rectal carcinoid tumor metastasis to a skull base meningioma

    PubMed Central

    Huang, Jennifer; Gupta, Amit; Badve, Chaitra; Cohen, Mark L; Wolansky, Leo J

    2016-01-01

    Carcinoid tumors are rare, slow-growing neuroendocrine tumors that most frequently develop in the gastrointestinal tract or lungs and have high potential for metastasis. Metastasis to the brain is rare, but to another intracranial tumor is extremely rare. Of the intracranial tumors, meningiomas are the most common to host metastases, which may be related to its rich vascularity and E-cadherin expression. We describe the case of a 65-year-old female with active chemotherapy-treated neuroendocrine carcinoma who presented with left-sided facial numbness, headaches, and blurry vision. Initial imaging revealed a 1 cm irregular dural-based left petrous apex mass suggestive of a meningioma that was re-imaged four months later as a rapidly enlarging, extra-axial, mass extending into the cavernous sinus, effacing Meckel’s cave that resembled a trigeminal schwannoma. Pathology revealed a carcinoid tumor metastatic to meningioma. While the mass displayed characteristic imaging findings of a schwannoma, rapid growth in the setting of known active malignancy should prompt the clinician to consider mixed pathology from metastatic disease or a more aggressive meningioma. PMID:26825133

  11. Early versus late distant metastasis and adjuvant chemotherapy alone versus both radiotherapy and chemotherapy in molecular apocrine breast cancer.

    PubMed

    Liu, Xiaozhen; Yang, Yang; Feng, Xiaolong; Shen, Honghong; Liu, Jian; Liu, Xia; Niu, Yun

    2016-08-02

    As a new subtype of breast cancer, molecular apocrine breast cancer (MABC) is estrogen receptor (ER) and progesterone receptor (PR) negative expression, but androgen receptor (AR) positive expression. The prognostic significance and clinical biological behavior of MABC have remained unclear up to now. This study aimed to analysis the distant metastasis behavior and response to adjuvant radiotherapy and chemotherapy of MABC subgroup. The report showed that there were significant differences between early and late distant metastasizing tumors with respect to Ki67, epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF) expressions by a retrospective analysis consisting of 410 invasive breast cancer patients, which included 205 MABC and 205 nonMABC cases. MABC subgroup metastasized earlier than nonMABC subgroup, and MABC showed a tendency for a higher metastasis rate in lung, liver and brain, but lower in bone. HER2-positive or VEGF-positive tumors were more inclined to develop bone metastasis within MABC subgroup. The survival rate was superior for patients undergone both adjuvant radiotherapy and chemotherapy than those undergone chemotherapy alone in nonMABC subgroup, but there was no significant difference in MABC subgroup. Our data suggested that MABC subgroup seemed to develop distant metastasis earlier than nonMABC subgroup, and patients with MABC indicated poor prognosis. This study might also provide a foundation for helping patients receive reasonable treatments according to molecular subtype.

  12. Early versus late distant metastasis and adjuvant chemotherapy alone versus both radiotherapy and chemotherapy in molecular apocrine breast cancer

    PubMed Central

    Liu, Xiaozhen; Yang, Yang; Feng, Xiaolong; Shen, Honghong; Liu, Jian; Liu, Xia; Niu, Yun

    2016-01-01

    As a new subtype of breast cancer, molecular apocrine breast cancer (MABC) is estrogen receptor (ER) and progesterone receptor (PR) negative expression, but androgen receptor (AR) positive expression. The prognostic significance and clinical biological behavior of MABC have remained unclear up to now. This study aimed to analysis the distant metastasis behavior and response to adjuvant radiotherapy and chemotherapy of MABC subgroup. The report showed that there were significant differences between early and late distant metastasizing tumors with respect to Ki67, epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF) expressions by a retrospective analysis consisting of 410 invasive breast cancer patients, which included 205 MABC and 205 nonMABC cases. MABC subgroup metastasized earlier than nonMABC subgroup, and MABC showed a tendency for a higher metastasis rate in lung, liver and brain, but lower in bone. HER2-positive or VEGF-positive tumors were more inclined to develop bone metastasis within MABC subgroup. The survival rate was superior for patients undergone both adjuvant radiotherapy and chemotherapy than those undergone chemotherapy alone in nonMABC subgroup, but there was no significant difference in MABC subgroup. Our data suggested that MABC subgroup seemed to develop distant metastasis earlier than nonMABC subgroup, and patients with MABC indicated poor prognosis. This study might also provide a foundation for helping patients receive reasonable treatments according to molecular subtype. PMID:27340922

  13. RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis.

    PubMed

    Sato, Ryo; Nakano, Teppei; Hosonaga, Mari; Sampetrean, Oltea; Harigai, Ritsuko; Sasaki, Takashi; Koya, Ikuko; Okano, Hideyuki; Kudoh, Jun; Saya, Hideyuki; Arima, Yoshimi

    2017-01-01

    Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non-small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients.

  14. RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis

    PubMed Central

    Hosonaga, Mari; Koya, Ikuko

    2017-01-01

    Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non–small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients. PMID:28210624

  15. Nodular amyloidosis of the lung and the breast mimicking breast carcinoma with pulmonary metastasis.

    PubMed

    Liaw, Y S; Kuo, S H; Yang, P C; Chen, C L; Luh, K T

    1995-05-01

    Nodular amyloidosis of the breast and lung is a rare condition of unknown aetiology. The disease runs a benign course, but offers a diagnostic problem due to nonspecific histological features. We describe the case of a 56 year old woman with a 5 year history of multiple nodules of both lungs and left breast, clinically mimicking breast carcinoma with pulmonary metastasis. To our knowledge, this is the first case of cytologically proven amyloidosis diagnosed by ultrasound-guided percutaneous transthoracic fine-needle aspiration of pulmonary nodules.

  16. Leptomeningeal metastasis in breast cancer – a systematic review

    PubMed Central

    Scott, Brian J.; Oberheim-Bush, Nancy A.; Kesari, Santosh

    2016-01-01

    Background There is limited data on the impact of specific patient characteristics, tumor subtypes or treatment interventions on survival in breast cancer LM. Methods A systematic review was conducted to assess the impact of hormone receptor and HER-2 status on survival in breast cancer LM. A search for clinical studies published between 1/1/2007 and 7/1/2012 and all randomized-controlled trials was performed. Survival data from all studies are reported by study design (prospective trials, retrospective cohort studies, case studies). Results A total of 36 studies with 851 LM breast cancer subjects were identified. The majority (87%) were treated with intrathecal chemotherapy. Pooled median overall survival ranged from 14.9-18.1 weeks depending on study type. Breast cancer LM survival (15 weeks) was longer than other solid tumor LM 8.3 weeks and lung cancer LM 8.7 weeks, but shorter than LM lymphoma (15.4 versus 24.2 weeks). The impact of hormone receptor and HER-2 status on survival could not be determined. Conclusions A median overall survival of 15 weeks in prospective studies of breast cancer LM provides a historical comparison for future LM breast cancer trials. Other outcomes including the impact of molecular status on survival could not be determined based on available studies. PMID:26543235

  17. Gene expression profiles of circulating tumor cells versus primary tumors in metastatic breast cancer.

    PubMed

    Onstenk, Wendy; Sieuwerts, Anieta M; Weekhout, Marleen; Mostert, Bianca; Reijm, Esther A; van Deurzen, Carolien H M; Bolt-de Vries, Joan B; Peeters, Dieter J; Hamberg, Paul; Seynaeve, Caroline; Jager, Agnes; de Jongh, Felix E; Smid, Marcel; Dirix, Luc Y; Kehrer, Diederik F S; van Galen, Anne; Ramirez-Moreno, Raquel; Kraan, Jaco; Van, Mai; Gratama, Jan W; Martens, John W M; Foekens, John A; Sleijfer, Stefan

    2015-06-28

    Before using circulating tumor cells (CTCs) as liquid biopsy, insight into molecular discrepancies between CTCs and primary tumors is essential. We characterized CellSearch-enriched CTCs from 62 metastatic breast cancer (MBC) patients with ≥5 CTCs starting first-line systemic treatment. Expression levels of 35 tumor-associated, CTC-specific genes, including ESR1, coding for the estrogen receptor (ER), were measured by reverse transcription quantitative polymerase chain reaction and correlated to corresponding primary tumors. In 30 patients (48%), gene expression profiles of 35 genes were discrepant between CTCs and the primary tumor, but this had no prognostic consequences. In 15 patients (24%), the expression of ER was discrepant. Patients with ER-negative primary tumors and ER-positive CTCs had a longer median TTS compared to those with concordantly ER-negative CTCs (8.5 versus 2.1 months, P = 0.05). From seven patients, an axillary lymph node metastasis was available. In two patients, the CTC profiles better resembled the lymph node metastasis than the primary tumor. Our findings suggest that molecular discordances between CTCs and primary tumors frequently occur, but that this bears no prognostic consequences. Alterations in ER-status between primary tumors and CTCs might have prognostic implications.

  18. Metastasis of the gallbladder from the breast cancer.

    PubMed

    Fleres, Francesco; Rossitto, Maurizio; Foti, Agata; Macrì, Antonio; Cucinotta, Eugenio

    2014-12-29

    Le lesioni metastatiche della colecisti costituiscono una condizione clinica non frequente. Nella maggior parte dei casi si tratta di metastasi da melanoma, da tumore renale e da tumori della cervice. Lesioni metastatiche colecistiche da tumore primitivo della mammella sono descritte raramente in letteratura. In questa nota viene presentato il caso di una donna di 83 anni, sottoposta ad intervento chirurgico di colecistectomia videolaparoscopica (VL) per colelitiasi, con riscontro all’esame istologico del pezzo operatorio di una lesione di tipo metastatico Il carcinoma della mammella ed in particolare la varietà istologica duttale infiltrante si associa con elevata frequenza a metastasi loco-regionali e a distanza, quest’ultime a carico di ossa, fegato, polmone e SNC. Lesioni metastatiche a carico del tratto gastrointestinale, del peritoneo, del retroperitoneo e della pelvi possono essere causate soprattutto dal carcinoma lobulare invasivo, variante istologica meno frequente rispetto al tumore duttale rappresentando circa il 10% di tutti i carcinomi mammari. In questa nota è stata condotta una analisi dei dati della Letteratura sulle lesioni secondarie della colecisti da carcinoma della mammella che ha permesso di confermare la rarità di tale patologia descritta solamente in 18 pazienti: 12 di origine lobulare infiltrante, 1 di origine duttale e 2 misto duttale e lobulare infiltrante. La prognosi del carcinoma mammario metastatico è considerato incerto e spesso infausto. Clinicamente è difficile sospettare una localizzazione metastatica da carcinoma mammario primario nella colecisti, ma riteniamo che sia necessario conoscere bene questa possibilità di metastasi e da tenere a mente durante il follow-up di pazienti con cancro al seno. Sebbene la colecistectomia sia considerata come trattamento palliativo nelle pazienti con metastasi alla colecisti da carcinoma mammario, è consigliabile nei casi sintomatici.

  19. Talin regulates moesin–NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis

    PubMed Central

    Wang, Yarong; Bravo-Cordero, Jose Javier; Sharma, Ved P.; Miskolci, Veronika; Hodgson, Louis

    2014-01-01

    Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin–NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis. PMID:24891603

  20. Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis.

    PubMed

    Beaty, Brian T; Wang, Yarong; Bravo-Cordero, Jose Javier; Sharma, Ved P; Miskolci, Veronika; Hodgson, Louis; Condeelis, John

    2014-06-09

    Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.

  1. Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

    PubMed Central

    Martínez-Iglesias, Olaia A.; Alonso-Merino, Elvira; Gómez-Rey, Sara; Velasco-Martín, Juan Pedro; Martín Orozco, Rosa; Luengo, Enrique; García Martín, Rosa; Ibáñez de Cáceres, Inmaculada; Fernández, Agustín F.; Fraga, Mario F.; González-Peramato, Pilar; Varona, Constantino; Palacios, José; Regadera, Javier; Aranda, Ana

    2016-01-01

    Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies. PMID:26729869

  2. Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis.

    PubMed

    Martínez-Iglesias, Olaia A; Alonso-Merino, Elvira; Gómez-Rey, Sara; Velasco-Martín, Juan Pedro; Martín Orozco, Rosa; Luengo, Enrique; García Martín, Rosa; Ibáñez de Cáceres, Inmaculada; Fernández, Agustín F; Fraga, Mario F; González-Peramato, Pilar; Varona, Constantino; Palacios, José; Regadera, Javier; Aranda, Ana

    2016-01-19

    Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.

  3. Lung Cancer with Skin and Breast Metastasis: A Case Report and Literature Review

    PubMed Central

    Schmidt, Marie Frances; Ghosh, Meenakshi; Sinha Ray, Abhisekh; Manhas, Saveena; Oke, Vikram; Agu, Chidozie Charles; Basunia, Md. Rawshan; Enriquez, Danilo; Quist, Joseph; Bianchi, Catherine; Hans, Ravi; Kandel, Saroj

    2015-01-01

    Lung cancer is one of the most common cancers in America. Frequent sites of metastasis include the Hilar lymph nodes, adrenal glands, liver, brain, and bone. The following case report is of a primary lung cancer with metastases to the breast and skin. Case. A 48-year-old African American male with a past medical history of poorly differentiated left breast cancer status after modified radical mastectomy (MRM), chronic obstructive pulmonary disease, and smoking (20 pack-years) presents to the ER with progressive shortness of breath on exertion, upper back pain, and weight loss for 2 months in duration. On physical examination he is found to have a MRM scar on his left breast and a left periumbilical cutaneous mass. Chest X-ray and chest CT reveal a right upper lobe mass and biopsies from the breast, lung, and the periumbilical mass indicate a poorly differentiated carcinoma of unclear etiology; all tumor markers are negative. The patient is male and a chronic smoker; therefore the diagnosis is made as lung carcinoma with metastases to the breast and skin. Conclusion. A high index of suspicion for cutaneous metastases should be cast when investigating cutaneous pathologies in patients at risk for primary lung malignancy. PMID:25861506

  4. Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model

    PubMed Central

    Yang, F; Hu, M; Lei, Q; Xia, Y; Zhu, Y; Song, X; Li, Y; Jie, H; Liu, C; Xiong, Y; Zuo, Z; Zeng, A; Li, Y; Yu, L; Shen, G; Wang, D; Xie, Y; Ye, T; Wei, Y

    2015-01-01

    Breast carcinoma is the most common female cancer with considerable metastatic potential. Signal transducers and activators of the transcription 3 (Stat3) signaling pathway is constitutively activated in many cancers including breast cancer and has been validated as a novel potential anticancer target. Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3. The potency of nifuroxazide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that nifuroxazide decreased the viability of three breast cancer cell lines and induced apoptosis of cancer cells in a dose-dependent manner. In addition, western blot analysis demonstrated that the occurrence of its apoptosis was associated with activation of cleaved caspases-3 and Bax, downregulation of Bcl-2. Moreover, nifuroxazide markedly blocked cancer cell migration and invasion, and the reduction of phosphorylated-Stat3Tyr705, matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 50 mg/kg/day nifuroxazide suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without detectable toxicity. Meanwhile, histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells, MMP-9-positive cells and an increase in cleaved caspase-3-positive cells upon nifuroxazide. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung. Our data indicated that nifuroxazide may potentially be a therapeutic agent for growth and metastasis of breast cancer. PMID:25811798

  5. Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model.

    PubMed

    Yang, F; Hu, M; Lei, Q; Xia, Y; Zhu, Y; Song, X; Li, Y; Jie, H; Liu, C; Xiong, Y; Zuo, Z; Zeng, A; Li, Y; Yu, L; Shen, G; Wang, D; Xie, Y; Ye, T; Wei, Y

    2015-03-26

    Breast carcinoma is the most common female cancer with considerable metastatic potential. Signal transducers and activators of the transcription 3 (Stat3) signaling pathway is constitutively activated in many cancers including breast cancer and has been validated as a novel potential anticancer target. Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3. The potency of nifuroxazide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that nifuroxazide decreased the viability of three breast cancer cell lines and induced apoptosis of cancer cells in a dose-dependent manner. In addition, western blot analysis demonstrated that the occurrence of its apoptosis was associated with activation of cleaved caspases-3 and Bax, downregulation of Bcl-2. Moreover, nifuroxazide markedly blocked cancer cell migration and invasion, and the reduction of phosphorylated-Stat3(Tyr705), matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 50 mg/kg/day nifuroxazide suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without detectable toxicity. Meanwhile, histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells, MMP-9-positive cells and an increase in cleaved caspase-3-positive cells upon nifuroxazide. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung. Our data indicated that nifuroxazide may potentially be a therapeutic agent for growth and metastasis of breast cancer.

  6. Lung cancer with skin and breast metastasis: a case report and literature review.

    PubMed

    Bhattarai, Bikash; Schmidt, Marie Frances; Ghosh, Meenakshi; Sinha Ray, Abhisekh; Manhas, Saveena; Oke, Vikram; Agu, Chidozie Charles; Basunia, Md Rawshan; Enriquez, Danilo; Quist, Joseph; Bianchi, Catherine; Hans, Ravi; Kandel, Saroj

    2015-01-01

    Lung cancer is one of the most common cancers in America. Frequent sites of metastasis include the Hilar lymph nodes, adrenal glands, liver, brain, and bone. The following case report is of a primary lung cancer with metastases to the breast and skin. Case. A 48-year-old African American male with a past medical history of poorly differentiated left breast cancer status after modified radical mastectomy (MRM), chronic obstructive pulmonary disease, and smoking (20 pack-years) presents to the ER with progressive shortness of breath on exertion, upper back pain, and weight loss for 2 months in duration. On physical examination he is found to have a MRM scar on his left breast and a left periumbilical cutaneous mass. Chest X-ray and chest CT reveal a right upper lobe mass and biopsies from the breast, lung, and the periumbilical mass indicate a poorly differentiated carcinoma of unclear etiology; all tumor markers are negative. The patient is male and a chronic smoker; therefore the diagnosis is made as lung carcinoma with metastases to the breast and skin. Conclusion. A high index of suspicion for cutaneous metastases should be cast when investigating cutaneous pathologies in patients at risk for primary lung malignancy.

