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Sample records for breast cancer target

  1. 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

  2. Targeting of Breast Cancer with Triptolide Nanoparticles

    DTIC Science & Technology

    2005-08-01

    AD Award Number: W81XWH-04-1-0766 TITLE: Targeting of Breast Cancer with Triptolide Nanoparticles PRINCIPAL INVESTIGATOR: Shanmin Yang, M.D...NUMBER Targeting of Breast Cancer with Triptolide Nanoparticles 5b. GRANT NUMBER W81XWH-04-1-0766 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...breast cancer is not well studied. In past year, we have successfully finished the following works: 1) demonstrated the effectiveness of TPL in inhibition

  3. Targeted Therapy for Breast Cancer Prevention

    PubMed Central

    den Hollander, Petra; Savage, Michelle I.; Brown, Powel H.

    2013-01-01

    With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID:24069582

  4. Cripto: A Target for Breast Cancer Treatment

    DTIC Science & Technology

    2005-06-01

    AD Award Number: DAMD17-01-1-0165 TITLE: Cripto: A, Target for Breast Cancer Treatment PRINCIPAL INVESTIGATOR: Eileen D. Adamson, Ph.D. CONTRACTING...CONTRACT NUMBER Cripto: A Target for Breast Cancer Treatment 5b. GRANT NUMBER DAMD17-01-1-0165 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...Target for Breast Cancer Treatment " As reported fully in June 2004, the IDEA grant was not successful in the original mission of finding a peptide that

  5. Targeted Gene Therapy for Breast Cancer

    DTIC Science & Technology

    1998-08-01

    AD AWARD NUMBER DAMD17-97-1-7232 TITLE: Targeted Gene Therapy for Breast Cancer PRINCIPAL INVESTIGATOR: Jinha M. Park CONTRACTING ORGANIZATION...FUNDING NUMBERS Targeted Gene Therapy for Breast Cancer DAMD17-97-1-7232 6. AUTHOR(S) Jinha M. Park 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8...of surface mAb has been internalized by receptor-mediated endocytosis. These mAbs show promise in the specific delivery of gene therapy vectors

  6. Targeting ESR1-Mutant Breast Cancer

    DTIC Science & Technology

    2015-09-01

    AWARD NUMBER: W81XWH-14-1-0359 TITLE: Targeting ESR1- Mutant Breast Cancer PRINCIPAL INVESTIGATOR: Dr. Sarat Chandarlapaty CONTRACTING...31 Aug 2015 4. TITLE AND SUBTITLE Targeting ESR1- Mutant Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0359 5c. PROGRAM ELEMENT...current FDA approved hormonal therapies and that more potent, selective estrogen receptor degraders (SERDs) will enable complete inhibition of mutant

  7. Targeting Energy Metabolic Pathways as Therapeutic Intervention for Breast Cancer

    DTIC Science & Technology

    2012-10-01

    Intervention for Breast Cancer PRINCIPAL INVESTIGATOR: Yan Cheng, Ph.D. CONTRACTING ORGANIZATION: Pennsylvania State University...Targeting Energy Metabolic Pathways as Therapeutic Intervention for Breast Cancer 5b. GRANT NUMBER W81XWH-11-1-0649 5c. PROGRAM ELEMENT NUMBER...causes of cancer mortality in women. Current therapies for breast cancer mainly target molecular signaling pathways that promote tumor cell

  8. Targeting ESR1-Mutant Breast Cancer

    DTIC Science & Technology

    2015-09-01

    Award Number: W81XWH-14-1-0360 TITLE: Targeting ESR1- Mutant Breast Cancer PRINCIPAL INVESTIGATOR: Geoffrey L. Greene, Ph.D. CONTRACTING...ADDRESS. 1. REPORT DATE September 2015 2. REPORT TYPE Annual 3. DATES COVERED 1 Sep 2014 - 31 Aug 2015 4. TITLE AND SUBTITLE Targeting ESR1- Mutant ...approved hormonal therapies and that more potent, selective estrogen receptor degraders (SERDs) will enable complete inhibition of mutant ER signaling and

  9. 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

  10. Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers

    DTIC Science & Technology

    2014-10-01

    AWARD NUMBER: W81XWH-13-1-0400 TITLE: Targeting Epigenetics Therapy for Estrogen Receptor...2014 4. TITLE AND SUBTITLE Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers 5a. CONTRACT NUMBER 5b...estrogen- receptor positive breast cancer, estrogen receptor negative breast cancer, epigenetics , nuclear hormone receptor, estrogen Overall

  11. Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

    DTIC Science & Technology

    2013-09-01

    anti- cancer drugs. We developed various kinds of nuclear-targeted charge- reversal nanoparticles (TCRNs) which can directly localize and release drug...breast cancer chemotherapy (12 Months): a. In vitro test drug release profile at pH 7.4. b. Test stability in blood. c. In vitro test cellular...anti-breast cancer activity. TASK 3. To in vivo evaluate TCRNs’ anti-breast cancer efficacy (12 months) a. In vivo test biodistribution and tumor

  12. New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers.

    PubMed

    Nwabo Kamdje, Armel Hervé; Seke Etet, Paul Faustin; Vecchio, Lorella; Tagne, Richard Simo; Amvene, Jeremie Mbo; Muller, Jean-Marc; Krampera, Mauro; Lukong, Kiven Erique

    2014-12-16

    Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy, including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin, Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed.

  13. New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers

    PubMed Central

    Kamdje, Armel Hervé Nwabo; Etet, Paul Faustin Seke; Vecchio, Lorella; Tagne, Richard Simo; Amvene, Jeremie Mbo; Muller, Jean-Marc; Krampera, Mauro; Lukong, Kiven Erique

    2014-01-01

    Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy, including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin, Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed. PMID:25516852

  14. Breast Cancer Survivorship Care: Targeting a Colorectal Cancer Education Intervention

    PubMed Central

    Homan, Sherri G.; Yun, Shumei; Stewart, Bob R.; Armer, Jane M.

    2015-01-01

    Breast cancer survivors are at risk of developing a second primary cancer. Colorectal cancer (CRC) is one of the leading second primary cancers, and it is often preventable. We developed a multi-component educational tool to inform and encourage women breast cancer survivors to engage in CRC screening. To assess the strengths and weakness of the tool and to improve the relevancy to the target audience, we convened four focus groups of women breast cancer survivors in Missouri. We also assessed the potential impact of the tool on the knowledge, attitudes, and beliefs regarding CRC and collected information on the barriers to CRC screening through pre- and post-focus groups’ questionnaires. A total of 43 women breast cancer survivors participated and provided very valuable suggestions on design and content to update the tool. Through the process and comparing pre- and post-focus group assessments, a significantly higher proportion of breast cancer survivors strongly agreed or agreed that CRC is preventable (78.6% vs. 96.9%, p = 0.02) and became aware that they were at a slightly increased risk for CRC (18.6% vs. 51.7%, p = 0.003). The most cited barrier was the complexity of preparation for colonoscopy. PMID:26258794

  15. Breast Cancer Survivorship Care: Targeting a Colorectal Cancer Education Intervention.

    PubMed

    Homan, Sherri G; Yun, Shumei; Stewart, Bob R; Armer, Jane M

    2015-08-06

    Breast cancer survivors are at risk of developing a second primary cancer. Colorectal cancer (CRC) is one of the leading second primary cancers, and it is often preventable. We developed a multi-component educational tool to inform and encourage women breast cancer survivors to engage in CRC screening. To assess the strengths and weakness of the tool and to improve the relevancy to the target audience, we convened four focus groups of women breast cancer survivors in Missouri. We also assessed the potential impact of the tool on the knowledge, attitudes, and beliefs regarding CRC and collected information on the barriers to CRC screening through pre- and post-focus groups' questionnaires. A total of 43 women breast cancer survivors participated and provided very valuable suggestions on design and content to update the tool. Through the process and comparing pre- and post-focus group assessments, a significantly higher proportion of breast cancer survivors strongly agreed or agreed that CRC is preventable (78.6% vs. 96.9%, p = 0.02) and became aware that they were at a slightly increased risk for CRC (18.6% vs. 51.7%, p = 0.003). The most cited barrier was the complexity of preparation for colonoscopy.

  16. Androgen Receptor: A Complex Therapeutic Target for Breast Cancer.

    PubMed

    Narayanan, Ramesh; Dalton, James T

    2016-12-02

    Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER) and human epidermal growth factor receptor (HER2) are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR) is evolving as a molecular target for cancers that have developed resistance to conventional treatments. The high expression of AR in breast cancer and recent discovery and development of new nonsteroidal drugs targeting the AR provide a strong rationale for exploring it again as a therapeutic target in this disease. Ironically, both nonsteroidal agonists and antagonists for the AR are undergoing clinical trials, making AR a complicated target to understand in breast cancer. This review provides a detailed account of AR's therapeutic role in breast cancer.

  17. Androgen Receptor: A Complex Therapeutic Target for Breast Cancer

    PubMed Central

    Narayanan, Ramesh; Dalton, James T.

    2016-01-01

    Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER) and human epidermal growth factor receptor (HER2) are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR) is evolving as a molecular target for cancers that have developed resistance to conventional treatments. The high expression of AR in breast cancer and recent discovery and development of new nonsteroidal drugs targeting the AR provide a strong rationale for exploring it again as a therapeutic target in this disease. Ironically, both nonsteroidal agonists and antagonists for the AR are undergoing clinical trials, making AR a complicated target to understand in breast cancer. This review provides a detailed account of AR’s therapeutic role in breast cancer. PMID:27918430

  18. Targeting Angiogenesis in Metastatic Breast Cancer

    PubMed Central

    Reddy, Sangeetha; Raffin, Michael

    2012-01-01

    Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC. PMID:22843553

  19. Targeting metabolism in breast cancer: How far we can go?

    PubMed Central

    Long, Jing-Pei; Li, Xiao-Na; Zhang, Feng

    2016-01-01

    Adjuvant therapies for breast cancer have achieved great success in recent years and early breast cancer is now a curable or chronic disease. Targeted therapies, including endocrine therapy and human epidermal growth factor receptor-2 targeted therapy, marked a new era of breast cancer treatment. However, except for chemotherapy, an efficient drug treatment to improve the overall survival of breast cancer patients is still lacking for triple negative breast cancer. Furthermore, a certain proportion of breast cancer patients present with resistance to drug therapy, making it much more difficult to control the deterioration of the disease. Recently, altered energy metabolism has become one of the hallmarks of cancer, including breast cancer, and it may be linked to drug resistance. Targeting cellular metabolism is becoming a promising strategy to overcome drug resistance in cancer therapy. This review discusses metabolic reprogramming in breast cancer and the possible complex mechanism of modulation. We also summarize the recent advances in metabolic therapy targeted glycolysis, glutaminolysis and fatty acids synthesis in breast cancer. PMID:26862496

  20. Targeting Breast Cancer Recurrence via Hedgehog-mediated Sensitization of Breast Cancer Stem Cells

    DTIC Science & Technology

    2011-07-01

    established a treatment model in which the Smoothened agonist was sufficient to partially rescue the Sonic Hedgehog knockout suggesting that similar... Hedgehog -mediated Sensitization of Breast Cancer Stem Cells PRINCIPAL INVESTIGATOR: David J. Robbins, Ph.D...June 2010 – 14 June 2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Breast Cancer Recurrence via Hedgehog -mediated Sensitization of

  1. Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

    DTIC Science & Technology

    2012-09-01

    TASK 3. To in vivo evaluate TCRNs’ anti-breast cancer efficacy (12 months) a. In vivo test biodistribution and tumor targeting efficiency using...the physiological temperature. The modified G5-PEG showed a promise as a drug carrier for cancer chemotherapy. 2.2 Synthesis of degradable...AD_________________ Award Number: W81XWH-09-1-0502 TITLE: Breast Cancer -Targeted Nuclear Drug