  7. Novel chemokine-like activities of histones in tumor metastasis

    PubMed Central

    Chen, Ruochan; Xie, Yangchun; Zhong, Xiao; Fu, Yongmin; Huang, Yan; Zhen, Yixiang; Pan, Pinhua; Wang, Haichao; Bartlett, David L.; Billiar, Timothy R.; Lotze, Michael T.; Zeh, Herbert J.; Fan, Xue-Gong; Tang, Daolin; Kang, Rui

    2016-01-01

    Histones are intracellular nucleosomal components and extracellular damage-associated molecular pattern molecules that modulate chromatin remodeling, as well as the immune response. However, their extracellular roles in cell migration and invasion remain undefined. Here, we demonstrate that histones are novel regulators of tumor metastasis with chemokine-like activities. Indeed, exogenous histones promote both hepatocellular carcinoma (HCC) cell migration and invasion through toll-like receptor (TLR)4, but not TLR2 or the receptor for advanced glycosylation end product. TLR4-mediated activation of nuclear factor-κB (NF-κB) by extracellular signal-regulated kinase (ERK) is required for histone-induced chemokine (e.g., C-C motif ligand 9/10) production. Pharmacological and genetic inhibition of TLR4-ERK-NF-κB signaling impairs histone-induced chemokine production and HCC cell migration. Additionally, TLR4 depletion (by using TLR4−/− mice and TLR4-shRNA) or inhibition of histone release/activity (by administration of heparin and H3 neutralizing antibody) attenuates lung metastasis of HCC cells injected via the tail vein of mice. Thus, histones promote tumor metastasis of HCC cells through the TLR4-NF-κB pathway and represent novel targets for treating patients with HCC. PMID:27623211

  8. Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer.

    PubMed

    Wu, Sheng-Kai; Chiang, Chi-Feng; Hsu, Yu-Hone; Lin, Tzu-Hung; Liou, Houng-Chi; Fu, Wen-Mei; Lin, Win-Li

    2014-01-01

    The blood-brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers.

  9. S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer

    PubMed Central

    Khotskaya, Yekaterina B; Goverdhan, Aarthi; Shen, Jia; Ponz-Sarvise, Mariano; Chang, Shih-Shin; Hsu, Ming-Chuan; Wei, Yongkun; Xia, Weiya; Yu, Dihua; Hung, Mien-Chie

    2014-01-01

    Breast cancer is the second-leading cause of oncology-related death in US women. Of all invasive breast cancers, patients with tumors lacking expression of the estrogen and progesterone hormone receptors and overexpression of human epidermal growth factor receptor 2 have the poorest clinical prognosis. These referred to as triple-negative breast cancer (TNBC) represent an aggressive form of disease that is marked by early-onset metastasis, high tumor recurrence rate, and low overall survival during the first three years post-diagnosis. In this report, we discuss a novel model of early-onset TNBC metastasis to bone and lungs, derived from MDA-MB-231 cells. Breast cancer cells injected intravenously produced rapid, osteolytic metastases in long bones and spines of athymic nude mice, with concurrent metastasis to lungs, liver, and soft tissues. From the bone metastases, we developed a highly metastatic luciferase-tagged cell line variant named MDA-231-LUC Met. In this report, we demonstrate that the Akt/mTOR/S6K1 axis is hyperactivated in these cells, leading to a dramatic increase in phosphorylation of S6 ribosomal protein at Ser235/236. Lastly, we provide evidence that inhibition of the furthest downstream kinase in the mTOR pathway, S6K1, with a highly specific inhibitor PF-4708671 inhibits cell migration, and thus may provide a potent anti-metastatic adjuvant therapy approach. PMID:25075253

  10. Overexpression of MMP-3 and uPA with Diminished PAI-1 Related to Metastasis in Ductal Breast Cancer Patients Attending a Public Hospital in Mexico City.

    PubMed

    Barajas-Castañeda, Luis Miguel; Cortés-Gutiérrez, Evelin; García-Rodríguez, Francisco Mario; Campos-Rodríguez, Rafael; Lara-Padilla, Eleazar; Enríquez-Rincón, Fernando; Castro-Mussot, María Eugenia; Figueroa-Arredondo, Paula

    2016-01-01

    Extracellular matrix metalloproteases and the fibrinolytic system are important protease systems interacting with each other in charge of remodeling and recycling of tissues. Their role in tumor invasion and metastasis is often discussed. In this study several metalloproteases such as MMP-1, MMP-3, MMP-9, and TIMP-1 together with molecules from the fibrinolytic system like uPA, its receptor uPAR, and its inhibitor, PAI-1, were studied by immune-histochemistry to establish a comparison with and without metastasis. From the (118) primary tumors of Mexican patients with ductal breast cancer studied, 56% were grade II and 69% were size T2; the group with metastatic ganglia included 64 samples (54.3%). In patients with metastasis the estimated expression of MMP-3 and uPA (resp., 28% and 45%) was higher than that from no metastatic tumors; it means there is higher expression of both markers in metastatic tumors (p < 0.05). At the same time, metastatic tumors showed statistically significant lower signal of PAI-1 (24%) than tumors without metastasis (p < 0.05). We concluded that overexpression of MMP-3 and uPA, altogether with diminished expression of PAI-1 from metastatic tumors, might be a crucial step towards metastasis in ductal breast cancer. Nevertheless, additional studies in different populations are necessary to establish a pattern.

  11. Overexpression of MMP-3 and uPA with Diminished PAI-1 Related to Metastasis in Ductal Breast Cancer Patients Attending a Public Hospital in Mexico City

    PubMed Central

    Barajas-Castañeda, Luis Miguel; Cortés-Gutiérrez, Evelin; García-Rodríguez, Francisco Mario; Campos-Rodríguez, Rafael; Lara-Padilla, Eleazar; Enríquez-Rincón, Fernando; Figueroa-Arredondo, Paula

    2016-01-01

    Extracellular matrix metalloproteases and the fibrinolytic system are important protease systems interacting with each other in charge of remodeling and recycling of tissues. Their role in tumor invasion and metastasis is often discussed. In this study several metalloproteases such as MMP-1, MMP-3, MMP-9, and TIMP-1 together with molecules from the fibrinolytic system like uPA, its receptor uPAR, and its inhibitor, PAI-1, were studied by immune-histochemistry to establish a comparison with and without metastasis. From the (118) primary tumors of Mexican patients with ductal breast cancer studied, 56% were grade II and 69% were size T2; the group with metastatic ganglia included 64 samples (54.3%). In patients with metastasis the estimated expression of MMP-3 and uPA (resp., 28% and 45%) was higher than that from no metastatic tumors; it means there is higher expression of both markers in metastatic tumors (p < 0.05). At the same time, metastatic tumors showed statistically significant lower signal of PAI-1 (24%) than tumors without metastasis (p < 0.05). We concluded that overexpression of MMP-3 and uPA, altogether with diminished expression of PAI-1 from metastatic tumors, might be a crucial step towards metastasis in ductal breast cancer. Nevertheless, additional studies in different populations are necessary to establish a pattern. PMID:27975070

  12. The PDZ protein TIP-1 facilitates cell migration and pulmonary metastasis of human invasive breast cancer cells in athymic mice

    SciTech Connect

    Han, Miaojun; Wang, Hailun; Zhang, Hua-Tang; Han, Zhaozhong

    2012-05-25

    Highlights: Black-Right-Pointing-Pointer This study has revealed novel oncogenic functions of TIP-1 in human invasive breast cancer. Black-Right-Pointing-Pointer Elevated TIP-1 expression levels in human breast cancers correlate to the disease prognosis. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the cell migration and pulmonary metastasis of human breast cancer cells. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the expression and functionality of motility-related genes. -- Abstract: Tax-interacting protein 1 (TIP-1, also known as Tax1bp3) inhibited proliferation of colon cancer cells through antagonizing the transcriptional activity of beta-catenin. However, in this study, elevated TIP-1 expression levels were detected in human invasive breast cancers. Studies with two human invasive breast cancer cell lines indicated that RNAi-mediated TIP-1 knockdown suppressed the cell adhesion, proliferation, migration and invasion in vitro, and inhibited tumor growth in mammary fat pads and pulmonary metastasis in athymic mice. Biochemical studies showed that TIP-1 knockdown had moderate and differential effects on the beta-catenin-regulated gene expression, but remarkably down regulated the genes for cell adhesion and motility in breast cancer cells. The decreased expression of integrins and paxillin was accompanied with reduced cell adhesion and focal adhesion formation on fibronectin-coated surface. In conclusion, this study revealed a novel oncogenic function of TIP-1 suggesting that TIP-1 holds potential as a prognostic biomarker and a therapeutic target in the treatment of human invasive breast cancers.

  13. miR-509 suppresses brain metastasis of breast cancer cells by modulating RhoC and TNF-α.

    PubMed

    Xing, F; Sharma, S; Liu, Y; Mo, Y-Y; Wu, K; Zhang, Y-Y; Pochampally, R; Martinez, L A; Lo, H-W; Watabe, K

    2015-09-10

    The median survival time of breast cancer patients with brain metastasis is less than 6 months, and even a small metastatic lesion often causes severe neurological disabilities. Because of the location of metastatic lesions, a surgical approach is limited and most chemotherapeutic drugs are ineffective owing to the blood brain barrier (BBB). Despite this clinical importance, the molecular basis of the brain metastasis is poorly understood. In this study, we have isolated RNA from samples obtained from primary breast tumors and also from brain metastatic lesions followed by microRNA profiling analysis. Our results revealed that the miR-509 is highly expressed in the primary tumors, whereas the expression of this microRNA is significantly decreased in the brain metastatic lesions. MicroRNA target prediction and the analysis of cytokine array for the cells ectopically expressed with miR-509 demonstrated that this microRNA was capable of modulating the two genes essential for brain invasion, RhoC and TNF-α that affect the invasion of cancer cells and permeability of BBB, respectively. Importantly, high levels of TNF-α and RhoC-induced MMP9 were significantly correlated with brain metastasis-free survival of breast cancer patients. Furthermore, the results of our in vivo experiments indicate that miR-509 significantly suppressed the ability of cancer cells to metastasize to the brain. These findings suggest that miR-509 has a critical role in brain metastasis of breast cancer by modulating the RhoC-TNF-α network and that this miR-509 axis may represent a potential therapeutic target or serve as a prognostic tool for brain metastasis.

  14. A novel and selective inhibitor of PKC ζ potently inhibits human breast cancer metastasis in vitro and in mice.

    PubMed

    Wu, Jing; Liu, Shuye; Fan, Zhijuan; Zhang, Lei; Tian, Yaqiong; Yang, Rui

    2016-06-01

    Cell motility and chemotaxis play pivotal roles in the process of tumor development and metastasis. Protein kinase C ζ (PKC ζ) mediates epidermal growth factor (EGF)-stimulated chemotactic signaling pathway through regulating cytoskeleton rearrangement and cell adhesion. The purpose of this study was to develop anti-PKC ζ therapeutics for breast cancer metastasis. In this study, a novel and high-efficient PKC ζ inhibitor named PKCZI195.17 was screened out through a substrate-specific strategy. MTT assay was used to determine the cell viability of human breast cancer MDA-MB-231, MDA-MB-435, and MCF-7 cells while under PKCZI195.17 treatment. Wound-healing, chemotaxis, and Matrigel invasion assays were performed to detect the effects of PKCZI195.17 on breast cancer cells migration and invasion. Adhesion, actin polymerization, and Western blotting were performed to detect the effects of PKCZI195.17 on cells adhesion and actin polymerization, and explore the downsteam signaling mechanisms involved in PKC ζ inhibition. MDA-MB-231 xenograft was used to measure the in vivo anti-metastasis efficacy of PKCZI195.17. The compound PKCZI195.17 selectively inhibited PKC ζ kinase activity since it failed to inhibit PKC α, PKC β, PKC δ, PKC η, AKT2, as well as FGFR2 activity. PKCZI195.17 significantly impaired spontaneous migration, chemotaxis, and invasion of human breast cancer MDA-MB-231, MDA-MB-435, and MCF-7 cells, while PKCZI195.17 did not obviously inhibited cells viability. PKCZI195.17 also inhibited cells adhesion and actin polymerization through attenuating the phosphorylations of integrin β1, LIMK, and cofilin, which might be the downstream effectors of PKC ζ-mediated chemotaxis in MDA-MB-231 cells. Furthermore, PKCZI195.17 suppressed the breast cancer metastasis and increased the survival time of breast tumor-bearing mice. In summary, PKCZI195.17 was a PKC ζ-specific inhibitor which dampened cancer cell migration and metastasis and may serve as a novel

  15. Transcriptional network analysis identifies BACH1 as a master regulator of breast cancer bone metastasis.

    PubMed

    Liang, Yajun; Wu, Heng; Lei, Rong; Chong, Robert A; Wei, Yong; Lu, Xin; Tagkopoulos, Ilias; Kung, Sun-Yuan; Yang, Qifeng; Hu, Guohong; Kang, Yibin

    2012-09-28

    The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes.

  16. Augmented reality for breast tumors visualization.

    PubMed

    Ghaderi, Mohammad Ali; Heydarzadeh, Mehrdad; Nourani, Mehrdad; Gupta, Gopal; Tamil, Lakshman

    2016-08-01

    3D visualization of breast tumors are shown to be effective by previous studies. In this paper, we introduce a new augmented reality application that can help doctors and surgeons to have a more accurate visualization of breast tumors; this system uses a marker-based image-processing technique to render a 3D model of the tumors on the body. The model can be created using a combination of breast 3D mammography by experts. We have tested the system using an Android smartphone and a head-mounted device. This proof of concept can be useful for oncologists to have a more effective screening, and surgeons to plan the surgery.

  17. MicroRNA-376b promotes breast cancer metastasis by targeting Hoxd10 directly

    PubMed Central

    An, Ning; Luo, Xinmei; Zhang, Ming; Yu, Ruilian

    2017-01-01

    Breast cancer is the most common malignant disease in women, and metastasis formed at distant anatomic sites was the major cause of cancer-related mortality. Thus, a novel therapy target and progression biomarker for breast cancer metastasis was necessary. microRNA (miR)-376b has been demonstrated to regulate angiogenesis; however, its role in cancer metastasis remains elusive. In the present study, the expression of miR-376b in normal breast tissue, JC and 4T1 cells was determined by qPCR. Furthermore, in vitro and in vivo experiments were performed to determine the effect of miR-376b on breast cancer metastasis. The direct target of miR-376b was determined by the luciferase assay and western blotting. The results indicated that silencing of miR-376b by the miR-376-mimic significantly inhibited 4T1 cell migration and invasion in vitro. Lung metastasis was also evidently decreased after silencing of miR-376b in 4T1 cells. Moreover, the luciferase assay and western blotting identified that Hoxd10 is the direct target of miR-376b during the regulation of breast cancer metastasis. To the best of our knowledge, the present study was the first to demonstrate the promoting breast cancer metastasis role of miR-376b by directly targeting Hoxd10. Therefore, it would be a novel therapy target and prognostic biomarker for breast cancer. PMID:28123472

  18. Tumor-Penetrating iRGD Peptide Inhibits Metastasis

    PubMed Central

    Sugahara, Kazuki N.; Braun, Gary B.; de Mendoza, Tatiana Hurtado; Kotamraju, Venkata Ramana; French, Randall P.; Lowy, Andrew M.; Teesalu, Tambet; Ruoslahti, Erkki

    2014-01-01

    Tumor-specific tissue-penetrating peptides deliver drugs into extravascular tumor tissue by increasing tumor vascular permeability through interaction with neuropilin (NRP). Here we report that a prototypic tumor-penetrating peptide iRGD (amino acid sequence: CRGDKGPDC) potently inhibits spontaneous metastasis in mice. The anti-metastatic effect was mediated by the NRP-binding RXXK peptide motif (CendR motif), and not by the integrin-binding RGD motif. iRGD inhibited migration of tumor cells and caused chemorepulsion in vitro in a CendR- and NRP-1-dependent manner. The peptide induced dramatic collapse of cellular processes and partial cell detachment, resulting in the repellent activity. These effects were prominently displayed when the cells were seeded on fibronectin, suggesting a role of CendR in functional regulation of integrins. The anti-metastatic activity of iRGD may provide a significant additional benefit when this peptide is used for drug delivery to tumors. PMID:25392370

  19. MSC-regulated microRNAs converge on the transcription factor FOXP2 and promote breast cancer metastasis.

    PubMed

    Cuiffo, Benjamin G; Campagne, Antoine; Bell, George W; Lembo, Antonio; Orso, Francesca; Lien, Evan C; Bhasin, Manoj K; Raimo, Monica; Hanson, Summer E; Marusyk, Andriy; El-Ashry, Dorraya; Hematti, Peiman; Polyak, Kornelia; Mechta-Grigoriou, Fatima; Mariani, Odette; Volinia, Stefano; Vincent-Salomon, Anne; Taverna, Daniela; Karnoub, Antoine E

    2014-12-04

    Mesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer.

  20. LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis.

    PubMed

    Hou, P; Zhao, Y; Li, Z; Yao, R; Ma, M; Gao, Y; Zhao, L; Zhang, Y; Huang, B; Lu, J

    2014-06-12

    LncRNAs have critical roles in various biological processes ranging from embryonic development to human diseases, including cancer progression, although their detailed mechanistic functions remain illusive. The lncRNA linc-ROR has been shown to contribute to the maintenance of induced pluripotent stem cells and embryonic stem cells. In this study, we discovered that linc-ROR was upregulated in breast tumor samples, and ectopic overexpression of linc-ROR in immortalized human mammary epithelial cells induced an epithelial-to-mesenchymal transition (EMT) program. Moreover, we showed that linc-ROR enhanced breast cancer cell migration and invasion, which was accompanied by generation of stem cell properties. Contrarily, silencing of linc-ROR repressed breast tumor growth and lung metastasis in vivo. Mechanistically, our data revealed that linc-ROR was associated with miRNPs and functioned as a competing endogenous RNA to mi-205. Specifically, linc-ROR prevented the degradation of mir-205 target genes, including the EMT inducer ZEB2. Thus our results indicate that linc-ROR functions as an important regulator of EMT and can promote breast cancer progression and metastasis through regulation of miRNAs. Potentially, the findings of this study implicate the relevance of linc-ROR as a possible therapeutic target for aggressive and metastatic breast cancers.

  1. Mucinous breast cancer with solitary metastasis to humeral head: a case report.

    PubMed

    Aljarrah, Adil; Al-Hashmi, Maryam; Malik, Kamran Ahmad; Sukhpal, Sawhney; Hussein, Samir; Al-Riyami, Marwa; Al-Moundhri, Mansour

    2013-09-01

    Breast cancer is the most common cause of metastatic deposits in the skeleton, and bone is the most common site of recurrence of breast cancer. Breast cancer metastasis most commonly affects the spine, ribs, pelvis, and proximal long bones; however, only 3.5% of breast cancer patients develop long-bone metastases. The humerus is the most common upper-extremity site for bony metastasis, and pathologic fractures can result. The patient in the current study presented with breast cancer and discovered to have humeral head metastasis during initial workup. The dilemma was in investigation the modality to confirm humeral head metastasis as there are many differential diagnoses with similar findings. After staging workup, the patient was treated with neoadjuvant chemotherapy followed by modified radical mastectomy and radiotherapy of the chest wall and the shoulder. The lesion in humerus was well healed.

  2. Role of c-Src and focal adhesion kinase in progression and metastasis of estrogen receptor-positive breast cancer

    SciTech Connect

    Planas-Silva, Maricarmen D. . E-mail: mcplanas@psu.edu; Bruggeman, Richard D.; Grenko, Ronald T.; Stanley Smith, J.

    2006-03-03

    The non-receptor tyrosine kinases c-Src and focal adhesion kinase (Fak) mediate signal transduction pathways that regulate cell proliferation, survival, invasion, and metastasis. Here, we investigated whether c-Src and Fak are activated during progression of hormone-dependent breast cancer. Maximally active c-Src was overexpressed in a subset of tamoxifen-resistant variants and in metastases of recurrent hormone-treated breast cancer. Active Fak was also frequently observed in these tumors. We also show that estrogen receptor (ER) can bind to Fak and that estrogen can modulate Fak autophosphorylation supporting a cross-talk between these two pathways. Inhibition of c-Src activity blocked proliferation of all tamoxifen-resistant variants, suggesting that inhibitors of c-Src-Fak activity may delay or prevent progression and metastasis of ER-positive tumors. These studies also raise the possibility that fully active forms of c-Src and Fak in breast tumors may be biomarkers to predict tamoxifen resistance and/or risk of recurrence in ER-positive breast cancer.

  3. Up-Regulation of RFC3 Promotes Triple Negative Breast Cancer Metastasis and is Associated With Poor Prognosis Via EMT.

    PubMed

    He, Zhen-Yu; Wu, San-Gang; Peng, Fang; Zhang, Qun; Luo, Ying; Chen, Ming; Bao, Yong

    2017-02-01

    Triple-negative breast cancer (TNBC) was regarded as the most aggressive and mortal subtype of breast cancer (BC) since the molecular subtype system has been established. Abundant studies have revealed that epithelial-mesenchymal transition (EMT) played a pivotal role during breast cancer metastasis and progression, especially in TNBC. Herein, we showed that inhibition the expression of replication factor C subunit 3 (RFC3) significantly attenuated TNBC metastasis and progression, which was associated with EMT signal pathway. In TNBC cells, knockdown of RFC3 can down-regulate mesenchymal markers and up-regulate epithelial markers, significantly attenuated cell proliferation, migration and invasion. Additionally, silencing RFC3 expression can decrease nude mice tumor volume, weight and relieve lung metastasis in vivo. Furthermore, we also demonstrated that overexpression of RFC3 in TNBC showed increased metastasis, progression and poor prognosis. We confirmed all of these results by immunohistochemistry analysis in 127 human TNBC tissues and found that RFC3 expression was significantly associated with poor prognosis in TNBC. Taken all these findings into consideration, we can conclude that up-regulation of RFC3 promotes TNBC progression through EMT signal pathway. Therefore, RFC3 could be an independent prognostic factor and therapeutic target for TNBC.

  4. Tie2 Regulates Tumor Metastasis of Oral Squamous Cell Carcinomas

    PubMed Central

    Kitajima, Daisuke; Kasamatsu, Atsushi; Nakashima, Dai; Miyamoto, Isao; Kimura, Yasushi; Saito, Tomoaki; Suzuki, Takane; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-01-01

    The endothelial-specific receptor, tyrosine kinase with immunoglobulin-like loops and epidermal growth factor homology domains-2 (Tie2) is a member of the tyrosine kinase family and is ubiquitous in normal tissues; however, little is known about the mechanisms and roles of Tie2 in oral squamous cell carcinomas (OSCCs). In the current study, we investigated the expression status of Tie2 in OSCCs by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry and the functional mechanisms of Tie2 using its overexpressed OSCC (oeTie2) cells and Tie2 blocking by its antibody. We found that Tie2 expression was down-regulated significantly (p < 0.05) in OSCCs compared with normal counterparts in vitro and in vivo. Interestingly, oeTie2 cells showed higher cellular adhesion (p < 0.05) and lower cellular invasion (p < 0.05) compared with control cells; whereas there was similar cellular proliferation in both transfectants. Furthermore, cellular adhesion was inhibited and invasion was activated by Tie2 function-blocking antibody (p < 0.05), indicating that Tie2 directly regulates cellular adhesion and invasion. As expected, among the clinical variables analyzed, Tie2-positivity in patients with OSCC was correlated closely with negative lymph node metastasis. These results suggested for the first time that Tie2 plays an important role in tumor metastasis and may be a potential biomarker for OSCC metastasis. PMID:27053959

  5. Suppression of breast cancer metastasis through the inactivation of ADP-ribosylation factor 1

    PubMed Central

    Xie, Xiayang; Tang, Shou-Ching; Cai, Yafei; Pi, Wenhu; Deng, Libin; Wu, Guangyu; Chavanieu, Alain; Teng, Yong

    2016-01-01

    Metastasis is the major cause of cancer-related death in breast cancer patients, which is controlled by specific sets of genes. Targeting these genes may provide a means to delay cancer progression and allow local treatment to be more effective. We report for the first time that ADP-ribosylation factor 1 (ARF1) is the most amplified gene in ARF gene family in breast cancer, and high-level amplification of ARF1 is associated with increased mRNA expression and poor outcomes of patients with breast cancer. Knockdown of ARF1 leads to significant suppression of migration and invasion in breast cancer cells. Using the orthotopic xenograft model in NSG mice, we demonstrate that loss of ARF1 expression in breast cancer cells inhibits pulmonary metastasis. The zebrafish-metastasis model confirms that the ARF1 gene depletion suppresses breast cancer cells to metastatic disseminate throughout fish body, indicating that ARF1 is a very compelling target to limit metastasis. ARF1 function largely dependents on its activation and LM11, a cell-active inhibitor that specifically inhibits ARF1 activation through targeting the ARF1-GDP/ARNO complex at the Golgi, significantly impairs metastatic capability of breast cancer cell in zebrafish. These findings underline the importance of ARF1 in promoting metastasis and suggest that LM11 that inhibits ARF1 activation may represent a potential therapeutic approach to prevent or treat breast cancer metastasis. PMID:27517156

  6. Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells

    NASA Astrophysics Data System (ADS)

    Deng, Senyi; Wu, Qinjie; Zhao, Yuwei; Zheng, Xin; Wu, Ni; Pang, Jing; Li, Xuejing; Bi, Cheng; Liu, Xinyu; Yang, Li; Liu, Lei; Su, Weijun; Wei, Yuquan; Gong, Changyang

    2015-03-01

    Circulating tumor cells (CTCs) play a crucial role in tumor metastasis, but it is rare for any chemotherapy regimen to focus on killing CTCs. Herein, we describe doxorubicin (Dox) micelles that showed anti-metastatic activity by killing CTCs. Dox micelles with a small particle size and high encapsulation efficiency were obtained using a pH-induced self-assembly method. Compared with free Dox, Dox micelles exhibited improved cytotoxicity, apoptosis induction, and cellular uptake. In addition, Dox micelles showed a sustained release behavior in vitro, and in a transgenic zebrafish model, Dox micelles exhibited a longer circulation time and lower extravasation from blood vessels into surrounding tissues. Anti-tumor and anti-metastatic activities of Dox micelles were investigated in transgenic zebrafish and mouse models. In transgenic zebrafish, Dox micelles inhibited tumor growth and prolonged the survival of tumor-bearing zebrafish. Furthermore, Dox micelles suppressed tumor metastasis by killing CTCs. In addition, improved anti-tumor and anti-metastatic activities were also confirmed in mouse tumor models, where immunofluorescent staining of tumors indicated that Dox micelles induced more apoptosis and showed fewer proliferation-positive cells. There were decreased side effects in transgenic zebrafish and mice after administration of Dox micelles. In conclusion, Dox micelles showed stronger anti-tumor and anti-metastatic activities and decreased side effects both in vitro and in vivo, which may have potential applications in cancer therapy.

  7. SWIFT MRI Enhances Detection of Breast Cancer Metastasis to the Lung

    PubMed Central

    Kobayashi, Naoharu; Idiyatullin, Djaudat; Corum, Curt; Weber, Joseph; Garwood, Michael; Sachdev, Deepali

    2014-01-01

    Purpose To evaluate the capability of longitudinal MR scans using sweep imaging with Fourier transformation (SWIFT) to detect breast cancer metastasis to the lung in mice. Methods Mice with breast cancer metastatic to the lung were generated by tail vein injection of MDA-MB-231-LM2 cells. Thereafter, MR imaging was performed every week using three different pulse sequences: SWIFT (TE~3 μs), concurrent dephasing and excitation (CODE; TE~300 μs), and 3D gradient echo (GRE; TE=2.2 ms). Motion during the long SWIFT MR scans was compensated for by rigid-body motion correction. Maximum intensity projection (MIP) images were generated to visualize changes in lung vascular structures during the development and growth of metastases. Results SWIFT MRI was more sensitive to signals from the lung parenchyma than CODE or 3D GRE MRI. Metastatic tumor growth in the lungs induced a progressive increase in intensity of parenchymal signals in SWIFT images. MIP images from SWIFT clearly visualized lung vascular structures and their disruption due to progression of breast cancer metastases in the lung. Conclusion SWIFT MRI’s sensitivity to fast-decaying signals and tolerance of magnetic susceptibility enhances its effectiveness at detecting structural changes in lung parenchyma and vasculature due to breast cancer metastases in the lung. PMID:24919566

  8. Intratumoral and peritumoral lymphatic vessel density both correlate with lymph node metastasis in breast cancer

    PubMed Central

    Zhang, Song; Yi, Shanhong; Zhang, Dong; Gong, Mingfu; Cai, Yuanqing; Zou, Liguang

    2017-01-01

    The status of lymph node involvement is an important prognostic factor for breast cancer. However, the presence of intratumoral lymphatic vessels in primary tumor lesions and the relationship between lymphatic vessel density (LVD) and lymph node metastasis (LNM) have not been firmly established. Therefore, we performed a meta-analysis study to investigate these issues. According to the pre-established inclusion and exclusion criteria, 13 studies, involving 1029 breast cancer patients, were included in this study. Using immunohistochemical staining, intratumoral lymphatic vessels were detected in 40.07% of breast cancer patients (240/599), and peritumoral lymphatics were detected in 77.09% (397/515). All studies demonstrated that peritumoral LVD was higher than intratumoral LVD, with a pooled standard mean difference and 95% confidence interval (95% CI) of 1.75 (1.28 to 2.21). Both intratumoral LVD and peritumoral LVD positively correlated with LNM, with correlation coefficients of 0.14 (95% CI 0.05 to 0.23) and 0.31 (95% CI 0.13 to 0.49), respectively. In summary, our study reports the overall detection rate of intratumoral lymphatics and demonstrates the associations between intratumoral LVD, peritumoral LVD, and LNM in breast cancer. Additionally, controlled studies with a larger number of subjects are needed to establish these relationships. PMID:28067327

  9. Methionine deprivation suppresses triple-negative breast cancer metastasis in vitro and in vivo

    PubMed Central

    Jang, Young Jin; Son, Joe Eun; Kwon, Jung Yeon; Lim, Tae-gyu; Kim, Sunghoon; Park, Jung Han Yoon; Kim, Jong-Eun; Lee, Ki Won

    2016-01-01

    Nutrient deprivation strategies have been proposed as an adjuvant therapy for cancer cells due to their increased metabolic demand. We examined the specific inhibitory effects of amino acid deprivation on the metastatic phenotypes of the human triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and Hs 578T, as well as the orthotopic 4T1 mouse TNBC tumor model. Among the 10 essential amino acids tested, methionine deprivation elicited the strongest inhibitory effects on the migration and invasion of these cancer cells. Methionine deprivation reduced the phosphorylation of focal adhesion kinase, as well as the activity and mRNA expression of matrix metalloproteinases MMP-2 and MMP-9, two major markers of metastasis, while increasing the mRNA expression of tissue inhibitor of metalloproteinase 1 in MDA-MB-231 cells. Furthermore, methionine restriction downregulated the metastasis-related factor urokinase plasminogen activatior and upregulated plasminogen activator inhibitor 1 mRNA expression. Animals on the methionine-deprived diet showed lower lung metastasis rates compared to mice on the control diet. Taken together, these results suggest that methionine restriction could provide a potential nutritional strategy for more effective cancer therapy. PMID:27579534

  10. Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism.

    PubMed

    Bonuccelli, Gloria; Tsirigos, Aristotelis; Whitaker-Menezes, Diana; Pavlides, Stephanos; Pestell, Richard G; Chiavarina, Barbara; Frank, Philippe G; Flomenberg, Neal; Howell, Anthony; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2010-09-01

    Previously, we proposed a new model for understanding the "Warburg effect" in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm "The Reverse Warburg Effect." Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by ∼2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by ∼10-fold. Thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the "Reverse Warburg Effect". Moreover, we discuss the possibility that it may be unwise to use lactate-containing i.v. solutions (such as Lactated Ringer's or Hartmann's solution) in cancer patients, given the dramatic metastasis-promoting properties of L-lactate. Also, we provide evidence for the up-regulation of oxidative mitochondrial metabolism and the TCA cycle in human breast cancer cells in vivo, via an informatics analysis of the existing raw transcriptional profiles of epithelial breast cancer cells and adjacent stromal cells. Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue.

  11. Non-invasive Detection of Breast Cancer Lymph Node Metastasis using Carbonic Anhydrases IX and XII Targeted Imaging Probes

    PubMed Central

    Tafreshi, Narges K.; Bui, Marilyn M.; Bishop, Kellsey; Lloyd, Mark C.; Enkemann, Steven A.; Lopez, Alexis S.; Abrahams, Dominique; Carter, Bradford W.; Vagner, Josef; Grobmyer, Stephen R.; Gillies, Robert J.; Morse, David L.

    2014-01-01

    Purpose To develop targeted molecular imaging probes for the non-invasive detection of breast cancer lymph node metastasis. Methods Six cell surface or secreted markers were identified by expression profiling and from the literature as being highly expressed in breast cancer lymph node metastases. Two of these markers were cell surface carbonic anhydrase isozymes (CAIX and/or CAXII) and were validated for protein expression by immunohistochemistry (IHC) of patient tissue samples on a breast cancer tissue microarray containing 47 normal breast tissue samples, 42 ductal carcinoma in situ, 43 invasive ductal carcinomas without metastasis, 46 invasive ductal carcinomas with metastasis and 49 lymph node macrometastases of breast carcinoma. Targeted probes were developed by conjugation of CAIX and CAXII specific monoclonal antibodies (mAbs) to a near-infrared fluorescent dye. Results Together, these two markers were expressed in 100% of the lymph node metastases surveyed. Selectivity of the imaging probes were confirmed by intravenous injection into nude mice bearing mammary fat pad tumors of marker expressing cells, and non-expressing cells or by pre-injection of unlabeled antibody. Imaging of LN metastases showed that peritumorally-injected probes detected nodes harboring metastatic tumor cells. As few as 1,000 cells were detected, as determined by implanting, under ultrasound guidance, a range in number of CAIX and CAXII expressing cells into the axillary LNs. Conclusion These imaging probes have potential for non-invasive staging of breast cancer in the clinic and elimination of unneeded surgery, which is costly and associated with morbidities. PMID:22016510

  12. Leptomeningeal metastasis of an intradural malignant peripheral nerve sheath tumor.

    PubMed

    Stark, Andreas M; Mehdorn, H Maximilian

    2013-08-01

    Malignant peripheral nerve sheath tumors (MPNST) are defined as any malignant tumor arising from or differentiating towards the peripheral nerve sheath. Intradural MPNST metastases are very rare. We report, to our knowledge, the first case of leptomeningeal metastasis of a MPNST to the spine and intracranial space. A 56-year-old woman with primary intradural MPNST of the S1 nerve root developed leptomeningeal metastases as well as brain metastases 19 months after diagnosis. The patient had a history of non-Hodgkins lymphoma for which she had received irradiation to the spine 15 years prior to this presentation. She had no stigmata of neurofibromatosis type 1. Patients with MPNST may also develop leptomeningeal metastases as demonstrated in this patient with intradural post-radiation MPNST.

  13. Microfluidic Device for Studying Tumor Cell Extravasation in Cancer Metastasis

    SciTech Connect

    Lin, Henry K; Thundat, Thomas George; Evans III, Boyd Mccutchen; Datar, Ram H; Reese, Benjamin E; Zheng, Siyang

    2010-01-01

    Metastasis is the process by which cancer spreads to form secondary tumors at downstream locations throughout the body. This uncontrolled spreading is the leading cause of death in patients with epithelial cancers and is the main reason that suppressing and targeting cancer has proven to be so challenging. Tumor cell extravasation is one of the key steps in cancer s progression towards a metastatic state. This occurs when circulating tumor cells found within the blood stream are able to transmigrate through the endothelium lining and basement membrane of the vasculature to form metastatic tumors at secondary sites within the body. Predicting the likelihood of this occurrence in patients, or being able to determine specific markers involved in this process could lead to preventative measures targeting these types of cancer; moreover, this may lead to the discovery of novel anti-metastatic drugs. We have developed a microfluidic device that has shown the extravasation of fluorescently labeled tumor cells across an endothelial cell lined membrane coated with matrigel followed by the formation of colonies. This device provides the advantages of combining a controlled environment, mimicking that found within the body, with real-time monitoring capabilities allowing for the study of these biomarkers and cellular interactions along with other potential mechanisms involved in the process of extravasation.