  2. Targeting HER2 Positive Breast Cancer with Chemopreventive Agents

    PubMed Central

    Wahler, Joseph; Suh, Nanjoo

    2015-01-01

    Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is a subtype of breast cancer that is exhibited in approximately 20-30% of breast cancer cases. The overexpression of HER2 is typically associated with a more aggressive disease and poor prognosis. Currently, the therapeutic drugs trastuzumab and lapatinib are the most commonly used to combat HER2+ breast cancer. However, tumors can develop resistance to these drugs. A better understanding of the mechanism of how HER2+ breast cancer works will help aid the development for new therapeutic approaches which more closely target the source of the signaling dysfunction. This review summarizes four major points in the context of HER2 over-expressing breast cancer (i) HER2 as a molecular target in breast cancer therapy, (ii) current treatment options as well as ongoing clinical studies, (iii) animal and cellular models for the study of HER2 over-expressing breast cancer, and (iv) future therapies and chemopreventive agents used to target HER2+ breast cancer. PMID:26442201

  3. Targeting the spindle assembly checkpoint for breast cancer treatment.

    PubMed

    Marques, Sandra; Fonseca, Joana; Silva, Patrícia M A; Bousbaa, Hassan

    2015-01-01

    Breast cancer is the most common malignancy in women worldwide and the second leading cause of cancer deaths after lung cancer. As in other malignancies, aneuploidy is a common feature of breast cancer and influences its behavior. Aneuploidy has been linked to inappropriate activity of the spindle assembly checkpoint (SAC), a surveillance mechanism that, in normal cells, prevents anaphase onset until correct alignment of all chromosomes at the metaphase is achieved. Interestingly, the widely used anti-microtubule drugs, vinca alkaloids and taxanes, kill cancer cells through chronic arrest in mitosis as a consequence of chronic SAC activation. Deregulated SAC has been reported in breast cancer in many reports and presents an attractive therapeutic strategy. We present here a review of the current knowledge on the SAC defects and the underlying molecular mechanisms in breast cancer, and discuss the potential of SAC components as targets for breast cancer therapies.

  4. Evolution of breast cancer therapeutics: Breast tumour kinase's role in breast cancer and hope for breast tumour kinase targeted therapy.

    PubMed

    Hussain, Haroon A; Harvey, Amanda J

    2014-08-10

    There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients' overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase (Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current "state of play" with respect to targeted therapy for breast cancer, as well as discussing Brk's role in the processes underlying tumour development and metastasis and its potential as a therapeutic target in breast cancer.

  5. Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

    DTIC Science & Technology

    2012-08-01

    Li, an outstanding leader in nanotechnology , we aimed to develop nanoparticles that can carry in vivo imaging agents to target breast cancer cells...and develop RSR-defect-targeting nanoparticles for diagnostic imaging, prevention, and treatment of breast cancer . As demonstrated in our first...antibody to hollow gold nanoparticles (HAuNP). REPORTABLE OUTCOMES Part of the our study has led to a publication in Cancer Research (7 and

  6. Skp2 is a Promising Therapeutic Target in Breast Cancer

    PubMed Central

    Wang, Zhiwei; Fukushima, Hidefumi; Inuzuka, Hiroyuki; Wan, Lixin; Liu, Pengda; Gao, Daming; Sarkar, Fazlul H.; Wei, Wenyi

    2011-01-01

    Breast cancer is the most common type of cancer among American women, and remains the second leading cause of cancer-related death for female in the United States. It has been known that several signaling pathways and various factors play critical roles in the development and progression of breast cancer, such as estrogen receptor, Notch, PTEN, human epidermal growth factor receptor 2, PI3K/Akt, BRCA1, and BRCA2. Emerging evidence has shown that the F-box protein S-phase kinase associated protein 2 (Skp2) also plays an important role in the pathogenesis of breast cancer. Therefore, in this brief review, we summarize the novel functions of Skp2 in the pathogenesis of breast cancer. Moreover, we provide further evidence regarding the state of our knowledge toward the development of novel Skp2 inhibitors especially natural “chemopreventive agents” as targeted approach for the prevention and/or treatment of breast cancer. PMID:22279619

  7. Targeting the androgen receptor in triple-negative breast cancer.

    PubMed

    Gucalp, Ayca; Traina, Tiffany A

    Triple-negative breast cancer represents approximately 15%-20% of all newly diagnosed breast cancers, but it accounts for a disproportionate number of breast cancer-related deaths each year. Owing to the lack of estrogen, progesterone, and human epidermal growth factor receptor 2 expression, patients with triple-negative breast cancer do not benefit from generally well-tolerated and effective therapies targeting the estrogen and human epidermal growth factor receptor 2 signaling pathways and are faced with an increased risk of disease progression and poorer overall survival. The heterogeneity of triple-negative breast cancer has been increasingly recognized and this may lead to therapeutic opportunities because of newly defined oncogenic drivers and targets. A subset of triple-negative breast tumors expresses the androgen receptor (AR) and this may benefit from treatments that inhibit the AR-signaling pathway. The first proof-of-concept trial established activity of the AR antagonist, bicalutamide, in patients with advanced AR+ triple-negative breast cancer. Since that time, evidence further supports the activity of other next-generation AR-targeted agents such as enzalutamide. Not unlike in estrogen receptor-positive breast cancer, mechanisms of resistance are being investigated and rationale exists for thoughtful, well-designed combination regimens such as AR antagonism with CDK4/6 pathway inhibitors or PI3K inhibitors. Furthermore, novel agents developed for the treatment of prostate cancer, which reduce androgen production such as abiraterone acetate and seviteronel, are being tested as well. This review summarizes the underlying biology of AR signaling in breast cancer development and the available clinical trial data for the use of anti-androgen therapy in the treatment of AR+ triple-negative breast cancer.

  8. 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

  9. BRCA1 as target for breast cancer prevention and therapy.

    PubMed

    Romagnolo, Alberto P G; Romagnolo, Donato F; Selmin, Ornella I

    2015-01-01

    The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, but reduced expression of BRCA1, due to mutations or epigenetic inactivation, leads to impaired mammary gland differentiation and increased risk of breast cancer development. Although BRCA1 acts as a tumor suppressor and is present in all cells, where it is essential for the maintenance of the genome integrity, it is still not clear why mutations in the BRCA1 gene predispose to breast and ovarian, but not to other types of cancer. In the first part of this review, we briefly discuss the function and regulation of the BRCA1 protein, including its role associated with familial and sporadic breast cancer. The second part is an overview of the therapeutic compounds used for breast cancer treatment targeting BRCA1, and the natural food components that hold potential preventive effect against those types of breast cancer in which BRCA1 expression is either reduced or lacking. Further studies elucidating the interactions between dietary compounds and cellular pathways, involved in regulation of BRCA1expression, are necessary for the development of strategies that may successfully prevent or treat breast cancer.

  10. Epigenetics as a Therapeutic Target in Breast Cancer

    PubMed Central

    Connolly, Roisin

    2012-01-01

    Epigenetics refers to alterations in gene expression due to modifications in histone acetylation and DNA methylation at the promoter regions of genes. Unlike genetic mutations, epigenetic alterations are not due to modifications in the gene primary nucleotide sequence. The importance of epigenetics in the initiation and progression of breast cancer has led many investigators to incorporate this novel and exciting field in breast cancer drug development. Several drugs that target epigenetic alterations, including inhibitors of histone deacetylase (HDAC) and DNA methyltransferase (DNMT), are currently approved for treatment of hematological malignancies and are available for clinical investigation in solid tumors. In this manuscript, we review the critical role of epigenetics in breast cancer including the potential for epigenetic alterations to serve as biomarkers determining breast cancer prognosis and response to therapy. We highlight initial promising results to date with use of epigenetic modifiers in patients with breast cancer and the ongoing challenges involved in the successful establishment of these agents for the treatment of breast cancer. PMID:22836913

  11. Nanomedicine-Mediated Therapies to Target Breast Cancer Stem Cells

    PubMed Central

    He, Lili; Gu, Jian; Lim, Lee Y.; Yuan, Zhi-xiang; Mo, Jingxin

    2016-01-01

    Accumulating evidences have suggested the existence of breast cancer stem cells (BCSCs), which possess the potential of both self-renewal and differentiation. The origin of BCSCs might have relationship to the development of normal mammary stem cells. BCSCs are believed to play a key role in the initiation, recurrence and chemo-/radiotherapy resistances of breast cancer. Therefore, elimination of BCSCs is crucial for breast cancer therapy. However, conventional chemo and radiation therapies cannot eradicate BCSCs effectively. Fortunately, nanotechnology holds great potential for specific and efficient anti-BCSCs treatment. “Smart” nanocarriers can distinguish BCSCs from the other breast cancer cells and selectively deliver therapeutic agents to the BCSCs. Emerging findings suggest that BCSCs in breast cancer could be successfully inhibited and even eradicated by functionalized nanomedicines. In this review, we focus on origin of BCSCs, strategies used to target BCSCs, and summarize the nanotechnology-based delivery systems that have been applied for eliminating BCSCs in breast cancer. PMID:27679576

  12. Therapeutic targets of triple-negative breast cancer: a review

    PubMed Central

    Jamdade, Vinayak S; Sethi, Nikunj; Mundhe, Nitin A; Kumar, Parveen; Lahkar, Mangala; Sinha, Neeraj

    2015-01-01

    Breast cancer (BC) is the second most common cause of cancer deaths. Triple-negative breast cancer (TNBC) does not show immunohistochemical expression of oestrogen receptors, progesterone receptors or HER2. At present, no suitable treatment option is available for patients with TNBC. This dearth of effective conventional therapies for the treatment of advanced stage breast cancer has provoked the development of novel strategies for the management of patients with TNBC. This review presents recent information associated with different therapeutic options for the treatment of TNBC focusing on promising targets such as the Notch signalling, Wnt/β-catenin and Hedgehog pathways, in addition to EGFR, PARP1, mTOR, TGF-β and angiogenesis inhibitors. PMID:26040571

  13. Matrix metalloproteinases as breast cancer drivers and therapeutic targets

    PubMed Central

    Radisky, Evette S.; Radisky, Derek C.

    2015-01-01

    Members of the matrix metalloproteinase (MMP) family have been identified as poor prognosis markers for breast cancer patients and as drivers of many facets of the tumor phenotype in experimental models. Early enthusiasm for MMPs as therapeutic targets was tempered following disappointing clinical trials that utilized broad spectrum, small molecule catalytic site inhibitors. However, subsequent research has continued to define key roles for MMPs as breast cancer promoters, to elucidate the complex roles that that these proteins play in breast cancer development and progression, and to identify how these roles are linked to specific and unique biochemical features of individual members of the MMP family. Here, we provide an overview of the structural features of the MMPs, then discuss clinical studies identifying which MMP family members are linked with breast cancer development and new experimental studies that reveal how these specific MMPs may play unique roles in the breast cancer microenvironment. We conclude with a discussion of the most promising avenues for development of therapeutic agents capable of targeting the tumor-promoting properties of MMPs. PMID:25961550

  14. Clinical Implementation of Novel Targeted Therapeutics in Advanced Breast Cancer.

    PubMed

    Chamberlin, Mary D; Bernhardt, Erica B; Miller, Todd W

    2016-11-01

    The majority of advanced breast cancers have genetic alterations that are potentially targetable with drugs. Through initiatives such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), data can be mined to provide context for next-generation sequencing (NGS) results in the landscape of advanced breast cancer. Therapies for targets other than estrogen receptor alpha (ER) and HER2, such as cyclin-dependent kinases CDK4 and CDK6, were recently approved based on efficacy in patient subpopulations, but no predictive biomarkers have been found, leaving clinicians to continue a trial-and-error approach with each patient. Next-generation sequencing identifies potentially actionable alterations in genes thought to be drivers in the cancerous process including phosphatidylinositol 3-kinase (PI3K), AKT, fibroblast growth factor receptors (FGFRs), and mutant HER2. Epigenetically directed and immunologic therapies have also shown promise for the treatment of breast cancer via histone deacetylases (HDAC) 1 and 3, programmed T cell death 1 (PD-1), and programmed T cell death ligand 1 (PD-L1). Identifying biomarkers to predict primary resistance in breast cancer will ultimately affect clinical decisions regarding adjuvant therapy in the first-line setting. However, the bulk of medical decision-making is currently made in the secondary resistance setting. Herein, we review the clinical potential of PI3K, AKT, FGFRs, mutant HER2, HDAC1/3, PD-1, and PD-L1 as therapeutic targets in breast cancer, focusing on the rationale for therapeutic development and the status of clinical testing. J. Cell. Biochem. 117: 2454-2463, 2016. © 2016 Wiley Periodicals, Inc.