  14. Photonic Breast Tomography and Tumor Aggressiveness Assessment

    DTIC Science & Technology

    2008-07-01

    component involved application and further refinement of optical tomographic imaging using independent component analysis ( OPTICA ) for locating and cross...section imaging of a tumor in a model cancerous breast assembled using ex vivo breast tissue specimens. The OPTICA approach was able to detect...infrared imaging, optical tomography using independent component analysis ( OPTICA ), training, molecular imaging, cancer biology 16. SECURITY

  15. Analysis of clinicopathological factors associated with bone metastasis in breast cancer.

    PubMed

    Chen, Jing; Zhu, Shu; Xie, Xiu-zhen; Guo, Shan-feng; Tong, Liang-qian; Zhou, Sheng; Zhao, Ming; Xianyu, Zhi-qun; Zhu, Xiao-hua; Xiong, Wei

    2013-02-01

    Breast cancer is the second leading cause of cancer death in women today. Once breast cancer metastasizes to bone, mortality increases. Thus, there is an urgent need to identify patients with high risk of bone metastasis, and to find predictive factors for the occurrence of bone metastasis at an earlier stage of breast cancer. Three hundred and sixty patients with pathologically proved breast cancer visiting the Department of Nuclear Medicine for whole body bone scan from January 2006 and January 2009 were investigated in this study. Clinicopathological information was obtained, which consisted of age, menopausal status, clinical staging, lymph node stage, histological grade, the expression of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2). Correlation between bone metastasis and the associated factors was tested by using the Chi-square test. A Cox multivariate analysis was used to assess the factors which independently contributed to survival after bone metastasis in breast cancer patients. Survival curves were drawn for metastasis-free interval and the independent factors which contributed to survival, using the Kaplan-Meier method. Twenty-four patients were excluded from subsequent analysis. Three hundred and thirty-six enrolled patients ranged in age from 22 to 77 years (mean, 47.8 years). ER/PR status [ER(+) vs. ER(-), χ (2)=4.328, P=0.037; ER(+)PR(+) vs. ER(+)PR(-), χ (2)=4.425, P=0.035] and histological grade (χ (2)=7.131, P=0.028) were significantly associated with bone metastasis. ER status (x (2)=8.315, P=0.004) and metastasis-free interval (χ (2)=6.863, P=0.009) were independent prognostic factors for survival in breast cancer patients with bone metastasis. Our study suggested that ER/PR status and histological grade are risk factors for the development of bone metastasis in breast cancer patients. However, ER status and metastasis-free interval are independent prognostic factors for survival in

  16. Studying tumor metastasis by in vivo imaging and flow cytometer

    NASA Astrophysics Data System (ADS)

    Wei, Xunbin; Guo, Jin; Liu, Guangda; Li, Yan; Chen, Yun; Zhang, Li; Tan, Yuan; Chen, Tong; Gu, Zhenqin; Wang, Chen

    2009-02-01

    Liver cancer is one of the most common malignancies in the world, with approximately 1,000,000 cases reported every year. This ranges from 15,000 cases in the United States to more than a 250,000 in China. About 80% of people with primary liver cancer are male. Although two-thirds of people have advanced liver disease when they seek medical help, one third of the patients have cancer that has not progressed beyond the liver. Primary liver cancer (hepatocellular carcinoma, or HCC) is associated with liver cirrhosis 60-80% of the time. HCC may metastasize to the lung, bones, kidney, and many other organs. Surgical resection, liver transplantation, chemotherapy and radiation therapy are the foundation of current HCC therapies. However the outcomes are poor-the survival rate is almost zero for metastatic HCC patients. Molecular mechanisms of HCC metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of HCC cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern liver tumor cell spread through the microenvironment in vivo in real-time confocal near-infrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess liver tumor cell spreading and the circulation kinetics of liver tumor cells. A real-time quantitative monitoring of circulating liver tumor cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

  17. AIF inhibits tumor metastasis by protecting PTEN from oxidation

    PubMed Central

    Shen, Shao-Ming; Guo, Meng; Xiong, Zhong; Yu, Yun; Zhao, Xu-Yun; Zhang, Fei-Fei; Chen, Guo-Qiang

    2015-01-01

    Apoptosis-inducing factor (AIF) exerts dual roles on cell death and survival, but its substrates as a putative oxidoreductase and roles in tumorigenesis remain elusive. Here, we report that AIF physically interacts with and inhibits the oxidation of phosphatase and tensin homolog on chromosome ten (PTEN), a tumor suppressor susceptible for oxidation-mediated inactivation. More intriguingly, we also identify PTEN as a mitochondrial protein and the ectopic expression of mitochondrial targeting sequence-carrying PTEN almost completely inhibits Akt phosphorylation in PTEN-deficient cells. AIF knockdown causes oxidation-mediated inactivation of the lipid phosphatase activity of PTEN, with ensuing activation of Akt kinase, phosphorylation of the Akt substrate GSK-3β, and activation of β-catenin signaling in cancer cells. Through its effect on β-catenin signaling, AIF inhibits epithelial–mesenchymal transition (EMT) and metastasis of cancer cells in vitro and in orthotopically implanted xenografts. Accordingly, the expression of AIF is correlated with the survival of human patients with cancers of multiple origins. These results identify PTEN as the substrate of AIF oxidoreductase and reveal a novel function for AIF in controlling tumor metastasis. PMID:26415504

  18. Monitoring tumor metastasis by in vivo imaging and flow cytometer

    NASA Astrophysics Data System (ADS)

    Gu, Zhenqin; Guo, Jin; Liu, Guangda; Li, Yan; Chen, Yun; Chen, Tong; Wang, Chen; Wei, Xunbin

    2009-08-01

    Prostate cancer is the most common malignancy in American men and the second leading cause of deaths from cancer, after lung cancer. The tumor usually grows slowly and remains confined to the gland for many years. During this time, the tumor produces little or no symptoms or outward signs. As the cancer advances, however, it can metastasize throughout other areas of the body, such as the bones, lungs, and liver. Surgical resection, hormonal therapy, chemotherapy and radiation therapy are the foundation of current prostate cancer therapies. Treatments for prostate cause both short- and long-term side effects that may be difficult to accept. Molecular mechanisms of prostate cancer metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of cancer cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern prostate cancer cell spread through the microenvironment in vivo in real-time confocal nearinfrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess prostate cancer cell spreading and the circulation kinetics of prostate cancer cells. A real- time quantitative monitoring of circulating prostate cancer cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

  19. Overexpression of AKIP1 predicts poor prognosis of patients with breast carcinoma and promotes cancer metastasis through Akt/GSK-3β/Snail pathway

    PubMed Central

    Mo, Dan; Li, Xinning; Li, Chunhong; Liang, Junrong; Zeng, Tian; Su, Naiwei; Jiang, Qipei; Huang, Jingjing

    2016-01-01

    Recent evidence has demonstrated that A kinase interacting protein 1 (AKIP1), a molecular regulator of protein kinase A, was overexpressed in breast cancer. However, the prognostic and biological role of AKIP1 in breast cancer is still elusive. The purpose of our study was to elucidate the role and molecular mechanism of AKIP1 in breast cancer development. The mRNA levels of AKIP1 in breast cancer and paired normal breast tissues were examined by quantitative real-time PCR. The relationship of AKIP1 expression with clinicopathological characteristics and clinical prognosis of breast cancer patients was investigated. In vitro migration and invasion assays were performed in MCF-7 and SK-BR-3 cells to determine its role in metastasis and the possible mechanism. The result showed that AKIP1 expression was up-regulated in breast cancer tissues compared with that in normal breast tissues. High expression of AKIP1 was associated significantly with advanced tumor stage (P<0.001), tumor size (P=0.029), and lymph node metastasis (P=0.004). Moreover, overexpression of AKIP1 was significantly correlated with poor overall survival and recurrence-free survival (P=0.038 and P=0.005, respectively). Furthermore, down-regulation of AKIP1 remarkably inhibited breast cancer cell motility and invasion through inhibiting the Akt/GSK-3β/Snail pathway. Therefore, AKIP1 may represent a prospective prognostic indicator and a potential therapeutic target of breast cancer. PMID:27904695

  20. The ELK3-GATA3 axis orchestrates invasion and metastasis of breast cancer cells in vitro and in vivo

    PubMed Central

    Kong, Sun-Young; Kim, Kwang-Soo; Kim, Jiewan; Kim, Min Kyeong; Lee, Ki Hong; Lee, Je-Yong; Oh, Nuri; Park, Ji-In; Park, Ji-Hoon; Heo, Sun-Hee; Shim, Sung Han; Lee, Dong Ryul; Kim, Keun Pil; Park, Kyung-Soon

    2016-01-01

    Triple-negative breast cancer is a highly aggressive tumor subtype that lacks effective therapeutic targets. Here, we show that ELK3 is overexpressed in a subset of breast cancers, in particular basal-like and normal-like/claudin-low cell lines. Suppression of ELK3 in MDA-MB-231 cells led to transdifferentiation from an invasive mesenchymal phenotype to a non-invasive epithelial phenotype both in vitro and in vivo. Suppression of ELK3 resulted in extensive changes in genome expression profiles. Among these, GATA3, a master suppressor of metastasis, was epigenetically activated. Also, suppression of GATA3 led to the restoration of migration and invasion. These results suggest that the ELK3-GATA3 axis is a major pathway that promotes metastasis of MDA-MB-231 cells. PMID:27556500

  1. Development of Patient Derived Xenograft Models of Overt Spontaneous Breast Cancer Metastasis: A Cautionary Note

    PubMed Central

    Paez-Ribes, Marta; Man, Shan; Xu, Ping; Kerbel, Robert S.

    2016-01-01

    Several approaches are being evaluated to improve the historically limited value of studying transplanted primary tumors derived by injection of cells from established cell lines for predicting subsequent cancer therapy outcomes in patients and clinical trials. These approaches include use of genetically engineered mouse models (GEMMs) of spontaneous tumors, or patient tumor tissue derived xenografts (PDXs). Almost all such therapy studies utilizing such models involve treatment of established primary tumors. An alternative approach we have developed involves transplanted human tumor xenografts derived from established cell lines to treat mice with overt visceral metastases after primary tumor resection. The rationale is to mimic the more challenging circumstance of treating patients with late stage metastatic disease. These metastatic models entail prior in vivo selection of heritable, phenotypically stable variants with increased aggressiveness for spontaneous metastasis; they were derived by orthotopic injection of tumor cells followed by primary tumor resection and serial selection of distant spontaneous metastases, from which variant cell lines having a more aggressive heritable metastatic phenotype were established. We attempted to adopt this strategy for breast cancer PDXs. We studied five breast cancer PDXs, with the emphasis on two, called HCI-001 and HCI-002, both derived from triple negative breast cancer patients. However significant technical obstacles were encountered. These include the inherent slow growth rates of PDXs, the rarity of overt spontaneous metastases (detected in only 3 of 144 mice), very high rates of tumor regrowths at the primary tumor resection site, the failure of the few human PDX metastases isolated to manifest a more aggressive metastatic phenotype upon re-transplantation into new hosts, and the formation of metastases which were derived from de novo mouse thymomas arising in aged SCID mice that we used for the experiments. We

  2. ‘The charmingest place’: non-coding RNA, lineage tracing, tumor heterogeneity, metastasis and metabolism - new methods in mammary gland development and cancer: the fifth ENBDC Workshop

    PubMed Central

    2013-01-01

    The European Network for Breast Development and Cancer (ENBDC) Workshop on ‘Methods in Mammary Gland Development and Cancer’ has grown into the essential, international technical discussion forum for scientists with interests in the normal and neoplastic breast. The fifth ENBDC meeting was held in Weggis, Switzerland in April, 2013, and focussed on emerging, state-of-the-art techniques for the study of non-coding RNA, lineage tracing, tumor heterogeneity, metastasis and metabolism. PMID:24103450

  3. Freehand 3D ultrasound breast tumor segmentation

    NASA Astrophysics Data System (ADS)

    Liu, Qi; Ge, Yinan; Ou, Yue; Cao, Biao

    2007-12-01

    It is very important for physicians to accurately determine breast tumor location, size and shape in ultrasound image. The precision of breast tumor volume quantification relies on the accurate segmentation of the images. Given the known location and orientation of the ultrasound probe, We propose using freehand three dimensional (3D) ultrasound to acquire original images of the breast tumor and the surrounding tissues in real-time, after preprocessing with anisotropic diffusion filtering, the segmentation operation is performed slice by slice based on the level set method in the image stack. For the segmentation on each slice, the user can adjust the parameters to fit the requirement in the specified image in order to get the satisfied result. By the quantification procedure, the user can know the tumor size varying in different images in the stack. Surface rendering and interpolation are used to reconstruct the 3D breast tumor image. And the breast volume is constructed by the segmented contours in the stack of images. After the segmentation, the volume of the breast tumor in the 3D image data can be obtained.

  4. MicroRNA-340 inhibits the migration, invasion, and metastasis of breast cancer cells by targeting Wnt pathway.

    PubMed

    Mohammadi-Yeganeh, Samira; Paryan, Mahdi; Arefian, Ehsan; Vasei, Mohammad; Ghanbarian, Hossein; Mahdian, Reza; Karimipoor, Morteza; Soleimani, Masoud

    2016-07-01

    MicroRNAs (miRNAs) play a key role in tumor metastasis based on their capacity to regulate the expression of tumor-related genes. Over-expression of key genes such as c-MYC and CTNNB1 (encoding β-catenin) in Wnt/β-catenin-dependent and ROCK1 in Wnt/β-catenin-independent signaling pathways (Rho/Rho-associated kinase (ROCK) signaling pathway) has already been identified as the hallmarks of many tumors, and their role in breast cancer has also been investigated and confirmed. miR-340 characterization as an onco-suppressor miRNA has been previously reported. However, the mechanism by which it inhibits metastasis has not been completely elucidated. Quantitative real-time PCR (qPCR), Western blot, and luciferase assays were used to confirm the effect of miR-340 on the 3'-untranslated region (UTR) of the target genes. Lentiviral particles containing miR-340 were also used to evaluate the effect of miR-340 restoration on cell proliferation, migration, and invasion in vitro in the invasive MDA-MB-231 cell line. By applying bioinformatic approaches for the prediction of miRNAs targeting 3'-UTRs of CTNNB1, c-MYC, and ROCK1, we found out that miR-340 could dramatically down-regulate metastasis by targeting Wnt signaling in breast cancer cells. In the current study, analyzing miR-340 by reverse transcription quantitative PCR (RT-qPCR) in MDA-MB-231 showed that it was remarkably down-regulated in the metastatic breast cancer cell line. We found that restoration of miR-340 in the invasive breast cancer cell line, MDA-MB-231, suppresses the expression of the target genes' messenger RNA (mRNA) and protein and, as a result, inhibits tumor cell invasion and metastasis. Our findings highlight the ability of bioinformatic approaches to find miRNAs targeting specific genes. By bioinformatic analysis, we confirmed the important role of miR-340 as a pivotal regulator of breast cancer metastasis in targeting previously validated (ROCK1) and potentially novel genes, i.e., (CTNNB1 and c-MYC).

  5. Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis.

    PubMed

    Kang, Shin-Ae; Hasan, Nafis; Mann, Aman P; Zheng, Wei; Zhao, Lichao; Morris, Lynsie; Zhu, Weizhu; Zhao, Yan D; Suh, K Stephen; Dooley, William C; Volk, David; Gorenstein, David G; Cristofanilli, Massimo; Rui, Hallgeir; Tanaka, Takemi

    2015-06-01

    Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)(-)/CD44(+) hormone-independent breast cancer cells, but not of the ER(+)/CD44(-/low) hormone-dependent breast cancer cells. Coincidentally, CD44(+) breast cancer cells were abundant in metastatic lung and brain lesions in ER(-) breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER(-)/CD44(+) breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44(+) cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER(-)/CD44(+) breast cancer.

  6. Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone.

    PubMed

    Lu, Xin; Kang, Yibin

    2009-10-16

    Metastatic spread of cancer to distant vital organs, including lung and bone, is the overwhelming cause of breast cancer mortality and morbidity. Effective treatment of systemic metastasis relies on the identification and functional characterization of metastasis mediators to multiple organs. Overexpression of the chemokine (C-C motif) ligand 2 (CCL2) is frequently associated with advanced tumor stage and metastatic relapse in breast cancer. However, the functional mechanism of CCL2 in promoting organ-specific metastasis of breast cancer has not been rigorously investigated. Here, we used organ-specific metastatic sublines of the MDA-MB-231 human breast cancer cell line to demonstrate that overexpression of CCL2 promotes breast cancer metastasis to both lung and bone. Conversely, blocking CCL2 function with a neutralizing antibody reduced lung and bone metastases. The enhancement of lung and bone metastases by CCL2 was associated with increased macrophage infiltration and osteoclast differentiation, respectively. By performing functional assays with primary cells isolated from the wild type, CCL2 and CCR2 knock-out mice, we showed that tumor cell-derived CCL2 depends on its receptor CCR2 (chemokine, CC motif, receptor 2) expressed on stromal cells to exert its function in promoting macrophage recruitment and osteoclast differentiation. Overall, these data demonstrated that CCL2-expressing breast tumor cells engage CCR2(+) stromal cells of monocytic origin, including macrophages and preosteoclasts, to facilitate colonization in lung and bone. Therefore, CCL2 and CCR2 are promising therapeutic targets for simultaneously inhibiting lung and bone metastasis of breast cancer.

  7. A Giant Phyllodes Tumor of the Breast

    PubMed Central

    Schillebeeckx, Charlotte; Verbeeck, Guy; Daenen, Geert; Servaes, Dirk; Bronckaers, Marc

    2016-01-01

    Phyllodes tumors of the breast are rare, accounting for less than 1% of the breast tumors. They are mostly seen in women between 45 and 49 years old. These are fast growing tumors with a large spectrum of behavior (from benign to metastatic) and can resemble fibroadenomas. Correct diagnosis mostly through core needle biopsy is important to decide whether a surgical excision has to be done. Here we report a case of a 57-year-old woman with a fast growing, ulcerated tumor in the left breast. Core needle biopsy suggested a malignant phyllodes tumor with heterologous liposarcomatous differentiation. Treatment with total mastectomy and adjuvant radiotherapy followed. Primary treatment is always surgery, whether radiotherapy or chemotherapy has to follow remains uncertain. There is a high-recurrence rate, especially when the surgical margins are narrow. PMID:27746880

  8. HER2 mediated de novo production of TGFβ leads to SNAIL driven epithelial-to-mesenchymal transition and metastasis of breast cancer.

    PubMed

    Gupta, Parul; Srivastava, Sanjay K

    2014-12-01

    HER2 is an important determinant of poor prognosis in breast cancer patients. Studies indicate that HER2 positive tumors are mostly resistant to therapy and have high metastatic potential however, the underlying mechanisms remain unknown. In this study, MDA-MB-231 and MCF-7 breast cancer cells with their HER2 overexpressing syngeneic variants were used to delineate the role of HER2 in EMT and metastasis. Our results demonstrated that HER2 overexpression increased the invasive potential of cells. Our results also showed that HER2 overexpression lead to the production of TGFβ resulting in the activation of TGFβ/SMAD signaling. Furthermore, activation of SNAIL, SLUG and ZEB-1, the transcriptional repressors of E-cadherin and increased mesenchymal characteristics were observed in high HER2 cells. Interestingly, EMT by HER2 was mediated through TGFβ. Intravenous injection of high HER2 MDA-MB-231 (HH) cells in athymic nude mice showed early and substantial metastasis as compared to the parent cells establishing the direct role of HER2 in metastasis. Our results showed that inhibition of HER2 mediated EMT by cucurbitacin B a triterpenoid, resulted in the suppression of brain metastasis of breast cancer cells. Taken together, our results identify a novel mechanism of HER2 in promoting breast cancer metastasis through de novo synthesis of TGFβ leading to EMT, an initial and essential step of metastasis.

  9. Laminin-511: a multi-functional adhesion protein regulating cell migration, tumor invasion and metastasis.

    PubMed

    Pouliot, Normand; Kusuma, Nicole

    2013-01-01

    Laminins are major constituents of basement membranes. At least 16 isoforms have now been described, each with distinct spatio-temporal expression patterns and functions. The laminin-511 heterotrimer (α5β1γ1) is one of the more recent isoforms to be identified and a potent adhesive and pro-migratory substrate for a variety of normal and tumor cell lines in vitro. As our understanding of its precise function in normal tissues and in pathologies is rapidly unraveling, current evidence suggests an important regulatory role in cancer. This review describes published data on laminin-511 expression in several malignancies and experimental evidence from both in vitro and in vivo studies supporting its functional role during tumor progression. A particular emphasis is put on more recent studies from our laboratory and that of others indicating that laminin-511 contributes to tumor dissemination and metastasis in advanced breast carcinomas and other tumor types. Collectively, the experimental evidence suggests that high expression of laminin-511 has prognostic significance and that targeting tumor-laminin-511 interactions may have therapeutic potential in advanced cancer patients.

  10. Quantitative protein profiling of tumor angiogenesis and metastasis biomarkers in mouse and human models

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tumor and stromal cells secrete a variety of proteins acting as extracellular signals and creating a supportive microenvironment for tumor development, angiogenesis, and metastasis. We used the Luminex immunoassay platform (including MILLIPLEX® MAP cytokine/chemokine, bone metabolism, adipocyte, M...

  11. Pathogenesis of Breast Cancer Metastasis to Brain: a Comprehensive Approach to the Signaling Network.

    PubMed

    Tayyeb, Bahrami; Parvin, Mehdipour

    2016-01-01

    There is a general consensus that breast cancer is a rising trend disease in the world. It is one of the most common cancer types and is the leading cause of death among women's cancers. There are several reasons for this high rate of mortality including metastasis which is responsible for about 90 % of cancer-related mortality. Therefore, recognition and understanding of metastatic process is important, and by considering the key role of pathophysiological route in metastasis as a multistep cascade of "invasion-metastasis," it might modify and improve our insight toward this complex phenomenon. Moreover, it can provide novel approaches for designing advanced targeted therapies. The present work aimed to review the published papers regarding molecular basis of metastatic process of breast cancer to brain metastasis, especially related genes and signaling network. Furthermore, the use of molecular aspects of metastatic breast cancer to brain was discussed in horizon of future treatment of breast cancer.

  12. S100A4 Elevation Empowers Expression of Metastasis Effector Molecules in Human Breast Cancer

    PubMed Central

    Ismail, Thamir M.; Bennett, Daimark; Platt-Higgins, Angela M.; Al-Medhity, Morteta; Barraclough, Roger; Rudland, Philip S.

    2017-01-01

    Many human glandular cancers metastasize along nerve tracts, but the mechanisms involved are generally poorly understood. The calcium-binding protein S100A4 is expressed at elevated levels in human cancers, where it has been linked to increased invasion and metastasis. Here we report genetic studies in a Drosophila model to define S100A4 effector functions that mediate metastatic dissemination of mutant Ras-induced tumors in the developing nervous system. In flies overexpressing mutant RasVal12 and S100A4, there was a significant increase in activation of the stress kinase JNK and production of the matrix metalloproteinase MMP1. Genetic or chemical blockades of JNK and MMP1 suppressed metastatic dissemination associated with S100A4 elevation, defining required signaling pathway(s) for S100A4 in this setting. In clinical specimens of human breast cancer, elevated levels of the mammalian paralogs MMP2, MMP9, and MMP13 are associated with a 4- to 9-fold relative decrease in patient survival. In individual tumors, levels of MMP2 and MMP13 correlated more closely with levels of S100A4, whereas MMP9 levels correlated more closely with the S100 family member S100P. Overall, our results suggest the existence of evolutionarily conserved pathways used by S100A4 to promote metastatic dissemination, with potential prognostic and therapeutic implications for metastasis by cancers that preferentially exploit nerve tract migration routes. PMID:27927689

  13. Genomic landscapes of breast fibroepithelial tumors.

    PubMed

    Tan, Jing; Ong, Choon Kiat; Lim, Weng Khong; Ng, Cedric Chuan Young; Thike, Aye Aye; Ng, Ley Moy; Rajasegaran, Vikneswari; Myint, Swe Swe; Nagarajan, Sanjanaa; Thangaraju, Saranya; Dey, Sucharita; Nasir, Nur Diyana Md; Wijaya, Giovani Claresta; Lim, Jing Quan; Huang, Dachuan; Li, Zhimei; Wong, Bernice Huimin; Chan, Jason Yong Sheng; McPherson, John R; Cutcutache, Ioana; Poore, Gregory; Tay, Su Ting; Tan, Wai Jin; Putti, Thomas Choudary; Ahmad, Buhari Shaik; Iau, Philip; Chan, Ching Wan; Tang, Anthony P H; Yong, Wei Sean; Madhukumar, Preetha; Ho, Gay Hui; Tan, Veronique Kiak Mien; Wong, Chow Yin; Hartman, Mikael; Ong, Kong Wee; Tan, Benita K T; Rozen, Steven G; Tan, Patrick; Tan, Puay Hoon; Teh, Bin Tean

    2015-11-01

    Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications.

  14. [Right Hemi-Colectomy for a Metastatic Transverse Colon Tumor from Breast Cancer Following Bilateral Breast Cancer Resection - A Case Report].

    PubMed

    Okamura, Shu; Yanagisawa, Tetsu; Ohishi, Kazuhito; Murata, Kohei; Nushijima, Yoichiro; Hamano, Rie; Fukuchi, Nariaki; Ebisui, Chikara; Yokouchi, Hideoki; Kinuta, Masakatsu

    2016-11-01

    We herein report the case of a 75-year-old female patient who underwent 4 surgeries for bilateral breast cancer and its recurrence. When she presented at a clinic with an irritable colon, a fist-sized tumor was palpated in the right upper abdomen at her first medical examination. Abdominal CT scan at the clinic revealed a tumor with a maximum diameter of 10 cm on the right side of the transverse colon and multiple swollen mesenteric lymph nodes. Therefore, the patient was referred to our hospital for surgery. Colonoscopy revealed stenosis of the same lesion with an edematous mucosa and sclerosis. Using immunohistochemistry, a biopsy specimen from the lesion tested positive for CK AE1+AE3, and negative for CD20(-)and CD3 (-). As a result, the tumor was diagnosed as a poorly differentiated adenocarcinoma. We performed right hemicolectomy to avoid her intestinal obstruction. Tumor cells were mainly present at the subserosa, according to HEstaining. Using immunostaining, the cells were tested for the following markers: CDX2(-), GCDFP15(weakly positive), CK7(strongly positive), CD20(partially positive), E R(+), PgR(-), and HER2(1+), characterizing the tumor as metastasis of breast cancer. Although gastro-intestinal metastasis from breast cancer is rare, and colon metastasis is even rarer, it might be necessary to rule out the possibility of a metastatic colon tumor from breast cancer when treating patients with a colon tumor who have undergone surgery for breast cancer.

  15. Breast metastasis from recurrent gallbladder adenocarcinoma: a case report with review of the literature

    PubMed Central

    Faouzi, Houssin; Salmi, Nariman; Ettahri, Hamza; Elghissassi, Ibrahim; Mrabti, Hind; Errihani, Hassan

    2016-01-01

    Gallbladder adenocarcinoma has a poor prognostic. The leading modes of dissemination in gallbladder cancer (GBC) are lymphatic, vascular, neural, intraperitoneal, and intraductal. The most common site of dissemination is liver. Breast metastasis in GBC is an unusual site of dissemination. Only few cases have been reported in the literature. We report a rare case of solitary breast metastasis from recurrent gallbladder carcinoma in light of existing literature. PMID:27512606

  16. Rare case of breast tumor secondary to rectal adenocarcinoma.

    PubMed

    Sanchez, Lisette Delgado; Chelliah, Thandavababu; Meisher, Irina; Niranjan, Selvanayagam

    2008-10-01

    Primary breast cancer is the most common malignancy in women. Metastatic cancer to the breast is very rare. Colorectal cancers usually metastasize to the liver and the lung; other sites of metastasis from colon cancer are uncommon and are usually found in association with extensive liver and/or lung metastases. This is a report of a rare case of aggressive rectal cancer with metastasis to the breast without liver or lung metastases.

  17. Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry.

    PubMed

    Yu, Changhui; Tang, Wei; Wang, Yuhao; Shen, Qiang; Wang, Bin; Cai, Chunqing; Meng, Xiaojing; Zou, Fei

    2016-07-01

    The renin-angiotensin system (RAS) is an important component of the tumor microenvironment and plays a key role in promoting cancer cell proliferation, angiogenesis, metabolism, migration and invasion. Meanwhile, the arm of angiotensin-converting enzyme (ACE)2/angiotensin-(1-7) [Ang-(1-7)]/Mas axis in connection with RAS is associated with anti-proliferative, vasodilatory and anti-metastatic properties. Previous studies have shown that Ang-(1-7) reduces the proliferation of orthotopic human breast tumor growth by inhibiting cancer-associated fibroblasts. However, the role of ACE/Ang-(1-7)/Mas axis in the metastasis of breast cancer cells is still unknown. In the present study, we found that ACE2 protein level is negatively correlated with the metastatic ability of breast cancer cells and breast tumor grade. Upregulation of ACE2/Ang-(1-7)/Mas axis inhibits breast cancer cell migration and invasion in vivo and in vitro. Mechanistically, ACE2/Ang-(1-7)/Mas axis activation inhibits store-operated calcium entry (SOCE) and PAK1/NF-κB/Snail1 pathways, and induces E-cadherin expression. In summary, our results demonstrate that downregulation of ACE2/Ang-(1-7)/Mas axis stimulates breast cancer metastasis through the activation of SOCE and PAK1/NF-κB/Snail1 pathways. These results provide new mechanisms by which breast cancer develop metastasis and shed light on developing novel anti-metastasis therapeutics for metastatic breast cancer by modulating ACE2/Ang-(1-7)/Mas axis.

  18. Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo.

    PubMed

    Nelson, Michaela; Yang, Ming; Millican-Slater, Rebecca; Brackenbury, William J

    2015-10-20

    Voltage-gated Na+ channels (VGSCs) mediate action potential firing and regulate adhesion and migration in excitable cells. VGSCs are also expressed in cancer cells. In metastatic breast cancer (BCa) cells, the Nav1.5 α subunit potentiates migration and invasion. In addition, the VGSC-inhibiting antiepileptic drug phenytoin inhibits tumor growth and metastasis. However, the functional activity of Nav1.5 and its specific contribution to tumor progression in vivo has not been delineated. Here, we found that Nav1.5 is up-regulated at the protein level in BCa compared with matched normal breast tissue. Na+ current, reversibly blocked by tetrodotoxin, was retained in cancer cells in tumor tissue slices, thus directly confirming functional VGSC activity in vivo. Stable down-regulation of Nav1.5 expression significantly reduced tumor growth, local invasion into surrounding tissue, and metastasis to liver, lungs and spleen in an orthotopic BCa model. Nav1.5 down-regulation had no effect on cell proliferation or angiogenesis within the in tumors, but increased apoptosis. In vitro, Nav1.5 down-regulation altered cell morphology and reduced CD44 expression, suggesting that VGSC activity may regulate cellular invasion via the CD44-src-cortactin signaling axis. We conclude that Nav1.5 is functionally active in cancer cells in breast tumors, enhancing growth and metastatic dissemination. These findings support the notion that compounds targeting Nav1.5 may be useful for reducing metastasis.

  19. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models

    PubMed Central

    Liu, Huiping; Patel, Manishkumar R.; Prescher, Jennifer A.; Patsialou, Antonia; Qian, Dalong; Lin, Jiahui; Wen, Susanna; Chang, Ya-Fang; Bachmann, Michael H.; Shimono, Yohei; Dalerba, Piero; Adorno, Maddalena; Lobo, Neethan; Bueno, Janet; Dirbas, Frederick M.; Goswami, Sumanta; Somlo, George; Condeelis, John; Contag, Christopher H.; Gambhir, Sanjiv Sam; Clarke, Michael F.

    2010-01-01

    To examine the role of breast cancer stem cells (BCSCs) in metastasis, we generated human-in-mouse breast cancer orthotopic models using patient tumor specimens, labeled with optical reporter fusion genes. These models recapitulate human cancer features not captured with previous models, including spontaneous metastasis in particular, and provide a useful platform for studies of breast tumor initiation and progression. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. These advances in BCSC imaging revealed that CD44+ cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. PMID:20921380

  20. Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy*

    PubMed Central

    Gong, Chang; Liu, Bodu; Yao, Yandan; Qu, Shaohua; Luo, Wei; Tan, Weige; Liu, Qiang; Yao, Herui; Zou, Lee; Su, Fengxi; Song, Erwei

    2015-01-01

    Circulating tumor cells (CTCs) are seeds for cancer metastasis and are predictive of poor prognosis in breast cancer patients. Whether CTCs and primary tumor cells (PTCs) respond to chemotherapy differently is not known. Here, we show that CTCs of breast cancer are more resistant to chemotherapy than PTCs because of potentiated DNA repair. Surprisingly, the chemoresistance of CTCs was recapitulated in PTCs when they were detached from the extracellular matrix. Detachment of PTCs increased the levels of reactive oxygen species and partially activated the DNA damage checkpoint, converting PTCs to a CTC-like state. Inhibition of checkpoint kinases Chk1 and Chk2 in CTCs reduces the basal checkpoint response and sensitizes CTCs to DNA damage in vitro and in mouse xenografts. Our results suggest that DNA damage checkpoint inhibitors may benefit the chemotherapy of breast cancer patients by suppressing the chemoresistance of CTCs and reducing the risk of cancer metastasis. PMID:25897074

  1. Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy.

    PubMed

    Gong, Chang; Liu, Bodu; Yao, Yandan; Qu, Shaohua; Luo, Wei; Tan, Weige; Liu, Qiang; Yao, Herui; Zou, Lee; Su, Fengxi; Song, Erwei

    2015-06-12

    Circulating tumor cells (CTCs) are seeds for cancer metastasis and are predictive of poor prognosis in breast cancer patients. Whether CTCs and primary tumor cells (PTCs) respond to chemotherapy differently is not known. Here, we show that CTCs of breast cancer are more resistant to chemotherapy than PTCs because of potentiated DNA repair. Surprisingly, the chemoresistance of CTCs was recapitulated in PTCs when they were detached from the extracellular matrix. Detachment of PTCs increased the levels of reactive oxygen species and partially activated the DNA damage checkpoint, converting PTCs to a CTC-like state. Inhibition of checkpoint kinases Chk1 and Chk2 in CTCs reduces the basal checkpoint response and sensitizes CTCs to DNA damage in vitro and in mouse xenografts. Our results suggest that DNA damage checkpoint inhibitors may benefit the chemotherapy of breast cancer patients by suppressing the chemoresistance of CTCs and reducing the risk of cancer metastasis.

  2. The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer

    PubMed Central

    Ha, Ngoc-Han; Long, Jirong; Cai, Qiuyin; Shu, Xiao Ou

    2016-01-01

    Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies. PMID:27656887

  3. Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models

    PubMed Central

    Bottos, Alessia; Gotthardt, Dagmar; Gill, Jason W.; Gattelli, Albana; Frei, Anna; Tzankov, Alexandar; Sexl, Veronika; Wodnar-Filipowicz, Aleksandra; Hynes, Nancy E.

    2016-01-01

    The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. Furthermore, we show that immunostimulation with IL-15 overcomes the enhancing effect of JAKi on metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumour environment. The impact of JAKi on NK cells and the potential value of immunostimulators to overcome the weakened tumour immunosurveillance, are worthwhile considering in the clinical setting of breast cancer. PMID:27406745

  4. Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration.