  15. Targeted Therapies for Brain Metastases from Breast Cancer

    PubMed Central

    Venur, Vyshak Alva; Leone, José Pablo

    2016-01-01

    The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%–30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways. PMID:27649142

  16. Triple-negative breast cancer: new perspectives for targeted therapies

    PubMed Central

    Tomao, Federica; Papa, Anselmo; Zaccarelli, Eleonora; Rossi, Luigi; Caruso, Davide; Minozzi, Marina; Vici, Patrizia; Frati, Luigi; Tomao, Silverio

    2015-01-01

    Breast cancer is a heterogeneous disease, encompassing a large number of entities showing different morphological features and having clinical behaviors. It has became apparent that this diversity may be justified by distinct patterns of genetic, epigenetic, and transcriptomic aberrations. The identification of gene-expression microarray-based characteristics has led to the identification of at least five breast cancer subgroups: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2, and basal-like. Triple-negative breast cancer is a complex disease diagnosed by immunohistochemistry, and it is characterized by malignant cells not expressing estrogen receptors or progesterone receptors at all, and human epidermal growth factor receptor 2. Along with this knowledge, recent data show that triple-negative breast cancer has specific molecular features that could be possible targets for new biological targeted drugs. The aim of this article is to explore the use of new drugs in this particular setting, which is still associated with poor prognosis and high risk of distant recurrence and death. PMID:25653541

  17. Resistance to Targeted Therapies in Breast Cancer.

    PubMed

    Braga, Sofia

    2016-01-01

    Seventy five percent of all breast cancer (BC) patients express estrogen receptor (ER) but a quarter to half of patients with ER positive BC relapse on ET (endocrine therapy), tamoxifen, aromatase inhibitors (AIs), surgical castration, amongst other treatment strategies. ER positive BC at relapse loses ER expression in 20 % of cases and reduces quantitative ER expression most of the time. ER is not the only survival pathway driving ER positive BC and escape pathways intrinsic or acquired are activated during ET. This overview gives an account of ligand-independent ER activation, namely by receptor networks cross talk, and by the various genomic factors and mechanisms leading to ET response failure. Also the mechanisms of Her1 and Her2 inhibition resistance are dealt within this overview, along with the therapeutic indications and limitations of tyrosine kinase inhibitors, PARP inhibitors, PI3K/AKT/mTOR inhibitors, RAS/RAF/MEK/ERK/MAPK inhibitors, and antiangiogenic drugs. In spite of the many advances in controlling the division of BC cells and the progression of BC tumors these still remain the main cause of death among women in age range of 20-50 years requiring even more efforts in new therapeutic approaches besides the drugs within the scope of the overview.

  18. Targeting the Ron-DEK Signaling Axis in Breast Cancer

    DTIC Science & Technology

    2013-09-01

    The first objective of Task 2 was to test DEK-targeting 1716 Herpes Simplex Viruses (1716HSV) on breast cancer cells. A panel of vectors was...characterized transgenic model wherein wild type Ron is overexpressed selectively in the mammary epithelium by the mouse mammary tumor virus ...degree of knockdown that could be achieved. Three DEK targeting viruses were tested for DEK knockdown in HeLa cells. These included GFP-expressing

  19. Targeting the Ron-DEK Signaling Axis in Breast Cancer

    DTIC Science & Technology

    2013-09-01

    The first objective of Task 2 was to test DEK-targeting 1716 Herpes Simplex Viruses (1716HSV) on breast cancer cells. A panel of vectors was...characterized transgenic model wherein wild type Ron is overexpressed selectively in the mammary epithelium by the mouse mammary tumor virus ...of knockdown that could be achieved. Three DEK targeting viruses were tested for DEK knockdown in HeLa cells. These included GFP-expressing viruses

  20. CXCR4 in breast cancer: oncogenic role and therapeutic targeting

    PubMed Central

    Xu, Chao; Zhao, Hong; Chen, Haitao; Yao, Qinghua

    2015-01-01

    Chemokines are 8–12 kDa peptides that function as chemoattractant cytokines and are involved in cell activation, differentiation, and trafficking. Chemokines bind to specific G-protein-coupled seven-span transmembrane receptors. Chemokines play a fundamental role in the regulation of a variety of cellular, physiological, and developmental processes. Their aberrant expression can lead to a variety of human diseases including cancer. C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or CD184, is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12). CXCR4 belongs to the superfamily of the seven transmembrane domain heterotrimeric G protein-coupled receptors and is functionally expressed on the cell surface of various types of cancer cells. CXCR4 also plays a role in the cell proliferation and migration of these cells. Recently, CXCR4 has been reported to play an important role in cell survival, proliferation, migration, as well as metastasis of several cancers including breast cancer. This review is mainly focused on the current knowledge of the oncogenic role and potential drugs that target CXCR4 in breast cancer. Additionally, CXCR4 proangiogenic molecular mechanisms will be reviewed. Strict biunivocal binding affinity and activation of CXCR4/CXCL12 complex make CXCR4 a unique molecular target for prevention and treatment of breast cancer. PMID:26356032

  1. CXCR4 in breast cancer: oncogenic role and therapeutic targeting.

    PubMed

    Xu, Chao; Zhao, Hong; Chen, Haitao; Yao, Qinghua

    2015-01-01

    Chemokines are 8-12 kDa peptides that function as chemoattractant cytokines and are involved in cell activation, differentiation, and trafficking. Chemokines bind to specific G-protein-coupled seven-span transmembrane receptors. Chemokines play a fundamental role in the regulation of a variety of cellular, physiological, and developmental processes. Their aberrant expression can lead to a variety of human diseases including cancer. C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or CD184, is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12). CXCR4 belongs to the superfamily of the seven transmembrane domain heterotrimeric G protein-coupled receptors and is functionally expressed on the cell surface of various types of cancer cells. CXCR4 also plays a role in the cell proliferation and migration of these cells. Recently, CXCR4 has been reported to play an important role in cell survival, proliferation, migration, as well as metastasis of several cancers including breast cancer. This review is mainly focused on the current knowledge of the oncogenic role and potential drugs that target CXCR4 in breast cancer. Additionally, CXCR4 proangiogenic molecular mechanisms will be reviewed. Strict biunivocal binding affinity and activation of CXCR4/CXCL12 complex make CXCR4 a unique molecular target for prevention and treatment of breast cancer.

  2. Exercise Intervention in Targeting Adiposity and Inflammation With Movement to Improve Prognosis in Breast Cancer

    ClinicalTrials.gov

    2017-03-21

    Cancer Survivor; Central Obesity; Estrogen Receptor Positive; Postmenopausal; Progesterone Receptor Positive; Stage I Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  3. 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

  4. Potential therapeutic targets in energy metabolism pathways of breast cancer.

    PubMed

    Islam, Rowshan Ara; Hossain, Sazzad; Chowdhury, Ezharul Hoque

    2017-03-30

    Mutations in proto-oncogenes and tumor suppressor genes make cancer cells proliferate indefinitely. As they possess almost all mechanisms for cell proliferation and survival like healthy cells, it is difficult to specifically target cancer cells in the body. Current treatments in most of the cases are harmful to healthy cells as well. Thus, it would be of great prudence to target specific characters of cancer cells. Since cancer cells avidly use glucose and glutamine to survive and proliferate by upregulating the relevant enzymes and their specific isoforms having important regulatory roles, it has been of great interest recently to target the energy-related metabolic pathways as part of the therapeutic interventions. This paper summarizes the roles of energy metabolism and their cross-talks with other important signaling pathways in regulating proliferation, invasion and metastasis in breast cancer. As breast cancer is a highly heterogeneous disease, a clear understanding of the variations of energy metabolism in different molecular subtypes would help in treating each type with a very customized, safer and efficient treatment regimen, by targeting specific glucose metabolism and related pathways with gene silencing nucleic acid sequences or small molecule drugs, or the combination of both.

  5. The Antihelmintic Drug Pyrvinium Pamoate Targets Aggressive Breast Cancer

    PubMed Central

    Xu, Wei; Lacerda, Lara; Debeb, Bisrat G.; Atkinson, Rachel L.; Solley, Travis N.; Li, Li; Orton, Darren; McMurray, John S.; Hang, Brian I.; Lee, Ethan; Klopp, Ann H.; Ueno, Naoto T.; Reuben, James M.; Krishnamurthy, Savitri; Woodward, Wendy A.

    2013-01-01

    WNT signaling plays a key role in the self-renewal of tumor initiation cells (TICs). In this study, we used pyrvinium pamoate (PP), an FDA-approved antihelmintic drug that inhibits WNT signaling, to test whether pharmacologic inhibition of WNT signaling can specifically target TICs of aggressive breast cancer cells. SUM-149, an inflammatory breast cancer cell line, and SUM-159, a metaplastic basal-type breast cancer cell line, were used in these studies. We found that PP inhibited primary and secondary mammosphere formation of cancer cells at nanomolar concentrations, at least 10 times less than the dose needed to have a toxic effect on cancer cells. A comparable mammosphere formation IC50 dose to that observed in cancer cell lines was obtained using malignant pleural effusion samples from patients with IBC. A decrease in activity of the TIC surrogate aldehyde dehydrogenase was observed in PP-treated cells, and inhibition of WNT signaling by PP was associated with down-regulation of a panel of markers associated with epithelial-mesenchymal transition. In vivo, intratumoral injection was associated with tumor necrosis, and intraperitoneal injection into mice with tumor xenografts caused significant tumor growth delay and a trend toward decreased lung metastasis. In in vitro mammosphere-based and monolayer-based clonogenic assays, we found that PP radiosensitized cells in monolayer culture but not mammosphere culture. These findings suggest WNT signaling inhibition may be a feasible strategy for targeting aggressive breast cancer. Investigation and modification of the bioavailability and toxicity profile of systemic PP are warranted. PMID:24013655

  6. Breast Cancer

    MedlinePlus

    ... version of this page please turn Javascript on. Breast Cancer What is Breast Cancer? How Tumors Form The body is made up ... tumors form in the breast tissue. Who Gets Breast Cancer? Breast cancer is one of the most common ...

  7. Breast cancer stem cells, EMT and therapeutic targets

    SciTech Connect

    Kotiyal, Srishti; Bhattacharya, Susinjan

    2014-10-10

    Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.

  8. Breast cancer targeting novel microRNA-nanoparticles for imaging

    NASA Astrophysics Data System (ADS)

    Natarajan, Arutselvan; Venugopal, Senthil K.; DeNardo, Sally J.; Zern, Mark A.