    PubMed

    Emdad, Luni; Sarkar, Devanand; Su, Zao-Zhong; Lee, Seok-Geun; Kang, Dong-Chul; Bruce, Jeffrey N; Volsky, David J; Fisher, Paul B

    2007-05-01

    Tumor progression and metastasis are complex processes involving intricate interplay among multiple gene products. Astrocyte elevated gene (AEG)-1 was cloned as an human immunodeficiency virus (HIV)-1-inducible and tumor necrosis factor-alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes (PHFA) by a rapid subtraction hybridization approach. AEG-1 down-regulates the expression of the glutamate transporter EAAT2; thus, it is implicated in glutamate-induced excitotoxic damage to neurons as evident in HIV-associated neurodegeneration. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells, and AEG-1 cooperates with Ha-ras to augment the transformed phenotype of normal immortal cells. Moreover, AEG-1 is overexpressed in >95% of human malignant glioma samples when compared with normal human brain. Overexpression of AEG-1 increases and siRNA inhibition of AEG-1 decreases migration and invasion of human glioma cells, respectively. AEG-1 contains a lung-homing domain facilitating breast tumor metastasis to lungs. These findings indicate that AEG-1 might play a pivotal role in the pathogenesis, progression and metastasis of diverse cancers. Our recent observations indicate that AEG-1 exerts its effects by activating the nuclear factor kappa B (NF-kappaB) pathway and AEG-1 is a downstream target of Ha-ras and plays an important role in Ha-ras-mediated tumorigenesis. These provocative findings are intensifying interest in AEG-1 as a crucial regulator of tumor progression and metastasis and as a potential mediator of neurodegeneration. In this review, we discuss the cloning, structure and function(s) of AEG-1 and provide recent insights into the diverse actions and intriguing properties of this molecule.

  5. Tubeimoside-1 suppresses breast cancer metastasis through downregulation of CXCR4 chemokine receptor expression

    PubMed Central

    Peng, Yaojin; Zhong, Yan; Li, Gao

    2016-01-01

    To examine the effect of TBMS1on breast cancer metastasis, and investigate the potential mechanism by which Tubeimoside-1 (TBMS1) inhibits the CXCR4 expression in breast cancer cells. The expression of CXCR4 in breast cancer cell lines was determined by immunoblotting and real-time PCR. The effect of TBMS1 on NF-κB binding activity was evaluated by EMSA assay and ChIP analysis. Cell proliferation and invasion were analyzed by MTT assay and transwell invasion assay, respectively. The effect of TBMS1 on breast cancer metastasis was further evaluated in a metastasis model of nude mice. TBMS1 suppressed the expression of CXCR4 through inhibition of NF-κB binding activity. TBMS1 inhibited CXCL12-induced invasion in breast cancer cells, while ectopic expression of CXCR4 abolished the inhibitive activity of TBMS1. TBMS1 suppressed breast cancer metastasis in the metastatic model of nude mice. TBMS1 suppressed the CXCR4-mediated metastasis of breast cancer by inhibiting NF-κB binding activity. [BMB Reports 2016; 49(9): 502-507] PMID:27157541

  6. [Breast cancer metastasis in distal phalanx of the big toe. Case report].

    PubMed

    Carlesimo, B; Tempesta, M; Fioramonti, P; Bistoni, G; Ruggiero, M; Marchetti, F

    2009-01-01

    Breast cancer represents the most prevalent malignancies in women and bone is the first site of metastasis in 26-50% of cases. Usually metastasis involve limbs in 16%. We present a rare case of 47-year-old woman, who underwent to monolateral mastectomy for lobular cancer. After 8 years from surgery, she presented pain, swelling and functional limitations, gradually increasing, to the left big toe. X-rays and MRI showed a lucent area of bone destruction on the shaft of the distal phalanx of the left big toe. Surgical biopsy on the excised bone assessed for breast cancer metastasis.

  7. Development of a new method for identification and quantification in cerebrospinal fluid of malignant cells from breast carcinoma leptomeningeal metastasis

    PubMed Central

    2012-01-01

    Background The diagnosis of leptomeningeal metastasis (LM) in patients with solid tumors remains difficult. The usual diagnostic methods of cytomorphological assessment of cerebro-spinal fluid (CSF) and gadolinium enhanced MRI of the entire neuraxis lack both specificity and sensitivity. The Veridex CellSearch® technology has been designed for the detection of circulating tumor cells (CTC) in blood from cancer patients and validated for the follow-up and prognosis of breast, prostate, colorectal, and lung cancer. Our aim was to adapt this technology for the detection and the enumeration of tumor cells in the CSF of breast cancer patients presenting with LM. Methods On the occasion of a randomized phase III study evaluating the role of the intrathecal treatment in LM from breast cancer (DEPOSEIN, EudraCT N°: 2010-023134-23), the CellSearch® technology was adapted to direct enrichment, enumeration and visualization of tumor cells in 5 mL CSF samples, collected on CellSave® Preservative Tubes and analyzed within 3 days after CSF sampling. Results Sixteen CSF of 8 patients with primary breast cancer presenting with LM were studied. EpCAM+/cytokeratin + cells with typical morphology could be observed and enumerated sequentially with reproducible results in low or elevated numbers in 8 patients. Conclusion This methodology, established on a limited volume of sample and allowing delayed processing, could prove of great interest in the diagnosis and follow-up of cancer patients with LM, especially to appreciate the efficacy of chemotherapy. PMID:23145812

  8. Metformin may protect nondiabetic breast cancer women from metastasis.

    PubMed

    El-Haggar, Sahar Mohammed; El-Shitany, Nagla A; Mostafa, Mohamed Farouk; El-Bassiouny, Noha Ahmed

    2016-04-01

    Metformin, a widely prescribed oral hypoglycemic agent, has recently received a big interest because of its potential antitumorigenic effects in different cancer types. The present study investigated the impact of adding metformin to breast cancer adjuvant therapy in nondiabetic women on, insulin like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), insulin, fasting blood glucose (FBG), the molar ratio of IGF-1 to IGFBP-3, homeostatic model assessment of insulin resistance (HOMA-IR) and metastasis. 102 women with newly diagnosed breast cancer were divided into 2 main groups, a control group and a metformin group. All women were treated with adjuvant therapy, according to the protocols of Ministry of Health and Population and National Cancer Institute, Egypt. Moreover, the women in the metformin group received 850 mg of metformin twice daily. Blood samples were collected at baseline, after chemotherapy (CT), after 6 months of hormonal therapy (6-HT) and 12 months of hormonal therapy (12-HT) for analysis of serum IGF-1, IGFBP-3, insulin, FBG and cancer antigen 15-3 (CA15-3). Metformin resulted in a significant reduction of IGF-1, IGF-1: IGFBP-3 molar ratio, insulin, FBG and HOMA-IR. On the other hand, metformin caused a significant increase of IGFBP-3. Moreover, metformin significantly decreased the numbers of metastatic cases after 6-HT. Metformin may have potential antitumor and antimetastatic effects that need further clinical investigations. This may be attributed to either the significant increase of the apoptotic inducer IGFBP-3 or/and the significant reduction of mitogenic insulin, IGF-1, free bioactive IGF-1, FBG and HOMA-IR.

  9. Reconstitution of a metastatic-resistant tumor microenvironment with cancer-associated fibroblasts enables metastasis

    PubMed Central

    Murata, Takuya; Hoffman, Robert M.

    2017-01-01

    ABSTRACT The tumor microenvironment is critical for metastasis to occur. Subcutaneous xenografts of tumors in immunodeficient mice are usually encapsulated and rarely metastasize as opposed to orthotopic tumors which metastasize if the original tumor was metastatic. In the present report, we were able to reconstitute a metastatic tumor microenvironment by subcutaneously co-transplanting a human cervical cancer cell line and human cervical cancer-associated fibroblasts (CAFs), in athymic mice, which resulted in lymph node metastasis in 40% of the animals. In contrast, no metastasis occurred from the cervical cancer without CAFs. These results suggest that CAFs can overcome an anti-metastatic tumor environment and are a potential target to prevent metastasis. PMID:28103135

  10. Phyllodes Tumor in a Lactating Breast

    PubMed Central

    Murthy, Sudha S.; Raju, K. V. V. N.; Nair, Haripreetha G.

    2016-01-01

    Phyllodes tumor is attributed to a small fraction of primary tumors of the breast. Such tumors occur rarely in pregnancy and lactation. We report a case of a 25-year-old lactating mother presenting with a lump in the left breast. Core needle biopsy was opined as phyllodes tumor with lactational changes, and subsequent wide local excision confirmed the diagnosis of benign phyllodes tumor with lactational changes. The characteristic gross and microscopic findings of a well-circumscribed lesion with leaf-like fibroepithelial growth pattern and typical nonuniform or diffuse stromal proliferation with periductal accentuation even in the absence of mitotic figures can help clinch the diagnosis. Benign phyllodes is known for its recurrence and requires wide excision and close follow-up. It is vital to identify these lesions even on limited biopsies as therapeutic options differ. This case is presented for its rarity and the diagnostic challenge it poses in limited biopsy. PMID:27081326

  11. A regulatory loop involving miR-22, Sp1, and c-Myc modulates CD147 expression in breast cancer invasion and metastasis.

    PubMed

    Kong, Ling-Min; Liao, Cheng-Gong; Zhang, Yang; Xu, Jing; Li, Yu; Huang, Wan; Zhang, Yi; Bian, Huijie; Chen, Zhi-Nan

    2014-07-15

    Breast cancer is the most common cancer in women for which the metastatic process is still poorly understood. CD147 is upregulated in breast cancer and has been associated with tumor progression, but little is known about its regulatory mechanisms. In this study, we demonstrated that CD147 was overexpressed in breast cancer tissues and cell lines, and the high expression correlated with tumor invasion and metastasis. We also found that the transcription factors Sp1 and c-Myc could bind to the CD147 promoter and enhance its expression. The CD147 mRNA has a 748-bp 3'-untranslated region (UTR) with many miRNA target sites, suggesting possible regulation by miRNAs. We discovered that miR-22 repressed CD147 expression by directly targeting the CD147 3'UTR. We also determined that miR-22 could indirectly participate in CD147 modulation by downregulating Sp1 expression. miR-22 could form an autoregulatory loop with Sp1, which repressed miR-22 transcription by binding to the miR-22 promoter. Together with the c-Myc-mediated inhibition of miR-22 expression, our investigation identified a miR-22/Sp1/c-Myc network that regulates CD147 gene transcription. In addition, miR-22 overexpression suppressed breast cancer cell invasion, metastasis, and proliferation by targeting CD147 in vitro and in vivo. Furthermore, we found that miR-22 was significantly downregulated in breast cancer tissues and that its expression was inversely correlated with the tumor-node-metastasis stage and lymphatic metastasis in patients. Our study provides the first evidence that an miR-22/Sp1/c-Myc network regulates CD147 upregulation in breast cancer and that miR-22 represses breast cancer invasive and metastatic capacities.

  12. Identification of Genes Associated with Breast Cancer Metastasis to Bone on a Protein-Protein Interaction Network with a Shortest Path Algorithm.

    PubMed

    Cai, Yu-Dong; Zhang, Qing; Zhang, Yu-Hang; Chen, Lei; Huang, Tao

    2017-02-03

    Tumor metastasis is defined as the spread of tumor cells from one organ or part to another that is not directly connected to it, which significantly contributes to the progression and aggravation of tumorigenesis. Because it always involves multiple organs, the metastatic process is difficult to study in its entirety. Complete identification of the genes related to this process is an alternative way to study metastasis. In this study, we developed a computational method to identify such genes. To test our method, we selected breast cancer bone metastasis. A large network was constructed using human protein-protein interactions. On the basis of the validated genes related to breast and bone cancer, a shortest path algorithm was applied to the network to search for novel genes that may mediate breast cancer metastasis to bone. In addition, further rules constructed using the permutation FDR, the betweenness ratio, and the max-min interaction score were also employed in the method to make the inferred genes more reliable. Eighteen putative genes were identified by the method and were extensively analyzed. The confirmation results indicate that these genes participate in metastasis.

  13. MicroRNA miR-24 enhances tumor invasion and metastasis by targeting PTPN9 and PTPRF to promote EGF signaling.

    PubMed

    Du, William W; Fang, Ling; Li, Minhui; Yang, Xiangling; Liang, Yaoyun; Peng, Chun; Qian, Wei; O'Malley, Yunxia Q; Askeland, Ryan W; Sugg, Sonia L; Qian, Jun; Lin, Jiang; Jiang, Zide; Yee, Albert J; Sefton, Michael; Deng, Zhaoqun; Shan, Sze Wan; Wang, Chia-Hui; Yang, Burton B

    2013-03-15

    MicroRNAs are known to play regulatory roles in gene expression associated with cancer development. We analyzed levels of the microRNA miR-24 in patients with breast carcinoma and found that miR-24 was higher in breast carcinoma samples than in benign breast tissues. We generated constructs expressing miR-24 and studied its functions using both in vitro and in vivo techniques. We found that the ectopic expression of miR-24 promoted breast cancer cell invasion and migration. In vivo experiments in mice indicated that the expression of miR-24 enhanced tumor growth, invasion into local tissues, metastasis to lung tissues and decreased overall mouse survival. In the miR-24-expressing cells and tumors, EGFR was highly phosphorylated, whereas expression of the phosphatases tyrosine-protein phosphatase non-receptor type 9 (PTPN9) and receptor-type tyrosine-protein phosphatase F (PTPRF) were repressed. We confirmed that miR-24 could directly target both PTPN9 and PTPRF. Consistent with this, we found that the levels of phosphorylated epidermal growth factor receptor (pEGFR) were higher whereas the levels of PTPN9 and PTPRF were lower in the patients with metastatic breast carcinoma. Ectopic expression of PTPN9 and PTPRF decreased pEGFR levels, cell invasion, migration and tumor metastasis. Furthermore, we found that MMP2, MMP11, pErk, and ADAM15 were upregulated, whereas TIMP2 was downregulated; all of which supported the roles of miR-24 in tumor invasion and metastasis. Our results suggest that miR-24 plays a key role in breast cancer invasion and metastasis. miR-24 could potentially be a target for cancer intervention.

  14. The role of exosomes in tumor progression and metastasis (Review).

    PubMed

    Suchorska, Wiktoria M; Lach, Michal S

    2016-03-01

    Tumor cells have developed various mechanisms in defense against applied treatment, which prevent their total elimination from an organism. One of the underestimated mechanisms of defense is secretion of highly specialized double-membrane structures called exosomes. They play a crucial role in the control of the local microenvironment and intracellular communication. It has been shown that the exosomes can be carriers of various proteins, lipids, miRNAs and mRNAs. There are extensive data concerning the influence and participation by exosomes in metastasis and cancer progression. It has been demonstrated that exosomes are involved in multidrug resistance mechanisms, radiation-induced bystander effect and epithelial-mesenchymal transition. Furthermore, exosomes are able to form a premetastatic niche and enable the escape of cancer cells from recognition by host immune cells. Moreover, exosomes are responsible for the formation of vessels. This indicates the significance of secreted extracellular vesicles in the development and prognosis of cancer. The aim of the present review is to briefly describe the role of exosomes in tumor biology.

  15. Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

    PubMed Central

    Singh, Sandeep; Pillai, Smitha; Chellappan, Srikumar

    2011-01-01

    Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneficial effects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These effects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Specific signal transduction cascades that emanate from different nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor effects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent efforts to target the nicotinic acetylcholine receptors to combat cancer. PMID:21541211

  16. The promotion of breast cancer metastasis caused by inhibition of CSF-1R/CSF-1 signaling is blocked by targeting the G-CSF receptor.

    PubMed

    Swierczak, Agnieszka; Cook, Andrew D; Lenzo, Jason C; Restall, Christina M; Doherty, Judy P; Anderson, Robin L; Hamilton, John A

    2014-08-01

    Treatment options are limited for patients with breast cancer presenting with metastatic disease. Targeting of tumor-associated macrophages through the inhibition of colony-stimulating factor-1 receptor (CSF-1R), a key macrophage signaling pathway, has been reported to reduce tumor growth and metastasis, and these treatments are now in clinical trials. Here, we report that, surprisingly, treatment with neutralizing anti-CSF-1R and anti-CSF-1 antibodies, or with two different small-molecule inhibitors of CSF-1R, could actually increase spontaneous metastasis without altering primary tumor growth in mice bearing two independently derived mammary tumors. The blockade of CSF-1R or CSF-1 led to increased levels of serum G-CSF, increased frequency of neutrophils in the primary tumor and in the metastasis-associated lung, as well as increased numbers of neutrophils and Ly6C(hi) monocytes in the peripheral blood. Neutralizing antibody against the G-CSF receptor, which regulates neutrophil development and function, reduced the enhanced metastasis and neutrophil numbers that resulted from CSF-1R blockade. These results indicate that the role of the CSF-1R/CSF-1 system in breast cancer is far more complex than originally proposed, and requires further investigation as a therapeutic target.

  17. Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model.

    PubMed

    Chen, Xiaoyun; Wang, Jian; Cao, Ziquan; Hosaka, Kayoko; Jensen, Lasse; Yang, Huasheng; Sun, Yuping; Zhuang, Rujie; Liu, Yizhi; Cao, Yihai

    2015-07-14

    Retinoblastoma is a highly invasive malignant tumor that often invades the brain and metastasizes to distal organs through the blood stream. Invasiveness and metastasis of retinoblastoma can occur at the early stage of tumor development. However, an optimal preclinical model to study retinoblastoma invasiveness and metastasis in relation to drug treatment has not been developed. Here, we developed an orthotopic zebrafish model in which retinoblastoma invasion and metastasis can be monitored at a single cell level. We took the advantages of immune privilege and transparent nature of developing zebrafish embryos. Intravitreal implantation of color-coded retinoblastoma cells allowed us to kinetically monitor tumor cell invasion and metastasis. Further, interactions between retinoblastoma cells and surrounding microvasculatures were studied using a transgenic zebrafish that exhibited green fluorescent signals in blood vessels. We discovered that tumor cells invaded neighboring tissues and blood stream when primary tumors were at the microscopic sizes. These findings demonstrate that retinoblastoma metastasis occurs at the early stage and antiangiogenic drugs such as Vegf morpholino and sunitinib could potentially interfere with tumor invasiveness and metastasis. Thus, this orthotopic retinoblastoma model offers a new and unique opportunity to study the early events of tumor invasion, metastasis and drug responses.