    2009-02-01

    MicroRNAs (miRNAs) are one of the most prevalent small (~22 nucleotide) regulatory RNA classes in animals. These miRNAs constitute nearly one percent of genes in the human genome, making miRNA genes one of the more abundant types of regulatory molecules. MiRNAs have been shown to play important roles in cell development, apoptosis, and other fundamental biological processes. MiRNAs exert their influence through complementary base-pairing with specific target mRNAs, leading to degradation or translational repression of the targeted mRNA. We have identified and tested a novel microRNA (miR-491) and demonstrated increased apoptosis in hepatocellular carcinoma cells (HepG2) and in human breast cancer cells (HBT3477) in vitro. We prepared a novel cancer targeting assembly of gold nanoparticles (GNP) with Quantum dots, miR-491, and MAb-ChL6 coupled through streptavidin/biotin for effective transfection, and to induce apoptosis in specific cancer cells for imaging and targeted therapy. The targeting and apoptosis inducing ability was tested by confocal and electron microscopy. The MAb-GNP-miR491-Qdot construct effectively transfected into the HBT3477 cells and induced apoptosis the confirmation of these results would suggest a new class of molecules for the imaging and therapy of breast cancer.

  9. Targeting the HOX/PBX dimer in breast cancer.

    PubMed

    Morgan, Richard; Boxall, Angie; Harrington, Kevin J; Simpson, Guy R; Gillett, Cheryl; Michael, Agnieszka; Pandha, Hardev S

    2012-11-01

    The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1-HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer.

  10. Luminal-B breast cancer and novel therapeutic targets

    PubMed Central

    2011-01-01

    Gene expression profiling has led to a new molecular classification of breast cancer characterized by four intrinsic subtypes: basal-like, HER2-positive, luminal A, and luminal B. Despite expressing estrogen receptor, the luminal-B subtype confers increased risk of early relapse with endocrine therapy compared with the luminal-A subtype. Although luminal-B definitions vary, the hallmark appears to be increased expression of proliferation-related genes. Several biological pathways are identified as possible contributors to the poor outcomes, and novel agents targeting these pathways are being developed with aims to improve survival. We review the definition of luminal-B breast cancer, its pathological and clinical features, and potential targets for treatment. PMID:22217398

  11. Optoacoustic imaging of gold nanoparticles targeted to breast cancer cells

    NASA Astrophysics Data System (ADS)

    Eghtedari, Mohammad; Motamedi, Massoud; Popov, Vsevolod L.; Kotov, Nicholas A.; Oraevsky, Alexander A.

    2004-07-01

    Optoacoustic Tomography (OAT) is a rapidly growing technology that enables noninvasive deep imaging of biological tissues based on their light absorption. In OAT, the interaction of a pulsed laser with tissue increases the temperature of the absorbing components in a confined volume of tissue. Rapid perturbation of the temperature (<1°C) deep within tissue produces weak acoustic waves that easily travel to the surface of the tissue with minor attenuation. Abnormal angiogenesis in a malignant tumor, that increases its blood content, makes a native contrast for optoacoustic imaging; however, the application of OAT for early detection of malignant tumors requires the enhancement of optoacoustic signals originated from tumor by using an exogenous contrast agent. Due to their strong absorption, we have used gold nanoparticles (NP) as a contrast agent. 40nm spherical gold nanoparticles were attached to monoclonal antibody to target cell surface of breast cancer cells. The targeted cancer cells were implanted at depth of 5-6cm within a gelatinous object that optically resembles human breast. Experimental sensitivity measurements along with theoretical analysis showed that our optoacoustic imaging system is capable of detecting a phantom breast tumor with the volume of 0.15ml, which is composed of 25 million NP-targeted cancer cells, at a depth of 5 centimeters in vitro.

  12. Therapeutic Implications of Targeting Energy Metabolism in Breast Cancer

    PubMed Central

    Sakharkar, Meena K.; Shashni, Babita; Sharma, Karun; Dhillon, Sarinder K.; Ranjekar, Prabhakar R.; Sakharkar, Kishore R.

    2013-01-01

    PPARs are ligand activated transcription factors. PPARγ agonists have been reported as a new and potentially efficacious treatment of inflammation, diabetes, obesity, cancer, AD, and schizophrenia. Since cancer cells show dysregulation of glycolysis they are potentially manageable through changes in metabolic environment. Interestingly, several of the genes involved in maintaining the metabolic environment and the central energy generation pathway are regulated or predicted to be regulated by PPARγ. The use of synthetic PPARγ ligands as drugs and their recent withdrawal/restricted usage highlight the lack of understanding of the molecular basis of these drugs, their off-target effects, and their network. These data further underscores the complexity of nuclear receptor signalling mechanisms. This paper will discuss the function and role of PPARγ in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer. PMID:23431283

  13. Targeted Gene Therapy for Breast Cancer

    DTIC Science & Technology

    2005-06-01

    or transduced son, WI). A mouse monoclonal anti-human VEGF with 100 multiplicities of infection (MOI) of rAAV-sFlt-l. receptor-1 (FIt-1 receptor...only partial amounts of the cancer patients correlate with advanced and metastatic deficient protein/enzyme for phenotypic correction of disease and...activity of matrix metalloproteinase. Cancer Res 2000;60: 4- sulfatase to the retinal pigment epithelium of feline mucopolysacchar- 5410-3. idosis VI. J Gene Med 2002;4:613-321.

  14. Engineering Remotely Triggered Liposomes to Target Triple Negative Breast Cancer

    PubMed Central

    Sneider, Alexandra; Jadia, Rahul; Piel, Brandon; VanDyke, Derek; Tsiros, Christopher; Rai, Prakash

    2017-01-01

    Triple Negative Breast Cancer (TNBC) continues to present a challenge in the clinic, as there is still no approved targeted therapy. TNBC is the worst sub-type of breast cancer in terms of prognosis and exhibits a deficiency in estrogen, progesterone, and human epidermal growth factor 2 (HER2) receptors. One possible option for the treatment of TNBC is chemotherapy. The issue with many chemotherapy drugs is that their effectiveness is diminished due to poor water solubility, and the method of administration directly or with a co-solvent intravenously can lead to an increase in toxicity. The issues of drug solubility can be avoided by using liposomes as a drug delivery carrier. Liposomes are engineered, biological nanoconstructs that possess the ability to encapsulate both hydrophobic and hydrophilic drugs and have been clinically approved to treat cancer. Specific targeting of cancer cell receptors through the use of ligands conjugated to the surface of drug-loaded liposomes could lessen damage to normal, healthy tissue. This study focuses on polyethylene glycol (PEG)-coated, folate conjugated, benzoporphyrin derivative (BPD)-loaded liposomes for treatment via photodynamic therapy (PDT). The folate receptor is over expressed on TNBC cells so these liposomes are targeted for greater uptake into cancer cells. PDT involves remotely irradiating light at 690 nm to trigger BPD, a hydrophobic photosensitive drug, to form reactive oxygen species that cause tumor cell death. BPD also displays a fluorescence signal when excited by light making it possible to image the fluorescence prior to PDT and for theranostics. In this study, free BPD, non-targeted and folate-targeted PEGylated BPD-loaded liposomes were introduced to a metastatic breast cancer cell line (MDA-MB-231) in vitro. The liposomes were reproducibly synthesized and characterized for size, polydispersity index (PDI), zeta potential, stability, and BPD release kinetics. Folate competition tests, fluorescence

  15. Breast cancer

    MedlinePlus

    ... of a direct link between breast cancer and pesticides. Symptoms Early breast cancer often does not cause ... breast cancer should not drink alcohol at all) Alternative Names Cancer - breast; Carcinoma - ductal; Carcinoma - lobular; DCIS; ...

  16. Targeted Therapies in Triple-Negative Breast Cancer

    PubMed Central

    Marmé, Frederik; Schneeweiss, Andreas

    2015-01-01

    Summary Triple-negative breast cancer (TNBC) is a heterogeneous disease comprised of several biologically distinct subtypes. However, treatment is currently mainly relying on chemotherapy as there are no targeted therapies specifically approved for TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. New targeted approaches are, therefore, urgently needed. Currently, bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF)-A antibody, is the only targeted agent with an approval for the therapy of metastatic breast cancer, but does not provide a specific benefit in the TNBC subtype. This review discusses the current clinical developments in targeted approaches for TNBC, including anti-angiogenic therapies, epidermal growth factor receptor (EGFR)-targeted therapies, poly(ADP-ribose) polymerase (PARP) inhibitors and platinum salts, as well as novel strategies using immune-checkpoint inhibitors, which have recently demonstrated first promising results. Strategies focusing on specific subtypes of TNBC like anti-androgenic therapies for the luminal androgen receptor subtype (LAR) and others are also discussed. PMID:26557820

  17. 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.

  18. 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

  19. Targeted multidrug delivery system to overcome chemoresistance in breast cancer

    PubMed Central

    Tang, Yuan; Soroush, Fariborz; Tong, Zhaohui; Kiani, Mohammad F; Wang, Bin

    2017-01-01

    Chemotherapy has been widely used in breast cancer patients to reduce tumor size. However, most anticancer agents cannot differentiate between cancerous and normal cells, resulting in severe systemic toxicity. In addition, acquired drug resistance during the chemotherapy treatment further decreases treatment efficacy. With the proper treatment strategy, nanodrug carriers, such as liposomes/immunoliposomes, may be able to reduce undesired side effects of chemotherapy, to overcome the acquired multidrug resistance, and to further improve the treatment efficacy. In this study, a novel combinational targeted drug delivery system was developed by encapsulating antiangiogenesis drug bevacizumab into liposomes and encapsulating chemotherapy drug doxorubicin (DOX) into immunoliposomes where the human epidermal growth factor receptor 2 (HER2) antibody was used as a targeting ligand. This novel combinational system was tested in vitro using a HER2 positive and multidrug resistant breast cancer cell line (BT-474/MDR), and in vivo using a xenograft mouse tumor model. In vitro cell culture experiments show that immunoliposome delivery led to a high cell nucleus accumulation of DOX, whereas free DOX was observed mostly near the cell membrane and in cytoplasm due to the action of P-gp. Combining liposomal bevacizumab with immunoliposomal DOX achieved the best tumor growth inhibition and the lowest toxicity. Tumor size decreased steadily within a 60-day observation period indicating a potential synergistic effect between DOX and bevacizumab through the targeted delivery. Our findings clearly indicate that tumor growth was significantly delayed in the combinational liposomal drug delivery group. This novel combinational therapy has great potential for the treatment of patients with HER2/MDR double positive breast cancer. PMID:28176940

  20. Targeting Thyroid Hormone Receptor Beta in Triple Negative Breast Cancer

    PubMed Central

    Gu, Guowei; Gelsomino, Luca; Covington, Kyle R.; Beyer, Amanda R.; Wang, John; Rechoum, Yassine; Huffman, Kenneth; Carstens, Ryan; Ando, Sebastiano; Fuqua, Suzanne A.W.