  18. Macrophage Polarization: Anti-cancer Strategies to Target Tumor-associated Macrophage in Breast Cancer.

    PubMed

    Tariq, Muhammad; Zhang, Jieqiong; Liang, Guikai; Ding, Ling; He, Qiaojun; Yang, Bo

    2017-01-20

    Tumor-associated macrophages (TAMs) are the most abundant inflammatory cells and orchestrate different stages of breast cancer development. TAMs participate in the tumor angiogenesis, matrix remodeling, invasion, immunosuppression, metastasis, and chemoresistance in breast cancer. Several clinical studies indicate the association between the high influx of TAMs in tumor with poor prognosis in hepatocellular, ovarian, cervical, and breast cancer. Previously developed hypotheses have proposed that TAMs participate in antitumor responses of the body, while recently many clinical and experimental studies have revealed that TAMs in tumor microenvironment predominantly resemble with M2-like polarized macrophages and produce a high amount of anti-inflammatory factors which are directly responsible for the development of tumor. Various studies have shown that TAMs in tumor either enhance or antagonize the anti-tumor efficacy of cytotoxic agents, antibodies-targeting cancer cells, and therapeutic agents depending on the nature of treatment. Thereby, multiple roles of TAMs suggests that it is very important to develop novel therapeutic strategies to target TAMs in breast tumor. In this review, we have discussed the functional role of TAMs in breast cancer and summarized available recent advances potential therapeutic strategies that effectively target to TAMs cells. This article is protected by copyright. All rights reserved.

  19. Silencing β3 Integrin by Targeted ECO/siRNA Nanoparticles Inhibits EMT and Metastasis of Triple Negative Breast Cancer

    PubMed Central

    Mack, Margaret A.; Schiemann, William P.; Lu, Zheng-Rong

    2015-01-01

    Metastatic breast cancer is the second leading cause of cancer-related deaths amongst women. Triple-negative breast cancer (TNBC) is a highly aggressive subcategory of breast cancer and currently lacks well-defined molecular targets for effective targeted therapies. Disease relapse, metastasis, and drug resistance render standard chemotherapy ineffective in the treatment of TNBC. Since previous studies coupled β3 integrin to epithelial-mesenchymal transition (EMT) and metastasis, we exploited β3 integrin as a therapeutic target to treat TNBC by delivering β3 integrin siRNA via lipid ECO-based nanoparticles (ECO/siβ3). Treatment of TNBC cells with ECO/siβ3 was sufficient to effectively silence β3 integrin expression, attenuate TGF-β-mediated EMT and invasion, restore TGF-β-mediated cytostasis, and inhibit 3-dimensional organoid growth. Modification of ECO/siβ3 nanoparticles with an RGD peptide via a PEG spacer enhanced siRNA uptake by post-EMT cells. Intravenous injections of RGD-targeted ECO/siβ3 nanoparticles in vivo alleviated primary tumor burden, and more importantly, significantly inhibited metastasis. Mice bearing orthotopic, TGF-β-pre-stimulated MDA-MB-231 tumors that were treated with RGD-targeted ECO/siβ3 nanoparticles were free of metastases and relapse after primary tumor resection and 4 weeks after release from the treatment, in comparison to untreated mice. Collectively, these results highlight ECO/siβ3 nanoparticles as a promising therapeutic regimen to combat TNBC. PMID:25858145

  20. Tracking nonpalpable breast cancer for breast-conserving surgery with carbon nanoparticles: implication in tumor location and lymph node dissection.

    PubMed

    Jiang, Yanyan; Lin, Nan; Huang, Sheng; Lin, Chongping; Jin, Na; Zhang, Zaizhong; Ke, Jun; Yu, Yinghao; Zhu, Jianping; Wang, Yu

    2015-03-01

    To examine the feasibility of using carbon nanoparticles to track nonpalpable breast cancer for breast-conserving surgery. During breast-conserving surgery, it is often very challenging to determine the boundary of tumor and identify involved lymph nodes. Currently used methods are useful in identifying tumor location, but do not provide direct visual guidance for resection margin during surgery. The study was approved by the Institutional Review Board of the Fuzhou General Hospital (Fuzhou, China). The current retrospective analysis included 16 patients with nonpalpable breast cancer receiving breast-conserving surgery under the guidance of preoperative marking using a carbon nanoparticle, as well as 3 patients receiving carbon nanoparticle marking followed by neoadjuvant treatment and then breast-conserving surgery. The Tumor Node Metastasis stage in the 16 cases included: T1N0M0 in 7, T1N1M0 in 2, T2N0M0 in 4, and T2N1M0 in the remaining 3 cases. The nanoparticle was injected at 12 sites at 0.5 cm away from the apparent edge under colored ultrasonography along 6 tracks separated by 60 degrees (2 sites every track). Lymph node status was also examined. The resection edge was free from cancer cells in all 16 cases (and the 3 cases with neoadjuvant treatment). Cancer cells were identified in majority of stained lymph nodes, but not in any of the unstained lymph nodes. No recurrence or metastasis was noticed after the surgery (2 to 22-month follow-up; median: 6 months). Tracking nonpalpable breast cancer with carbon nanoparticle could guide breast-conserving surgery.

  1. The Role of Crk Adaptor Proteins in Breast Tumorigenesis and Bone Metastasis

    DTIC Science & Technology

    2012-09-01

    signature and the basal molecular subtypes found within breast cancer cell lines. Heatmap of the Crk signature in the Neve breast cancer cell line...metastasis to bone. Cancer Cell 2003, 3:537-549. 16. Minn AJ, Gupta GP, Siegel PM, Bos PD , Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J...prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC Genomics 2008, 9:239. 27. Neve RM, Chin K

  2. Lunasin Attenuates Obesity-Associated Metastasis of 4T1 Breast Cancer Cell through Anti-Inflammatory Property

    PubMed Central

    Hsieh, Chia-Chien; Wang, Chih-Hsuan; Huang, Yu-Shan

    2016-01-01

    Obesity prevalence is increasing worldwide and is accompanied by low-grade inflammation with macrophage infiltration, which is linked with a poorer breast cancer prognosis. Lunasin is a natural seed peptide with chemopreventive properties and multiple bioactivities. This is the first study to explore the chemopreventive effects of lunasin in the obesity-related breast cancer condition using 4T1 breast cancer cells, 3T3-L1 adipocytes, and conditioned media. An obesity-related environment, such as leptin-treatment or adipocyte-conditioned medium (Ad-CM), promoted 4T1 cell proliferation and metastasis. Lunasin treatment inhibited metastasis of breast cancer cells, partially through modestly inhibiting production of the angiogenesis-mediator vascular endothelial growth factor (VEGF) and significantly by inhibiting secretion in the Ad-CM condition. Subsequently, two adipocytes inflammation models, 3T3-L1 adipocytes were stimulated by tumor necrosis factor (TNF)-α, and RAW 264.7 cell-conditioned medium (RAW-CM) was used to mimic the obese microenvironment. Lunasin significantly inhibited interleukin (IL)-6 and macrophage chemoattractant protein (MCP)-1 secretion by TNF-α stimulation, and MCP-1 secretion in the RAW-CM model. This study highlights that lunasin suppressed 3T3-L1 adipocyte inflammation and inhibited 4T1 breast cancer cell migration. Interestingly, lunasin exerted more effective anti-metastasis activity in the obesity-related condition models, indicating that it possesses anti-inflammatory properties and blocks adipocyte-cancer cell cross-talk. PMID:27983683

  3. Macrophage mediated biomimetic delivery system for the treatment of lung metastasis of breast cancer.

    PubMed

    Fu, Jijun; Wang, Dan; Mei, Dong; Zhang, Haoran; Wang, Zhaoyang; He, Bing; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Zhang, Qiang

    2015-04-28

    The biomimetic delivery system (BDS) based on special types of endogenous cells like macrophages and T cells, has been emerging as a novel strategy for cancer therapy, due to its tumor homing property and biocompatibility. However, its development is impeded by complicated construction, low drug loading or negative effect on the cell bioactivity. The present report constructed a BDS by loading doxorubicin (DOX) into a mouse macrophage-like cell line (RAW264.7). It was found that therapeutically meaningful amount of DOX could be loaded into the RAW264.7 cells by simply incubation, without significantly affecting the viability of the cells. Drug could release from the BDS and maintain its activity. RAW264.7 cells exhibited obvious tumor-tropic capacity towards 4T1 mouse breast cancer cells both in vitro and in vivo, and drug loading did not alter this tendency. Importantly, the DOX loaded macrophage system showed promising anti-cancer efficacy in terms of tumor suppression, life span prolongation and metastasis inhibition, with reduced toxicity. In conclusion, it is demonstrated that the BDS developed here seems to overcome some of the main issues related to a BDS. The DOX loaded macrophages might be a potential BDS for targeted cancer therapy.

  4. Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth.

    PubMed

    Gonzalez, Maria E; Martin, Emily E; Anwar, Talha; Arellano-Garcia, Caroline; Medhora, Natasha; Lama, Arjun; Chen, Yu-Chih; Tanager, Kevin S; Yoon, Euisik; Kidwell, Kelley M; Ge, Chunxi; Franceschi, Renny T; Kleer, Celina G

    2017-01-31

    Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.

  5. Meaningful prevention of breast cancer metastasis: candidate therapeutics, preclinical validation, and clinical trial concerns.

    PubMed

    Zimmer, Alexandra S; Steeg, Patricia S

    2015-01-01

    The development of drugs to treat breast and other cancers proceeds through phase I dose finding, phase II efficacy, and phase III comparative studies in the metastatic setting, only then asking if metastasis can be prevented in adjuvant trials. Compounds without overt cytotoxic activity, such as those developed to inhibit metastatic colonization, will likely fail to shrink established lesions in the metastatic setting and never be tested in a metastasis prevention scenario where they were preclinically validated. We and others have proposed phase II primary and secondary metastasis prevention studies to address this need. Herein, we have asked whether preclinical metastasis prevention data agrees with the positive adjuvant setting trials. The data are limited but complimentary. We also review fundamental pathways involved in metastasis, including Src, integrins, focal adhesion kinase (FAK), and fibrosis, for their clinical progress to date and potential for metastasis prevention. Issues of inadequate preclinical validation and clinical toxicity profiles are discussed.

  6. Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer

    PubMed Central

    Fitamant, Julien; Guenebeaud, Céline; Coissieux, Marie-May; Guix, Catherine; Treilleux, Isabelle; Scoazec, Jean-Yves; Bachelot, Thomas; Bernet, Agnès; Mehlen, Patrick

    2008-01-01

    Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H were shown to belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these receptors a tumor suppressor activity. Expression of one of these dependence receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this dependence receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies. PMID:18353983

  7. Lyn modulates Claudin-2 expression and is a therapeutic target for breast cancer liver metastasis.

    PubMed

    Tabariès, Sébastien; Annis, Matthew G; Hsu, Brian E; Tam, Christine E; Savage, Paul; Park, Morag; Siegel, Peter M

    2015-04-20

    Claudin-2 enhances breast cancer liver metastasis and promotes the development of colorectal cancers. The objective of our current study is to define the regulatory mechanisms controlling Claudin-2 expression in breast cancer cells. We evaluated the effect of several Src Family Kinase (SFK) inhibitors or knockdown of individual SFK members on Claudin-2 expression in breast cancer cells. We also assessed the potential effects of pan-SFK and SFK-selective inhibitors on the formation of breast cancer liver metastases. This study reveals that pan inhibition of SFK signaling pathways significantly elevated Claudin-2 expression levels in breast cancer cells. In addition, our data demonstrate that pan-SFK inhibitors can enhance breast cancer metastasis to the liver. Knockdown of individual SFK members reveals that loss of Yes or Fyn induces Claudin-2 expression; whereas, diminished Lyn levels impairs Claudin-2 expression in breast cancer cells. The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis. Our findings may have major clinical implications and advise against the treatment of breast cancer patients with broad-acting SFK inhibitors and support the use of Lyn-specific inhibitors.

  8. ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

    PubMed

    Gallego-Ortega, David; Ledger, Anita; Roden, Daniel L; Law, Andrew M K; Magenau, Astrid; Kikhtyak, Zoya; Cho, Christina; Allerdice, Stephanie L; Lee, Heather J; Valdes-Mora, Fatima; Herrmann, David; Salomon, Robert; Young, Adelaide I J; Lee, Brian Y; Sergio, C Marcelo; Kaplan, Warren; Piggin, Catherine; Conway, James R W; Rabinovich, Brian; Millar, Ewan K A; Oakes, Samantha R; Chtanova, Tatyana; Swarbrick, Alexander; Naylor, Matthew J; O'Toole, Sandra; Green, Andrew R; Timpson, Paul; Gee, Julia M W; Ellis, Ian O; Clark, Susan J; Ormandy, Christopher J

    2015-12-01

    During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer.

  9. SURVIVIN as a marker for quiescent-breast cancer stem cells-An intermediate, adherent, pre-requisite phase of breast cancer metastasis.

    PubMed

    Siddharth, Sumit; Das, Sarita; Nayak, Anmada; Kundu, Chanakya Nath

    2016-10-01

    Cancer stem cells drive the metastatic cascade by undergoing epithelial to mesenchymal transition (EMT) and again mesenchymal to epithelial transition (MET). Using multiple breast cancer cell lines including cigarette smoke induced breast cancer cells and tumor derived primary cells from patient sample; we developed a breast cancer metastasis model and reported the existence of an adherent, distinct pre-metastatic phase, quiescent-breast cancer stem cells (Q-BCSCs) prior to attaining an EMT. SURVIVIN was found to be expressed in Q-BCSCs. Time dependant biphasic expression of SURVIVIN in Q-BCSCs reveals that Q-BCSCs is a pre-metastatic phase distinct from both epithelial and mesenchymal counterparts. SURVIVIN favours metastasis and up-regulates WNT/β-CATENIN pathway in a PI3 K/AKT-dependant manner for self-renewal. Knockdown of SURVIVIN in Q-BCSCs lost the metastatic property of cells by inhibiting invasion, EMT-MET, PI3 K/AKT/WNT cascade, and induced apoptosis. Thus, our data suggest the existence of a novel pre-metastatic phase (Q-BCSCs) before EMT and SURVIVIN acts as a marker for Quiescent-BCSCs.

  10. Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1

    PubMed Central

    Li, Xin; Fan, Shengjun; Pan, Xueyang; Xiaokaiti, Yilixiati; Duan, Jianhui; Shi, Yundi; Pan, Yan; Tie, Lu; Wang, Xin; Li, Yuhua; Li, Xuejun

    2016-01-01

    Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer. PMID:27863391

  11. MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer

    PubMed Central

    Xu, Xin; Zhang, Yun; Jasper, Jeff; Lykken, Erik; Alexander, Peter B.; Markowitz, Geoffrey J.; McDonnell, Donald P.; Li, Qi-Jing; Wang, Xiao-Fan

    2016-01-01

    Triple-negative breast cancer (TNBC) presents a major challenge in the clinic due to its lack of reliable prognostic markers and targeted therapies. Accumulating evidence strongly supports the notion that microRNAs (miRNAs) are involved in tumorigenesis and could serve as biomarkers for diagnostic purposes. To identify miRNAs that functionally suppress metastasis of TNBC, we employed a concerted approach with selecting miRNAs that display differential expression profiles from bioinformatic analyses of breast cancer patient databases and validating top candidates with functional assays using breast cancer cell lines and mouse models. We have found that miR-148a exhibits properties as a tumor suppressor as its expression is inversely correlated with the ability of both human and mouse breast cancer cells to colonize the lung in mouse xenograft tumor models. Mechanistically, miR-148a appears to suppress the extravasation process of cancer cells, likely by targeting two genes WNT1 and NRP1 in a cell non-autonomous manner. Importantly, lower expression of miR-148a is detected in higher-grade tumor samples and correlated with increased likelihood to develop metastases and poor prognosis in subsets of breast cancer patients, particularly those with TNBC. Thus, miR-148a is functionally defined as a suppressor of breast cancer metastasis and may serve as a prognostic biomarker for this disease. PMID:26967387

  12. MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis

    PubMed Central

    Cook, Rebecca S.; Jacobsen, Kristen M.; Wofford, Anne M.; DeRyckere, Deborah; Stanford, Jamie; Prieto, Anne L.; Redente, Elizabeth; Sandahl, Melissa; Hunter, Debra M.; Strunk, Karen E.; Graham, Douglas K.; Earp, H. Shelton

    2013-01-01

    MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK–/– mice. Transplantation of MerTK–/– bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, MerTK–/– leukocytes exhibited lower tumor cell–induced expression of wound healing cytokines, e.g., IL-10 and growth arrest-specific 6 (GAS6), and enhanced expression of acute inflammatory cytokines, e.g., IL-12 and IL-6. Intratumoral CD8+ T lymphocyte numbers were higher and lymphocyte proliferation was increased in tumor-bearing MerTK–/– mice compared with tumor-bearing wild-type mice. Antibody-mediated CD8+ T lymphocyte depletion restored tumor growth in MerTK–/– mice. These data demonstrate that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies. PMID:23867499

  13. MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis.

    PubMed

    Cook, Rebecca S; Jacobsen, Kristen M; Wofford, Anne M; DeRyckere, Deborah; Stanford, Jamie; Prieto, Anne L; Redente, Elizabeth; Sandahl, Melissa; Hunter, Debra M; Strunk, Karen E; Graham, Douglas K; Earp, H Shelton

    2013-08-01

    MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK-/- mice. Transplantation of MerTK-/- bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, MerTK-/- leukocytes exhibited lower tumor cell-induced expression of wound healing cytokines, e.g., IL-10 and growth arrest-specific 6 (GAS6), and enhanced expression of acute inflammatory cytokines, e.g., IL-12 and IL-6. Intratumoral CD8+ T lymphocyte numbers were higher and lymphocyte proliferation was increased in tumor-bearing MerTK-/- mice compared with tumor-bearing wild-type mice. Antibody-mediated CD8+ T lymphocyte depletion restored tumor growth in MerTK-/- mice. These data demonstrate that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies.