    2015-01-01

    Purpose Discover novel nuclear receptor targets in triple negative breast cancer Methods Expression microarray, western blot, qRT-PCR, MTT growth assay, soft agar anchorage-independent growth assay, TRE reporter transactivation assay, statistical analysis. Results We performed microarray analysis using 227 triple negative breast tumors, and clustered the tumors into five groups according to their nuclear receptor expression. Thyroid hormone receptor beta (TRβ) was one of the most differentially expressed nuclear receptors in group 5 compared to other groups. TRβ low expressing patients were associated with poor outcome. We evaluated the role of TRβ in triple negative breast cancer cell lines representing group 5 tumors. Knockdown of TRβ increased soft agar colony and reduced sensitivity to docetaxel and doxorubicin treatment. Docetaxel or doxorubicin long-term cultured cell lines also expressed decreased TRβ protein. Microarray analysis revealed cAMP/PKA signaling was the only KEGG pathways upregulated in TRβ knockdown cells. Inhibitors of cAMP or PKA, in combination with doxorubicin further enhanced cell apoptosis and restored sensitivity to chemotherapy. TRβ-specific agonists enhanced TRβ expression, and further sensitized cells to both docetaxel and doxorubicin. Sensitization was mediated by increased apoptosis with elevated cleaved PARP and caspase 3. Conclusions TRβ represents a novel nuclear receptor target in triple negative breast cancer; low TRβ levels were associated with enhanced resistance to both docetaxel and doxorubicin treatment. TRβ-specific agonists enhance chemosensitivity to these two agents. Mechanistically enhanced cAMP/PKA signaling was associated with TRβ’s effects on response to chemotherapy. PMID:25820519

  1. Targeting CD81 to Prevent Metastases in Breast Cancer

    DTIC Science & Technology

    2015-10-01

    expression in breast cancer cells impairs the number of circulating tumor cells . The experiments were performed using a protocol that we standardized for...detection of circulating tumor cells in an immunocompetent syngeneic mouse model of breast cancer using FASTcell™ system. 15. SUBJECT TERMS Breast...cancer metastases, CD81, Circulating Tumor Cells (CTCs) 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF

  2. Seamless Integration of Detection and Therapy for Breast Cancer using Targeted Engineered Nanoparticles

    DTIC Science & Technology

    2007-06-01

    Therapy for Breast Cancer using Targeted Engineered Nanoparticles PRINCIPAL INVESTIGATOR: Naomi J. Halas, Ph.D. CONTRACTING...5a. CONTRACT NUMBER Seamless Integration of Detection and Therapy for Breast Cancer using Targeted Engineered Nanoparticles 5b. GRANT NUMBER... nanoparticles and studying the efficiency of nanoparticle attachment to cancer cells. We have demonstrated in mouse tumor models a number of diagnostic

  3. Bone marrow endothelium-targeted therapeutics for metastatic breast cancer.

    PubMed

    Mai, Junhua; Huang, Yi; Mu, Chaofeng; Zhang, Guodong; Xu, Rong; Guo, Xiaojing; Xia, Xiaojun; Volk, David E; Lokesh, Ganesh L; Thiviyanathan, Varatharasa; Gorenstein, David G; Liu, Xuewu; Ferrari, Mauro; Shen, Haifa

    2014-08-10

    Effective treatment of cancer metastasis to the bone relies on bone marrow drug accumulation. The surface proteins in the bone marrow vascular endothelium provide docking sites for targeted drug delivery. We have developed a thioaptamer that specifically binds to E-selectin that is overexpressed in the vasculature of tumor and inflammatory tissues. In this study, we tested targeted delivery of therapeutic siRNA loaded in the E-selectin thioaptamer-conjugated multistage vector (ESTA-MSV) drug carrier to bone marrow for the treatment of breast cancer bone metastasis. We evaluated tumor type- and tumor growth stage-dependent targeting in mice bearing metastatic breast cancer in the bone, and carried out studies to identify factors that determine targeting efficiency. In a subsequent study, we delivered siRNA to knock down expression of the human STAT3 gene in murine xenograft models of human MDA-MB-231 breast tumor, and assessed therapeutic efficacy. Our studies revealed that the CD31(+)E-selectin(+) population accounted for 20.8%, 26.4% and 29.9% of total endothelial cells respectively inside the femur of mice bearing early, middle and late stage metastatic MDA-MB-231 tumors. In comparison, the double positive cells remained at a basal level in mice with early stage MCF-7 tumors, and jumped to 23.9% and 28.2% when tumor growth progressed to middle and late stages. Accumulation of ESTA-MSV inside the bone marrow correlated with the E-selectin expression pattern. There was up to 5-fold enrichment of the targeted MSV in the bone marrow of mice bearing early or late stage MDA-MB-231 tumors and of mice with late stage, but not early stage, MCF-7 tumors. Targeted delivery of STAT3 siRNA in ESTA-MSV resulted in knockdown of STAT3 expression in 48.7% of cancer cells inside the bone marrow. Weekly systemic administration of ESTA-MSV/STAT3 siRNA significantly extended survival of mice with MDA-MB-231 bone metastasis. In conclusion, targeting the overexpressed E

  4. 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

  5. B7-H4 as a Target for Breast Cancer Immunotherapy

    DTIC Science & Technology

    2013-06-01

    AD_________________ Award Number: W81XWH-11-1-0466 TITLE: B7-H4 as a Target for Breast Cancer ...COVERED 1 June 2011 - 31 May 2013 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER B7-H4 as a Target for Breast Cancer Immunotherapy 5b. GRANT NUMBER...immune escape generated in breast cancer . Here we report the generation of 84 mouse monoclonal antibodies for the detection of B7-H4 by ELISA, 25 for

  6. Review: Receptor Targeted Nuclear Imaging of Breast Cancer.

    PubMed

    Dalm, Simone U; Verzijlbergen, John Fred; De Jong, Marion

    2017-01-26

    Receptor targeted nuclear imaging directed against molecular markers overexpressed on breast cancer (BC) cells offers a sensitive and specific method for BC imaging. Currently, a few targets such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), somatostatin receptor (SSTR), and the gastrin releasing peptide receptor (GRPR) are being investigated for this purpose. Expression of these targets is BC subtype dependent and information that can be gained from lesion visualization is dependent on the target; ER-targeting radiotracers, e.g., can be used to monitor response to anti-estrogen treatment. Here we give an overview of the studies currently under investigation for receptor targeted nuclear imaging of BC. Main findings of imaging studies are summarized and (potential) purposes of lesion visualization by targeting these molecular markers are discussed. Since BC is a very heterogeneous disease and molecular target expression can vary per subtype, but also during disease progression or under influence of treatment, radiotracers for selected imaging purposes should be chosen carefully.

  7. Review: Receptor Targeted Nuclear Imaging of Breast Cancer

    PubMed Central

    Dalm, Simone U.; Verzijlbergen, John Fred; De Jong, Marion

    2017-01-01

    Receptor targeted nuclear imaging directed against molecular markers overexpressed on breast cancer (BC) cells offers a sensitive and specific method for BC imaging. Currently, a few targets such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), somatostatin receptor (SSTR), and the gastrin releasing peptide receptor (GRPR) are being investigated for this purpose. Expression of these targets is BC subtype dependent and information that can be gained from lesion visualization is dependent on the target; ER-targeting radiotracers, e.g., can be used to monitor response to anti-estrogen treatment. Here we give an overview of the studies currently under investigation for receptor targeted nuclear imaging of BC. Main findings of imaging studies are summarized and (potential) purposes of lesion visualization by targeting these molecular markers are discussed. Since BC is a very heterogeneous disease and molecular target expression can vary per subtype, but also during disease progression or under influence of treatment, radiotracers for selected imaging purposes should be chosen carefully. PMID:28134770

  8. "Targeting" triple-negative breast cancer: the lessons learned from BRCA1-associated breast cancers.

    PubMed

    Nanda, Rita

    2011-04-01

    Breast cancer has long been recognized as a heterogeneous entity, with distinct subsets characterized by differences in tumor biology and response to therapy. With the advent of molecular profiling, we have gained a further appreciation of the heterogeneity of this complex disease. While the last decade has seen advances in the treatment of hormone receptor (HR) and human epidermal growth factor receptor 2/erb-B2 (HER2)-positive breast cancers, outcomes for women with estrogen receptor (ER)-, progesterone receptor (PR)-, and HER2-negative-or "triple-negative"-breast cancer (TNBC) remain poor. A better understanding of the shared biology of BRCA1-associated breast cancer and sporadic TNBC holds much promise for changing the outlook for women with this aggressive disease. This review focuses on our current understanding of the clinicopathological features of TNBC, therapeutic options and ongoing research efforts.

  9. Targeting aberrant expression of Notch-1 in ALDH(+) cancer stem cells in breast cancer.

    PubMed

    Pal, Deeksha; Kolluru, Venkatesh; Chandrasekaran, Balaji; Baby, Becca V; Aman, Masarath; Suman, Suman; Sirimulla, Suman; Sanders, Mary Ann; Alatassi, Houda; Ankem, Murali K; Damodaran, Chendil

    2017-03-01

    We have previously reported that high aldehyde dehydrogenase (ALDH) enzyme activity in breast cancer cells results in breast cancer stem cell (BCSC) properties by upregualting Notch-1 and epithelial mesenchymal markers. This results in chemoresistance in breast cancer. Here, we examined the functional and clinical significance of ALDH expression by measuring the ALDH levels in breast cancer tissues by immunohistochemistry. There was a significantly higher ALDH expression in higher grade breast cancer tumor tissues (Grade- II and III) versus normal breast tissues. Injection of BCSC (ALDH(+) and CD44(+) /CD22(-) ) cells resulted in aggressive tumor growth in athymic mice versus ALDH(-) cells. The ALDH(+) and CD44(+) /CD22(-) tumors grow rapidly and are larger than ALDH(-) tumors which were slow growing and smaller. Molecularly, ALDH(+) tumors expressed higher expression of Notch-1 and EMT markers than ALDH(-) tumors. Oral administration of the naturally occurring Psoralidin (Pso, 25 mg/kg of body weight) significantly inhibited the growth in ALDH(+) and ALDH(-) tumors as well. Psoralidin inhibited Notch-1 mediated EMT activation in ALDH(+) and ALDH(-) tumors-this confirms our in vitro findings. Our results suggest that Notch-1 could be an attractive target and inhibition of Notch-1 by Psoralidin may prevent pathogenesis of breast cancer as well as metastasis. © 2016 Wiley Periodicals, Inc.

  10. Seamless Integration of Detection and Therapy for Breast Cancer using Targeted Engineered Nanoparticles

    DTIC Science & Technology

    2008-06-01

    and shell structures that can be further engineered to have highly controlled and ‘tunable’ properties. These include paramagnetic nanoparticles , which...Therapy for Breast Cancer using Targeted Engineered Nanoparticles PRINCIPAL INVESTIGATOR: Naomi J. Halas, Ph.D. CONTRACTING...5a. CONTRACT NUMBER Seamless Integration of Detection and Therapy for Breast Cancer using Targeted Engineered Nanoparticles 5b. GRANT NUMBER

  11. Human Progesterone A-Form as a Target for New Drug Discovery in Human Breast Cancer

    DTIC Science & Technology

    2001-07-01

    Progesterone A-Form as a Target for New Drug Discovery in Human Breast Cancer PRINCIPAL INVESTIGATOR: James Voltz Paloma Giangrande Donald McDonnell, Ph.D...SUBTITLE 5. FUNDING NUMBERS Human Progesterone A-Form as a Target for New Drug DAMD17-98-1-8070 Discovery in Human Breast Cancer 6. AUTHOR(S) James

  12. Insights into Orphan Nuclear Receptors as Prognostic Markers and Novel Therapeutic Targets for Breast Cancer

    PubMed Central

    Aesoy, Reidun; Clyne, Colin D.; Chand, Ashwini L.

    2015-01-01

    There is emerging evidence asserting the importance of orphan nuclear receptors (ONRs) in cancer initiation and progression. In breast cancer, there is a lot unknown about ONRs in terms of their expression profile and their transcriptional targets in the various stages of tumor progression. With the classification of breast tumors into distinct molecular subtypes, we assess ONR expression in the different breast cancer subtypes and with patient outcomes. Complementing this, we review evidence implicating ONR-dependent molecular pathways in breast cancer progression to identify candidate ONRs as potential prognostic markers and/or as therapeutic targets. PMID:26300846

  13. Mitochondrial targeted catalase suppresses invasive breast cancer in mice

    PubMed Central

    2011-01-01

    Background Treatment of invasive breast cancer has an alarmingly high rate of failure because effective targets have not been identified. One potential target is mitochondrial generated reactive oxygen species (ROS) because ROS production has been associated with changes in substrate metabolism and lower concentration of anti-oxidant enzymes in tumor and stromal cells and increased metastatic potential. Methods Transgenic mice expressing a human catalase gene (mCAT) were crossed with MMTV-PyMT transgenic mice that develop metastatic breast cancer. All mice (33 mCAT positive and 23 mCAT negative) were terminated at 110 days of age, when tumors were well advanced. Tumors were histologically assessed for invasiveness, proliferation and metastatic foci in the lungs. ROS levels and activation status of p38 MAPK were determined. Results PyMT mice expressing mCAT had a 12.5 per cent incidence of high histological grade primary tumor invasiveness compared to a 62.5 per cent incidence in PyMT mice without mCAT. The histological grade correlated with incidence of metastasis with 56 per cent of PyMT mice positive for mCAT showing evidence of pulmonary metastasis compared to 85.4 per cent of PyMT mice negative for mCAT with pulmonary metastasis (p ≤ 0.05). PyMT tumor cells expressing mCAT had lower ROS levels and were more resistant to hydrogen peroxide-induced oxidative stress than wild type tumor cells, suggesting that mCAT has the potential of quenching intracellular ROS and subsequent invasive behavior. The metastatic tumor burden in PyMT mice expressing mCAT was 0.1 mm2/cm2 of lung tissue compared with 1.3 mm2/cm2 of lung tissue in PyMT mice expressing the wild type allele (p ≤ 0.01), indicating that mCAT could play a role in mitigating metastatic tumor progression at a distant organ site. Expression of mCAT in the lungs increased resistance to hydrogen peroxide-induced oxidative stress that was associated with decreased activation of p38MAPK suggesting ROS signaling

  14. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody

    DTIC Science & Technology

    2013-05-01

    Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody PRINCIPAL INVESTIGATOR: Ulrich Bickel...of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody 5b. GRANT NUMBER W81XWH-12-1-0184 5c. PROGRAM ELEMENT NUMBER 6...tumors using a brain selective cell line, 231-BR, derived from human breast cancer . Therefore, the experimental model to be used must be immune

  15. 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.

  16. Proteogenomic integration reveals therapeutic targets in breast cancer xenografts

    PubMed Central

    Huang, Kuan-lin; Li, Shunqiang; Mertins, Philipp; Cao, Song; Gunawardena, Harsha P.; Ruggles, Kelly V.; Mani, D. R.; Clauser, Karl R.; Tanioka, Maki; Usary, Jerry; Kavuri, Shyam M.; Xie, Ling; Yoon, Christopher; Qiao, Jana W; Wrobel, John; Wyczalkowski, Matthew A.; Erdmann-Gilmore, Petra; Snider, Jacqueline E.; Hoog, Jeremy; Singh, Purba; Niu, Beifung; Guo, Zhanfang; Sun, Sam Qiancheng; Sanati, Souzan; Kawaler, Emily; Wang, Xuya; Scott, Adam; Ye, Kai; McLellan, Michael D.; Wendl, Michael C.; Malovannaya, Anna; Held, Jason M.; Gillette, Michael A.; Fenyö, David; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry; Davies, Sherri R.; Perou, Charles M.; Ma, Cynthia; Reid Townsend, R.; Chen, Xian; Carr, Steven A.; Ellis, Matthew J.; Ding, Li

    2017-01-01

    Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities. PMID:28348404

  17. Targeted Agents Active Against Breast Cancer: Q&A

    Cancer.gov

    ALTTO was a clinical trial designed to determine whether the combination of the monoclonal antibody trastuzumab (Herceptin) and the drug lapatinib (Tykerb) was more effective in treating HER2/ErbB2-positive breast cancer when combined with chemotherapy.

  18. Targeting Notch degradation system provides promise for breast cancer therapeutics.

    PubMed

    Liu, Jing; Shen, Jia-Xin; Wen, Xiao-Fen; Guo, Yu-Xian; Zhang, Guo-Jun

    2016-08-01

    Notch receptor signaling pathways play an important role, not only in normal breast development but also in breast cancer development and progression. As a group of ligand-induced proteins, different subtypes of mammalian Notch (Notch1-4) are sensitive to subtle changes in protein levels. Thus, a clear understanding of mechanisms of Notch protein turnover is essential for understanding normal and pathological mechanisms of Notch functions. It has been suggested that there is a close relationship between the carcinogenesis and the dysregulation of Notch degradation. However, this relationship remains mostly undefined in the context of breast cancer, as protein degradation is mediated by numerous signaling pathways as well as certain molecule modulators (activators/inhibitors). In this review, we summarize the published data regarding the regulation of Notch family member degradation in breast cancer, while emphasizing areas that are likely to provide new therapeutic modalities for mechanism-based anti-cancer drugs.

  19. Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

    DTIC Science & Technology

    2013-08-01

    collaboration with our colleague Dr. Chun Li, an outstanding leader in nanotechnology , we aimed to develop nanoparticles that can carry in vivo imaging...Pɘ.001. Task 4b. To develop nanoparticles to kill RSR-defective breast cancer cells through their binding to the RSR-defect-specific membrane...proteins on cancer cells. We have created the nanoparticles that can specifically bind to RSR-defect breast cells. We will continue to optimize

  20. Targeting the UPR to Circumvent Endocrine Resistance in Breast Cancer

    DTIC Science & Technology

    2015-10-01

    effects will be mediated in part by the inhibition of XBP1 splicing and its ability to regulate BCL2 family members and NFκB. Furthermore, a...and prevent survival (via pro-survival autophagy and an inhibition of apoptosis). We hypothesize that these effects will be mediated in part by the...synergistically to selectively kill AE resistant breast cancer cells in vitro and in vivo. KEYWORDS Breast Cancer, Drug Development, Endocrine

  1. Development of Biodegradable Zinc Oxide Nanowires Targeting Breast Cancer Metastasis

    DTIC Science & Technology

    2013-09-01

    potential as a new diagnostic and therapeutic strategy to combat the extremely aggressive TNB that is associated with poor prognosis. Figures... rat anti-mouse CD31 antibody and Cy3-labeled donkey anti- rat IgG (red). Immunofluorescence CD105/CD31 staining of various tissues ex vivo revealed...breast cancer. Hum Pathol, 2013. 44(11): p. 2581-9. 6. Imbert, A.M., et al., CD146 expression in human breast cancer cell lines induces phenotypic and

  2. Targeting the APOBEC3B-Induced Mutation Showers in Breast Cancer

    DTIC Science & Technology

    2015-06-01

    instability is one of the hallmarks of breast cancer and fuels tumor development as well as metastasis. Recent cancer genomics studies have revealed...8 4 1. Introduction Genomic instability is a hallmark of cancer , and it provides an opportunity for cancer therapy. Recent...AWARD NUMBER: W81XWH-14-1-0082 TITLE: Targeting the APOBEC3B-Induced Mutation Showers in Breast Cancer PRINCIPAL INVESTIGATOR: Lee Zou

  3. Cell-specific biomarkers and targeted biopharmaceuticals for breast cancer treatment.

    PubMed

    Liu, Mei; Li, Zhiyang; Yang, Jingjing; Jiang, Yanyun; Chen, Zhongsi; Ali, Zeeshan; He, Nongyue; Wang, Zhifei

    2016-08-01

    Breast cancer is the second leading cause of cancer death among women, and its related treatment has been attracting significant attention over the past decades. Among the various treatments, targeted therapy has shown great promise as a precision treatment, by binding to cancer cell-specific biomarkers. So far, great achievements have been made in targeted therapy of breast cancer. In this review, we first discuss cell-specific biomarkers, which are not only useful for classification of breast cancer subtyping but also can be utilized as goals for targeted therapy. Then, the innovative and generic-targeted biopharmaceuticals for breast cancer, including monoclonal antibodies, non-antibody proteins and small molecule drugs, are reviewed. Finally, we provide our outlook on future developments of biopharmaceuticals, and provide solutions to problems in this field.

  4. 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.

  5. Personalizing Aspirin Use for Targeted Breast Cancer Chemoprevention Among Postmenopausal Women

    PubMed Central

    Bardia, Aditya; Keenan, Tanya E.; Ebbert, Jon O.; Lazovich, DeAnn; Wang, Alice H.; Vierkant, Robert A.; Olson, Janet E.; Vachon, Celine M.; Limburg, Paul J.; Anderson, Kristin E.; Cerhan, James R.

    2016-01-01

    Objective To better understand the potential risk/benefit ratio for targeted chemoprevention, we evaluated the association of aspirin and other NSAIDs with incidence of postmenopausal breast cancer for risk subgroups defined by selected non-modifiable or difficult-to-modify breast cancer risk factors. Patients and Methods Postmenopausal women with no history of cancer on July 1, 1992 (N=26,580) were prospectively followed through December 31, 2005 for breast cancer incidence (N=1581). Risk subgroups were defined on family history of breast cancer, age at menarche, age at menopause, parity/age at first live birth, history of benign breast disease, and body mass index (BMI). Hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for other breast cancer risk factors were estimated using Cox models. Results Aspirin use was associated with a lower incidence of breast cancer for women with family history of breast cancer (HR=0.62 for 6+ per week vs. never use; 95%CI 0.41-0.93) and personal history of benign breast disease (HR=0.69; 95%CI 0.50-0.95), but not for women in higher risk subgroups for age at menarche, age at menopause, parity/age at first live birth or BMI. In contrast, inverse associations with aspirin use were observed in all lower risk subgroups. NSAID use had no association with breast cancer incidence. Conclusion Based on their increased risk of breast cancer, postmenopausal women with a family history of breast cancer or a history of benign breast disease could potentially be targeted for aspirin chemoprevention studies. Future studies are needed to confirm these findings. PMID:26678006

  6. Histamine H4 receptor: insights into a potential therapeutic target in breast cancer.

    PubMed

    Martinel Lamas, Diego J; Rivera, Elena S; Medina, Vanina A

    2015-06-01

    Breast cancer is the second most common cancer worldwide, and the leading cause of cancer death in women. Several studies underlined the critical role of histamine in breast cancer development and progression. This review addresses the latest evidence regarding the involvement of histamine and histamine receptors in breast cancer, focusing particularly in the histamine H4 receptor (H4R). Histamine concentration in breast cancer tissues was found to be higher than that in normal tissues of healthy controls by means of an increase in the activity of histidine decarboxylase (HDC), the enzyme involved in histamine production. The expression of H4R in different experimental models and human biopsies, the associated biological responses, as well as the in vivo treatment of experimental tumors with H4R ligands is reviewed. Evidence demonstrates that the H4R exhibits a key role in histamine-mediated biological processes such as cell proliferation, senescence and apoptosis in breast cancer. The polymorphisms of the H4R and HDC genes and their association with breast cancer risk and malignancy reinforce the critical (patho)physiological role of H4R in breast cancer. In addition, H4R agonists display anti-tumor effects in vivo in a triple negative breast cancer model. The findings support the exploitation of the H4R as a molecular target for breast cancer drug development.

  7. What Is Breast Cancer?

    MedlinePlus

    ... Research? Breast Cancer About Breast Cancer What Is Breast Cancer? Breast cancer starts when cells in the breast ... spread, see our section on Cancer Basics . Where breast cancer starts Breast cancers can start from different parts ...