  14. Comprehensive molecular portraits of human breast tumors

    PubMed Central

    2012-01-01

    Summary We analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing and reverse phase protein arrays. Our ability to integrate information across platforms provided key insights into previously-defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the Luminal A subtype. We identified two novel protein expression-defined subgroups, possibly contributed by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/p-HER2/HER1/p-HER1 signature within the HER2-Enriched expression subtype. Comparison of Basal-like breast tumors with high-grade Serous Ovarian tumors showed many molecular commonalities, suggesting a related etiology and similar therapeutic opportunities. The biologic finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer. PMID:23000897

  15. Regulation of the Na+/H+ Exchanger (NHE1) in Breast Cancer Metastasis.

    PubMed

    Amith, Schammim R; Fliegel, Larry

    2013-02-15

    The pH gradient in normal cells is tightly controlled by the activity of various pH-regulatory membrane proteins including the isoform protein of the Na(+)/H(+) exchanger (NHE1). NHE1 is constitutively active in a neoplastic microenvironment, dysregulating pH homeostasis and altering the survival, differentiation, and proliferation of cancer cells, thereby causing them to become tumorigenic. Cytoplasmic alkalinization in breast cancer cells occurs as a result of increased NHE1 activity and, while much is known about the pathophysiologic role of NHE1 in tumor progression with regard to ion flux, the regulation of its activity on a molecular level is only recently becoming evident. The membrane domain of NHE1 is sufficient for ion exchange. However, its activity is regulated through the phosphorylation of key amino acids in the cytosolic domain as well as by its interaction with other intracellular proteins and lipids. Here, we review the importance of these regulatory sites and what role they may play in the disrupted functionality of NHE1 in breast cancer metastasis.

  16. Expression of high affinity folate receptor in breast cancer brain metastasis.

    PubMed

    Leone, José Pablo; Bhargava, Rohit; Theisen, Brian K; Hamilton, Ronald L; Lee, Adrian V; Brufsky, Adam M

    2015-10-06

    High affinity folate receptor (HFR) can be overexpressed in breast cancer and is associated with poor prognosis, however the expression in breast cancer brain metastases (BCBM) is unknown. The aim of this study was to analyze the rate of HFR expression in BCBM and its role in the prognosis of this high-risk cohort. We analyzed 19 brain metastasis (BM) and 13 primary tumors (PT) from a total of 25 patients. HFR status was assessed by immunohistochemistry. Median follow-up was 4.2 years (range 0.6-18.5). HFR was positive in 4/19 BM (21.1%) and in 1/13 PT (7.7%). Positive samples had low H-scores (range 1-50). 56% of patients had apocrine differentiation. OS was similar between patients with positive HFR (median OS 48 months) and negative HFR (median OS 69 months) (P = 0.25); and between patients with apocrine differentiation (median OS 63 months) and those without apocrine differentiation (median OS 69 months) (P = 0.49). To the best of our knowledge, this is the first analysis of HFR expression in BCBM. While previous studies associated the presence of HFR with worse prognosis; in our cohort HFR was positive in only 21.1% of BM with low levels of positivity. Neither HFR nor apocrine features had impact in OS.

  17. Chemokine axes in breast cancer: factors of the tumor microenvironment reshape the CCR7-driven metastatic spread of luminal-A breast tumors.

    PubMed

    Weitzenfeld, Polina; Kossover, Olga; Körner, Cindy; Meshel, Tsipi; Wiemann, Stefan; Seliktar, Dror; Legler, Daniel F; Ben-Baruch, Adit

    2016-06-01

    Chemokine axes have been shown to mediate site-specific metastasis in breast cancer, but their relevance to different subtypes has been hardly addressed. Here, with the focus on the CCR7-CCL21 axis, patient datasets demonstrated that luminal-A tumors express relatively low CCR7 levels compared with more aggressive disease subtypes. Furthermore, lymph node metastasis was not associated with high CCR7 levels in luminal-A patients. The metastatic pattern of luminal-A breast tumors may be influenced by the way luminal-A tumor cells interpret signals provided by factors of the primary tumor microenvironment. Thus, CCR7-expressing human luminal-A cells were stimulated simultaneously by factors representing 3 tumor microenvironment arms typical of luminal-A tumors, hormonal, inflammatory, and growth stimulating: estrogen + TNF-α + epidermal growth factor. Such tumor microenvironment stimulation down-regulated the migration of CCR7-expressing tumor cells toward CCL21 and inhibited the formation of directional protrusions toward CCL21 in a novel 3-dimensional hydrogel system. CCL21-induced migration of CCR7-expressing tumor cells depended on PI3K and MAPK activation; however, when CCR7-expressing cancer cells were prestimulated by tumor microenvironment factors, CCL21 could not effectively activate these signaling pathways. In vivo, pre-exposure of the tumor cells to tumor microenvironment factors has put restraints on CCL21-mediated lymph node-homing cues and shifted the metastatic pattern of CCR7-expressing cells to the aggressive phenotype of dissemination to bones. Several of the aspects were also studied in the CXCR4-CXCL12 system, demonstrating similar patient and in vitro findings. Thus, we provide novel evidence to subtype-specific regulation of the CCR7-CCL21 axis, with more general implications to chemokine-dependent patterns of metastatic spread, revealing differential regulation in the luminal-A subtype.

  18. Unusual Benign Tumors of the Breast

    PubMed Central

    Adrada, Beatriz E; Krishnamurthy, Savitri; Carkaci, Selin; Posleman-Monetto, Flavia E; Ewere, Adesuwa; Whitman, Gary J

    2015-01-01

    The purpose of this article is to describe the imaging characteristics of a variety of benign breast tumors that may be encountered in daily practice, in order to formulate an appropriate differential diagnosis and to establish concordance between the imaging and the pathologic findings, and to assist the clinician with appropriate management. PMID:26085959

  19. Epigenetic regulation of HGF/Met receptor axis is critical for the outgrowth of bone metastasis from breast carcinoma.

    PubMed

    Bendinelli, Paola; Maroni, Paola; Matteucci, Emanuela; Desiderio, Maria Alfonsina

    2017-02-02

    Our translational research deals with the influence of microenvironment on the phenotype and colonization of bone metastases from breast carcinoma, and on pre-metastatic niche formation. The aim of the present study was to clarify the origin of hepatocyte growth factor (HGF), ligand of Met receptor, the control of the axis HGF/Met by DNA methylation, and its importance for the nexus supportive cells-metastatic cells and for metastasis outgrowth. In bone metastasis of the 1833-xenograft model, DNA methyltransferase blockade using the chemotherapic drug 5-aza-2'-deoxycytidine (decitabine) strongly reduced the expression of HGF/Met receptor axis and of E-cadherin, with decrease of metastasis wideness and osteolysis, prolonging mice survival. Thus, DNA methylation events acted as commanders of breast carcinoma cells metastatizing to bone influencing the epithelial phenotype. HGF emerged as a bone-marrow stimulus, and the exosomes seemed to furnish HGF to metastatic cells. In fact, decitabine treatment similarly affected some markers of these microvesicles and HGF, indicating that its supply to recipient cells was prevented. Notably, in bone metastasis the hypomethylation of HGF, Met and E-cadherin promoters did not appear responsible for their elevated expression, but we suggest the involvement of hypermethylated regulators and of Wwox oncosuppressor, the latter being affected by decitabine. Wwox expression increased under decitabine strongly localizing in nuclei of bone metastases. We hypothesize a role of Wwox in Met activity since in vitro Wwox overexpression downregulated the level of nuclear-Met protein fragment and Met stability, also under long exposure of 1833 cells to decitabine. HGF enhanced phosphoMet and the activity in nuclei, an effect partially prevented by decitabine. Altogether, the data indicated the importance to target the tumor microenvironment by blocking epigenetic mechanisms, which control critical events for colonization such as HGF/Met axis

  20. Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer.

    PubMed

    Lee, Ji Yun; Park, Kyunghee; Lim, Sung Hee; Kim, Hae Su; Yoo, Kwai Han; Jung, Ki Sun; Song, Haa-Na; Hong, Mineui; Do, In-Gu; Ahn, TaeJin; Lee, Se Kyung; Bae, Soo Youn; Kim, Seok Won; Lee, Jeong Eon; Nam, Seok Jin; Kim, Duk-Hwan; Jung, Hae Hyun; Kim, Ji-Yeon; Ahn, Jin Seok; Im, Young-Hyuck; Park, Yeon Hee

    2015-12-22

    Although breast cancer is the second most common cause of brain metastasis with a notable increase of incidence, genes that mediate breast cancer brain metastasis (BCBM) are not fully understood. To study the molecular nature of brain metastasis, we performed gene expression profiling of brain metastasis and matched primary breast cancer (BC). We used the Ion AmpliSeq Cancer Panel v2 covering 2,855 mutations from 50 cancer genes to analyze 18 primary BC and 42 BCBM including 15 matched pairs. The most common BCBM subtypes were triple-negative (42.9%) and basal-like (36.6%). In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0-7 mutations). Frequently detected somatic mutations included TP53 (59.5%), MLH1 (14.3%), PIK3CA (14.3%), and KIT (7.1%). We compared BCBM with patient-matched primary BC specimens. There were no significant differences in mutation profiles between the two groups. Notably, gene expression in BCBM such as TP53, PIK3CA, KIT, MLH1, and RB1 also seemed to be present in primary breast cancers. The TP53 mutation frequency was higher in BCBM than in primary BC (59.5% vs 38.9%, respectively). In conclusion, we found actionable gene alterations in BCBM that were maintained in primary BC. Further studies with functional testing and a delineation of the role of these genes in specific steps of the metastatic process should lead to a better understanding of the biology of metastasis and its susceptibility to treatment.

  1. Breast malignant phyllodes tumor with rare pelvic metastases and long-term overall survival

    PubMed Central

    Shan, Jinlan; Zhang, Shizhen; Wang, Zhen; Fu, Yanbiao; Li, Ling; Wang, Xiaochen

    2016-01-01

    Abstract Background: Malignant phyllodes tumor (PT) is a rare fibro epithelial neoplasm of the breast, which is poor prognosis due to high risk of recurrence and distant metastasis. Methods: We report a case of malignant PT. It had recurred locally five times, and the sixth relapse was occurred 54 months after first diagnosis, presenting a huge pelvic mass (14 cm × 11 cm) by CT scan. Histopathological examination has demonstrated a metastatic phyllodes tumor. After postoperative chemotherapy treatment, a longer survival has been achieved, which is more than 72 months. Results: Our case report describes a breast PT with several local recurrences and a rare metastasis (pelvic cavity), but long-term overall survival was achieved after surgery and chemotherapy. Conclusion: We conclude that trustworthy prognosticators that identify patients with excessive potential of aggressive clinical course should be explored. Moreover, proper treatment could prolong overall survival of metastatic PT patients. PMID:27661051

  2. Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis.

    PubMed

    Smart, DeeDee; Garcia-Glaessner, Alejandra; Palmieri, Diane; Wong-Goodrich, Sarah J; Kramp, Tamalee; Gril, Brunilde; Shukla, Sudhanshu; Lyle, Tiffany; Hua, Emily; Cameron, Heather A; Camphausen, Kevin; Steeg, Patricia S

    2015-10-01

    Most cancer patients with brain metastases are treated with radiation therapy, yet this modality has not yet been meaningfully incorporated into preclinical experimental brain metastasis models. We applied two forms of whole brain radiation therapy (WBRT) to the brain-tropic 231-BR experimental brain metastasis model of triple-negative breast cancer. When compared to sham controls, WBRT as 3 Gy × 10 fractions (3 × 10) reduced the number of micrometastases and large metastases by 87.7 and 54.5 %, respectively (both p < 0.01); whereas a single radiation dose of 15 Gy × 1 (15 × 1) was less effective, reducing metastases by 58.4 % (p < 0.01) and 47.1 % (p = 0.41), respectively. Neuroinflammation in the adjacent brain parenchyma was due solely to a reaction from metastases, and not radiotherapy, while adult neurogenesis in brains was adversely affected following both radiation regimens. The nature of radiation resistance was investigated by ex vivo culture of tumor cells that survived initial WBRT ("Surviving" cultures). The Surviving cultures surprisingly demonstrated increased radiosensitivity ex vivo. In contrast, re-injection of Surviving cultures and re-treatment with a 3 × 10 WBRT regimen significantly reduced the number of large and micrometastases that developed in vivo, suggesting a role for the microenvironment. Micrometastases derived from tumor cells surviving initial 3 × 10 WBRT demonstrated a trend toward radioresistance upon repeat treatment (p = 0.09). The data confirm the potency of a fractionated 3 × 10 WBRT regimen and identify the brain microenvironment as a potential determinant of radiation efficacy. The data also nominate the Surviving cultures as a potential new translational model for radiotherapy.

  3. Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis.

    PubMed

    Nakajima, Kosei; Kho, Dhong Hyo; Yanagawa, Takashi; Harazono, Yosuke; Hogan, Victor; Chen, Wei; Ali-Fehmi, Rouba; Mehra, Rohit; Raz, Avraham

    2016-03-15

    Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including tartrate-resistant acid phosphatase, and reduced the number of mature osteoclasts. Structurally, the 158-175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and colocalized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche.

  4. Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression.

    PubMed

    Singh, Manjulata; Mukundan, Shilpaa; Jaramillo, Maria; Oesterreich, Steffi; Sant, Shilpa

    2016-07-01

    Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates ("microtumors") of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150-600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor-positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple-negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor-positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732-43. ©2016 AACR.

  5. Inhibition of metastasis, angiogenesis, and tumor growth by Chinese herbal cocktail Tien-Hsien Liquid

    PubMed Central

    2010-01-01

    Background Advanced cancer is a multifactorial disease that demands treatments targeting multiple cellular pathways. Chinese herbal cocktail which contains various phytochemicals may target multiple dys-regulated pathways in cancer cells and thus may provide an alternative/complementary way to treat cancers. Previously we reported that the Chinese herbal cocktail Tien-Hsien Liguid (THL) can specifically induce apoptosis in various cancer cells and have immuno-modulating activity. In this study, we further evaluated the anti-metastatic, anti-angiogenic and anti-tumor activities of THL with a series of in vitro and in vivo experiments. Methods The migration and invasion of cancer cells and endothelial cells was determined by Boyden chamber transwell assays. The effect of THL on pulmonary metastasis was done by injecting CT-26 colon cancer cells intravenously to syngenic mice. The in vitro and in vivo microvessel formation was determined by the tube formation assay and the Matrigel plug assay, respectively. The in vivo anti-tumor effect of THL was determined by a human MDA-MB-231 breast cancer xenograft model. The expression of metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) was measured by gelatin zymography. The expression of HIF-1α and the phosphorylation of ERK1/2 were determined by Western blot. Results THL inhibited the migration and invasion ability of various cancer cells in vitro, decreased the secretion of MMP-2, MMP-9, and uPA and the activity of ERK1/2 in cancer cells, and suppressed pulmonary metastasis of CT-26 cancer cells in syngenic mice. Moreover, THL inhibited the migration, invasion, and tube formation of endothelial cells in vitro, decreased the secretion of MMP-2 and uPA in endothelial cells, and suppressed neovascularization in Matrigel plugs in mice. Besides its inhibitory effect on endothelial cells, THL inhibited hypoxia-induced HIF-1α and vascular endothelial growth factor-A expression in cancer cells. Finally

  6. Skull Metastasis of Gastric Gastrointestinal Stromal Tumor Successfully Managed by Surgery

    PubMed Central

    Park, Inkeun; Chung, Dong Hae; Yoo, Chan Jong; Shin, Dong Bok

    2017-01-01

    Gastrointestinal stromal tumors (GISTs) are rare, but are the most common mesenchymal neoplasm of the gastrointestinal tract. The most common sites of metastasis are liver and peritoneum, while bone metastasis is rare. We report on a patient with skull metastasis after seven years of treatment with imatinib for metastatic GIST. She underwent metastasectomy consisting of craniectomy with excision of the mass, and cranioplasty and continued treatment with imatinib and sunitinib, without evidence of cranial recurrence. She died of pneumonia sepsis one year after metastasectomy. Skull metastasis of GIST is a very rare presentation, and an aggressive multidisciplinary approach should be considered whenever possible. PMID:28061498

  7. Pertuzumab, trastuzumab and docetaxel reduced the recurrence of brain metastasis from breast cancer: a case report.

    PubMed

    Senda, Noriko; Yamaguchi, Ayane; Nishimura, Hideaki; Shiozaki, Toshiki; Tsuyuki, Shigeru

    2016-03-01

    The CLEOPATRA trial reported the survival benefit of pertuzumab with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients. However, there are a few case reports concerning the effects of a pertuzumab-containing regimen on brain metastases. A 55-year-old woman, who underwent curative surgery for breast cancer after neoadjuvant chemotherapy 5 years previously, developed repeated solitary brain metastasis in her right occipital lobe. Whole brain radiation therapy, stereotactic radiosurgery and 3 times of surgical resection were performed. Lapatinib and capecitabine plus tamoxifen were administered. The metastasis recurred in the stump of the previous surgery. Pertuzumab with trastuzumab plus docetaxel was initiated as second-line chemotherapy. A complete response of the brain metastasis was achieved, which persisted for 5 months. Pertuzumab with trastuzumab plus docetaxel was effective in reducing the brain metastases from breast cancer. Further studies are warranted to confirm the effect of this regimen on brain metastases.

  8. Osterix transcriptional factor is involved in the metastasis of human breast cancers.

    PubMed

    Dai, Qiang-Sheng; Zhou, Hong-Yan; Wu, Zhuang-Hong; Long, Jian-Ting; Shao, Nan; Cheang, Tuck-Yun; Wang, Shen-Ming

    2015-09-01

    The transcriptional factor Osterix is specifically expressed in bone tissues to regulate the differentiation and maturation of osteoblasts. Recent studies have also identified the expression of Osterix in a number of cancer tissues, such as kidney and lung cancers. However, the association of Osterix with the metastasis of breast cancers has never been reported. The present study, for the first time, provides evidence supporting the involvement of Osterix in breast cancer metastasis. Western blotting was employed to investigate the expression of Osterix in a number of human breast cancer cell lines with different metastatic features. Gain-of-function and loss-of-function experiments were performed in MCF7 cells (low level of metastasis) and MDA-MB-361 cells (high level of metastasis). The expression of several metastasis-associated genes was analyzed by western blotting and quantitative polymerase chain reaction. A firefly luciferase-based reporter gene assay was conducted in order to study whether Osterix regulated the promoter activities of the MMP2 and MMP9 genes, which play critical roles in cancer metastasis. The results showed that Osterix was highly expressed in the MDA-MB-231 and MDA-MB-361 cells, but was not de