  8. 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

  9. Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets

    PubMed Central

    Koizume, Shiro; Miyagi, Yohei

    2014-01-01

    Breast cancer is a leading cause of cancer death in women, worldwide. Fortunately, breast cancer is relatively chemosensitive, with recent advances leading to the development of effective therapeutic strategies, significantly increasing disease cure rate. However, disease recurrence and treatment of cases lacking therapeutic molecular targets, such as epidermal growth factor receptor 2 and hormone receptors, referred to as triple-negative breast cancers, still pose major hurdles in the treatment of breast cancer. Thus, novel therapeutic approaches to treat aggressive breast cancers are essential. Blood coagulation factor VII (fVII) is produced in the liver and secreted into the blood stream. Tissue factor (TF), the cellular receptor for fVII, is an integral membrane protein that plays key roles in the extrinsic coagulation cascade. TF is overexpressed in breast cancer tissues. The TF-fVII complex may be formed in the absence of injury, because fVII potentially exists in the tissue fluid within cancer tissues. The active form of this complex (TF-fVIIa) may stimulate the expression of numerous malignant phenotypes in breast cancer cells. Thus, the TF-fVII pathway is a potentially attractive target for breast cancer treatment. To date, a number of studies investigating the mechanisms by which TF-fVII signaling contributes to breast cancer progression, have been conducted. In this review, we summarize the mechanisms controlling TF and fVII synthesis and regulation in breast cancer cells. Our current understanding of the TF-fVII pathway as a mediator of breast cancer progression will be also described. Finally, we will discuss how this knowledge can be applied to the design of future therapeutic strategies. PMID:25493229

  10. A review on current nanomaterials and their drug conjugate for targeted breast cancer treatment

    PubMed Central

    Lee, Joanna Jinling; Saiful Yazan, Latifah; Che Abdullah, Che Azurahanim

    2017-01-01

    Breast cancer is the most common malignancy worldwide, especially among women, with substantial after-treatment effects. The survival rates of breast cancer have decreased over the years even with the existence of various therapeutic strategies, specifically, chemotherapy. Clinical drugs administered for breast cancer appear to be non-targeting to specific cancer sites leading to severe side effects and potentially harming healthy cells instead of just killing cancer cells. This leads to the need for designing a targeted drug delivery system. Nanomaterials, both organic and inorganic, are potential drug nanocarriers with the ability of targeting, imaging and tracking. Various types of nanomaterials have been actively researched together with their drug conjugate. In this review, we focus on selected nanomaterials, namely solid-lipid, liposomal, polymeric, magnetic nanoparticles, quantum dots, and carbon nanotubes and their drug conjugates, for breast cancer studies. Their advantages, disadvantages and previously conducted studies were highlighted. PMID:28392694

  11. Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer.

    PubMed

    Yu, Min; Li, Ruishu; Zhang, Juan

    2016-03-18

    Targeting mitochondrial biogenesis has become a potential therapeutic strategy in cancer due to their unique metabolic dependencies. In this study, we show that levofloxacin, a FDA-approved antibiotic, is an attractive candidate for breast cancer treatment. This is achieved by the inhibition of proliferation and induction of apoptosis in a panel of breast cancer cell lines while sparing normal breast cells. It also acts synergistically with conventional chemo drug in two independent in vivo breast xenograft mouse models. Importantly, levofloxacin inhibits mitochondrial biogenesis as shown by the decreased level of mitochondrial respiration, membrane potential and ATP. In addition, the anti-proliferative and pro-apoptotic effects of levofloxacin are reversed by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), confirming that levofloxacin's action in breast cancer cells is through inhibition of mitochondrial biogenesis. A consequence of mitochondrial biogenesis inhibition by levofloxacin in breast cancer cells is the deactivation of PI3K/Akt/mTOR and MAPK/ERK pathways. We further demonstrate that breast cancer cells have increased mitochondrial biogenesis than normal breast cells, and this explains their different sensitivity to levofloxacin. Our work suggest that levofloxacin is a useful addition to breast cancer treatment. Our work also establish the essential role of mitochondrial biogenesis on the activation of PI3K/Akt/mTOR and MAPK/ERK pathways in breast cancer cells.

  12. Targeted therapies with companion diagnostics in the management of breast cancer: current perspectives.

    PubMed

    Myers, Meagan B

    2016-01-01

    Breast cancer is a multifaceted disease exhibiting both intertumoral and intratumoral heterogeneity as well as variable disease course. Over 2 decades of research has advanced the understanding of the molecular substructure of breast cancer, directing the development of new therapeutic strategies against these actionable targets. In vitro diagnostics, and specifically companion diagnostics, have been integral in the successful development and implementation of these targeted therapies, such as those directed against the human epidermal growth factor receptor 2. Lately, there has been a surge in the development, commercialization, and marketing of diagnostic assays to assist in breast cancer patient care. More recently, multigene signature assays, such as Oncotype DX, MammaPrint, and Prosigna, have been integrated in the clinical setting in order to tailor decisions on adjuvant endocrine and chemotherapy treatment. This review provides an overview of the current state of breast cancer management and the use of companion diagnostics to direct personalized approaches in the treatment of breast cancer.

  13. Proinflammatory cytokines in breast cancer: mechanisms of action and potential targets for therapeutics.

    PubMed

    Goldberg, Jodi E; Schwertfeger, Kathryn L

    2010-09-01

    Inflammation within the tumor microenvironment correlates with increased invasiveness and poor prognosis in many types of cancer, including breast cancer. The cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha) and interleukin-1 beta (IL-1beta) are critical mediators of the inflammatory response. Numerous studies have also linked these cytokines to breast cancer progression. As a result, the mechanisms by which these cytokines promote breast cancer have been recently explored using both in vitro and in vivo models. The results from these studies have led to speculation regarding the possible usefulness of targeting these cytokines in breast cancer patients. This review summarizes the most recent studies pertaining to the mechanisms by which proinflammatory cytokines promote breast cancer. Furthermore, the possibilities of targeting these inflammatory mediators in breast cancer patients using inhibitors that are currently being used in the clinic for other inflammatory conditions are discussed. Understanding both the mechanisms by which inflammatory mediators promote breast cancer and the effectiveness of anti-inflammatory drugs in treating breast cancer will lead to novel therapeutic regimens to treat this devastating disease.

  14. Targeting Protein O-GlcNAc Modifications In Breast Cancer

    DTIC Science & Technology

    2010-09-30

    vivo (months 6-12, PI:Reginato): Preliminary studies indicate elevated O-GlcNAc in ERBB2 transformed cells, and suggest that lowering O-GlcNAc levels...proteins (with OGT RNAi or OGT inhibitor) inhibits oncogenic phenotypes in vivo (months 6-12, PI:Reginato): Preliminary studies indicate elevated O...agar) of ERBB2 expressing MCF-10A cells and breast cancer cell lines (SKBR3 and MDA-MB-453). (months 1-3) Our studies completed Breast cancer cell

  15. The innate and adaptive infiltrating immune systems as targets for breast cancer immunotherapy.

    PubMed

    Law, Andrew M K; Lim, Elgene; Ormandy, Christopher J; Gallego-Ortega, David

    2017-04-01

    A cancer cell-centric view has long dominated the field of cancer biology. Research efforts have focussed on aberrant cancer cell signalling pathways and on changes to cancer cell DNA. Mounting evidence demonstrates that many cancer-associated cell types within the tumour stroma co-evolve and support tumour growth and development, greatly modifying cancer cell behaviour, facilitating invasion and metastasis and controlling dormancy and sensitivity to drug therapy. Thus, these stromal cells represent potential targets for cancer therapy. Among these cell types, immune cells have emerged as a promising target for therapy. The adaptive and the innate immune system play an important role in normal mammary development and breast cancer. The number of infiltrating adaptive immune system cells with tumour-rejecting capacity, primarily, T lymphocytes, is lower in breast cancer compared with other cancer types, but infiltration occurs in a large proportion of cases. There is strong evidence demonstrating the importance of the immunosuppressive role of the innate immune system during breast cancer progression. A consideration of components of both the innate and the adaptive immune system is essential for the design and development of immunotherapies in breast cancer. In this review, we focus on the importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) as potential targets for breast cancer therapy.

  16. Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance?

    PubMed Central

    Williams, Michelle M.; Cook, Rebecca S.

    2015-01-01

    Apoptosis, cell death executed by caspases, is essential to normal breast development and homeostasis. Pro-apoptotic and anti-apoptotic signals are tightly regulated in normal breast epithelial cells. Dysregulation of this balance is required for breast tumorigenesis and increases acquired resistance to treatments, including molecularly targeted therapies, radiation and chemotherapies. The pro-apoptotic or anti-apoptotic Bcl-2 family members interact with each other to maintain mitochondrial integrity and regulate cellular commitment to apoptosis. Among the anti-apoptotic Bcl-2 family members, Mcl-1 is uniquely regulated by numerous oncogenic signaling pathways. This review will focus on the role of Bcl-2 family proteins in normal breast development, breast tumorigenesis and acquired resistance to breast cancer treatment strategies, while highlighting Mcl-1 as a promising target to improve breast cancer tumor cell killing. PMID:25784482

  17. Plasma Membrane Proteomics of Human Breast Cancer Cell Lines Identifies Potential Targets for Breast Cancer Diagnosis and Treatment

    PubMed Central

    Ziegler, Yvonne S.; Moresco, James J.; Tu, Patricia G.; Yates, John R.; Nardulli, Ann M.

    2014-01-01

    The use of broad spectrum chemotherapeutic agents to treat breast cancer results in substantial and debilitating side effects, necessitating the development of targeted therapies to limit tumor proliferation and prevent metastasis. In recent years, the list of approved targeted therapies has expanded, and it includes both monoclonal antibodies and small molecule inhibitors that interfere with key proteins involved in the uncontrolled growth and migration of cancer cells. The targeting of plasma membrane proteins has been most successful to date, and this is reflected in the large representation of these proteins as targets of newer therapies. In view of these facts, experiments were designed to investigate the plasma membrane proteome of a variety of human breast cancer cell lines representing hormone-responsive, ErbB2 over-expressing and triple negative cell types, as well as a benign control. Plasma membranes were isolated by using an aqueous two-phase system, and the resulting proteins were subjected to mass spectrometry analysis. Overall, each of the cell lines expressed some unique proteins, and a number of proteins were expressed in multiple cell lines, but in patterns that did not always follow traditional clinical definitions of breast cancer type. From our data, it can be deduced that most cancer cells possess multiple strategies to promote uncontrolled growth, reflected in aberrant expression of tyrosine kinases, cellular adhesion molecules, and structural proteins. Our data set provides a very rich and complex picture of plasma membrane proteins present on breast cancer cells, and the sorting and categorizing of this data provides interesting insights into the biology, classification, and potential treatment of this prevalent and debilitating disease. PMID:25029196

  18. The transcriptional modulator BCL6 as a molecular target for breast cancer therapy

    PubMed Central

    Walker, Sarah R.; Liu, Suhu; Xiang, Michael; Nicolais, Maria; Hatzi, Katerina; Giannopoulou, Eugenia; Elemento, Olivier; Cerchietti, Leandro; Melnick, Ari; Frank, David A.

    2014-01-01

    Inappropriate expression or activation of transcription factors can drive patterns of gene expression leading to the malignant behavior of breast cancer cells. We have found that the transcriptional repressor BCL6 is highly expressed in breast cancer cell lines, and its locus is amplified in about half of primary breast cancers. To understand how BCL6 regulates gene expression in breast cancer cells, we utilized ChIP-seq to identify the BCL6 binding sites on a genomic scale. This revealed that BCL6 regulates a unique cohort of genes in breast cancer cell lines compared to B cell lymphomas. Furthermore, BCL6 expression promotes the survival of breast cancer cells, and targeting BCL6 with a peptidomimetic inhibitor leads to apoptosis of these cells. Finally, combining a BCL6 inhibitor and a STAT3 inhibitor provided enhanced cell killing in triple negative breast cancer cell lines, suggesting that combination therapy may be particularly useful. Thus, targeting BCL6 alone or in conjunction with other signaling pathways may be a useful therapeutic strategy for treating breast cancer. PMID:24662818

  19. Targeting the Ron-DEK Signaling Axis in Breast Cancer

    DTIC Science & Technology

    2014-09-01

    cells from human head and neck squamous cell carcinomas (Supplementary Figures S6B and C...mediated positive regulation of β-catenin in both breast cancer and head and neck squamous cell carcinomas , which suggests that this oncogenic mechanism...cancer cell lines and in primary head and neck squamous cell carcinoma cells (Supplementary Figure S6D), which agrees with previous reports in

  20. Lewis Y Antigen as a Target for Breast Cancer Therapy

    DTIC Science & Technology

    1998-09-01

    that peptide mimotopes of adenocarcinomac associated carbohydrate forms that include Lewis Y may function4as a breast cancer vaccine , 3.) established the...the feasibility of peptide mimotopes and design requirements for their use as potential vaccine surrogates for carbohydrate antigens in future vaccine ...understanding mechanisms associated with the utility of peptide mimotopes for vaccine efficacy, priming with mimicking peptides might establish beneficial

  1. A Partnership Training Program: Studying Targeted Drug Delivery Using Nanoparticles in Breast Cancer Diagnosis and Therapy

    DTIC Science & Technology

    2013-10-01

    TITLE: A Partnership Training Program: Studying Targeted Drug Delivery Using Nanoparticles in Breast Cancer Diagnosis and Therapy PRINCIPAL...Drug Delivery Using Nanoparticles in Breast Cancer Diagnostics and Therapy 5a. CONTRACT NUMBER W81XWH-10-1-0767 5b. GRANT NUMBER 5c. PROGRAM...graduate and 3 undergraduate students from 7 departments at the Howard University have been trained in the use of nanoparticles as targeted drug

  2. Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

    DTIC Science & Technology

    2011-09-01

    finished the task 1 - To synthesize and optimize folic-acid- or LHRHfunctionalized charge reversal nanoparticles . The cationic polymer PEI and its block...proposal is to develop nuclear localizing nanoparticles to delivery DNA-toxins breast cancer cell nuclei to effectively overcoming the drug resistance. We...copolymer. This polymer was used to fabricate the nanoparticles . The ideal nanoparticles with optimal sizes and acid-triggered negative-to-positive

  3. A Systems Biology Approach to Evaluate Ezrin as a Therapeutic Target in Breast Cancer

    DTIC Science & Technology

    2009-10-01

    cancers. Existing breast cancer therapies target proteins whose effects are limited to certain subsets of breast cancer patients. We hypothesize that...characterization of the major cross-reacting allergens from the pollen of Parthenium hysterophorus". Madurai Kamaraj University, Madurai, India 1989...allergen in Parthenium pollen . J. Allergy Clin. Immunol. 98:903-912. Neetu Gupta, P. Sriramarao, R. Kori, and P. V. Subba Rao. 1995. Immunochemical

  4. miR-455 inhibits breast cancer cell proliferation through targeting CDK14.

    PubMed

    Wang, Bing; Zou, Aimei; Ma, Liqiang; Chen, Xiong; Wang, Lie; Zeng, Ximing; Tan, Ting

    2017-03-11

    Breast cancer is the most frequently occurring cancer in women worldwide, microRNAs (miRNAs) play critical role in the initiation and progression of breast cancer. Here, we studied the effect of miR-455 on cell proliferation of breast cancer, and found that miR-455 was downregulated in breast cancer tissues and cells. Its overexpression inhibited cell proliferation, whereas its knockdown promoted cell proliferation of breast cancer. We found a Cdc2-related protein kinase CDK14 was the target of miR-455, when the 3(')UTR of CDK14 was cloned into luciferase reporter vector and transfected into cells, miR-455 mimic could inhibit the luciferase activity in a dose-dependent manner, miR-455 inhibitor increased the luciferase activity, but the mutant miR-455 mimic couldn't change the luciferase activity, suggesting miR-455 directly bound to the 3(')UTR of CDK14. Meanwhile, we also found miR-455 inhibited Cyclin D1 expression and promoted p21 expression, confirming miR-455 inhibited cell proliferation. Double knockdown of miR-455 and CDK14 inhibited the proliferation of breast cancer cell, confirming miR-455 inhibiting cell proliferation by targeting CDK14. Moreover, miR-455 levels were negatively correlated with CDK14 levels in breast cancer tissues. Our finding revealed miR-455 inhibits breast cancer cell proliferation through targeting CDK14, it might be a target for breast cancer therapy.

  5. Inorganic Nanovehicle Targets Tumor in an Orthotopic Breast Cancer Model

    NASA Astrophysics Data System (ADS)

    Choi, Goeun; Kwon, Oh-Joon; Oh, Yeonji; Yun, Chae-Ok; Choy, Jin-Ho

    2014-03-01

    The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis.

  6. Targeted Drug Delivery Systems Mediated by a Novel Peptide in Breast Cancer Therapy and Imaging

    PubMed Central

    Chiu, Chien-Yu; Lin, Wei-Chuan; Yan, Shin-Long; Wang, Yi-Ping; Kuo, Yuan-Sung; Yeh, Chen-Yun; Lo, Albert; Wu, Han-Chung

    2013-01-01

    Targeted delivery of drugs to tumors represents a significant advance in cancer diagnosis and therapy. Therefore, development of novel tumor-specific ligands or pharmaceutical nanocarriers is highly desirable. In this study, we utilized phage display to identify a new targeting peptide, SP90, which specifically binds to breast cancer cells, and recognizes tumor tissues from breast cancer patients. We used confocal and electron microscopy to reveal that conjugation of SP90 with liposomes enables efficient delivery of drugs into cancer cells through endocytosis. Furthermore, in vivo fluorescent imaging demonstrated that SP90-conjugated quantum dots possess tumor-targeting properties. In tumor xenograft and orthotopic models, SP90-conjugated liposomal doxorubicin was found to improve the therapeutic index of the chemotherapeutic drug by selectively increasing its accumulation in tumors. We conclude that the targeting peptide SP90 has significant potential in improving the clinical benefits of chemotherapy in the treatment and the diagnosis of breast cancer. PMID:23776619

  7. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-12-01

    INVESTIGATOR: Rolf A. Brekken CONTRACTING ORGANIZATION: U niveristy of Texas Southwestern Medical Center Dallas, TX 75390-9105 REPORT DATE: December...COVERED (From - To) 30 Sep 2012 - 29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Phosphatidylserine for Radioimmunotherapy of Breast...antibody, PGN635, a fully human monoclonal antibody, was used to target exposed PS in the brain metastases. Our data show that PGN635 binds specifically

  8. mTOR function and therapeutic targeting in breast cancer

    PubMed Central

    Hare, Stephen H; Harvey, Amanda J

    2017-01-01

    The mTOR pathway was discovered in the late 1970s after the compound and natural inhibitor of mTOR, rapamycin was isolated from the bacterium Streptomyces hygroscopicus. mTOR is serine/threonine kinase belonging to the phosphoinositide 3-kinase related kinase (PIKK) family. It forms two distinct complexes; mTORC1 and mTORC2. mTORC1 has a key role in regulating protein synthesis and autophagy whilst mTORC2 is involved in regulating kinases of the AGC family. mTOR signaling is often over active in multiple cancer types including breast cancer. This can involve mutations in mTOR itself but more commonly, in breast cancer, this is related to an increase in activity of ErbB family receptors or alterations and mutations of PI3K signaling. Rapamycin and its analogues (rapalogues) bind to the intercellular receptor FKBP12, and then predominantly inhibit mTORC1 signaling via an allosteric mechanism. Research has shown that inhibition of mTOR is a useful strategy in tackling cancers, with it acting to slow tumor growth and limit the spread of a cancer. Rapalogues have now made their way into the clinic with the rapalogue everolimus (RAD-001/Afinitor) approved for use in conjunction with exemestane, in post-menopausal breast cancer patients with advanced disease who are HER-2 negative (normal expression), hormone receptor positive and whose prior treatment with non-steroidal aromatase inhibitors has failed. Testing across multiple trials has proven that everolimus and other rapalogues are a viable way of treating certain types of cancer. However, rapalogues have shown some drawbacks both in research and clinically, with their use often activating feedback pathways that counter their usefulness. As such, new types of inhibitors are being explored that work via different mechanisms, including inhibitors that are ATP competitive with mTOR and which act to perturb signaling from both mTOR complexes.

  9. S14 as a Therapeutic Target in Breast Cancer

    DTIC Science & Technology

    2006-08-01

    cases that are likely to recur. 15. SUBJECT TERMS fatty acids, metabolism, tumor markers 16. SECURITY CLASSIFICATION OF: 18. NUMBER OF PAGES...cells containing the S14 construct or empty vector. Four mg of T47D cell extract was used in the TAP in each case , and 25% of the purified protein...in examples shown). Patients- We studied 131 breast cancer cases consecutively diagnosed at Dartmouth in 1997-98; 44 ductal carcinomas in situ

  10. Targeting the Ron-DEK Signaling Axis in Breast Cancer

    DTIC Science & Technology

    2014-09-01

    cells from human head and neck squamous cell carcinomas (Supplementary Figures S6B and C), thus...positive regulation of β-catenin in both breast cancer and head and neck squamous cell carcinomas , which suggests that this oncogenic mechanism may be... cell lines and in primary head and neck squamous cell carcinoma cells (Supplementary Figure S6D), which agrees with previous reports in human

  11. Targeting Histone Abnormality in Triple Negative Breast Cancer

    DTIC Science & Technology

    2015-08-01

    possesses a critical oncogenic function in driving breast cancer development. Moreover, teams of the two PIs collaborated to study the combinatorial...tumorigenesis. To study the role of LSD1/HDACs axis in promoting transformation of TNBC (Aim 1A), gain- and loss-of- function of MCF10A progression model was...used. We observed that HDAC5 possessed a critical oncogenic function in driving TNBC development through blocking LSD1 protein degradation and re

  12. Targeting One-Carbon Metabolism in Breast Cancer

    DTIC Science & Technology

    2014-04-01

    gene and association studies with diabetes and diabetic nephropathy . Mol Genet Metab 82, 321–328. Elenbaas, B. (2001). Human breast cancer cells... Diabetic Nephropathy , and Increased GFPT2 mRNA Levels. Journal of Clinical Endocrinology & Metabolism 89, 748–755. 48 Zhang, W.C., Shyh-Chang, N...Twist (HMLE-Twist-ER) following treatment with hydroxytamoxifen (OHT) (Mani et al., 2008; Taube et al., 2010). Over a 15-day treatment with OHT, the

  13. Phytochemicals for breast cancer prevention by targeting aromatase.

    PubMed

    Adams, Lynn S; Chen, Shiuan

    2009-01-01

    Aromatase is a cytochrome P450 enzyme (CYP19) and is the rate limiting enzyme in the conversion of androgens to estrogens. Suppression of in situ estrogen production through aromatase inhibition is the current treatment strategy for hormone-responsive breast cancers. Drugs that inhibit aromatase have been developed and are currently utilized as adjuvant therapy for breast cancer in post-menopausal women with hormone dependent breast cancer. Natural compounds have been studied extensively for important biologic effects such as antioxidant, anti-tumor and anti-viral effects. A significant number of studies have also investigated the aromatase inhibitory properties of a variety of plant extracts and phytochemicals. The identification of natural compounds that inhibit aromatase could be useful both from a chemopreventive standpoint and in the development of new aromatase inhibitory drugs. This review will discuss whole food extracts and the common classes of phytochemicals which have been investigated for potential aromatase inhibitory activity. We will review reported aromatase inhibition, kinetic data and possible structural variations that may inhibit or enhance the interaction of phytochemicals with the aromatase enzyme.

  14. Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer

    PubMed Central

    Gasparyan, Mari; Xu, Fangying; Jiang, Hui; Lin, Chang-Ching; Myers, Ila; Korkaya, Hasan; Liu, Yajing; Connarn, Jamie; He, Huining; Zhang, Ning; Wicha, Max S.; Sun, Duxin

    2016-01-01

    Continued use of trastuzumab in PTEN-deficient HER2+ breast cancer induces the epithelial-to-mesenchymal transition (EMT), transforms HER2+ to triple negative breast cancer, and expands breast cancer stem cells (BCSCs). Using cancer cell lines with two distinct states, epithelial and mesenchymal, we identified novel targets during EMT in PTEN-deficient trastuzumab-resistant breast cancer. Differential gene expression and distinct responses to a small molecule in BT474 (HER2+ trastuzumab-sensitive) and the PTEN-deficient trastuzumab-resistant derivative (BT474-PTEN-LTT) provided the selection tools to identify targets during EMT. siRNA knockdown and small molecule inhibition confirmed MEOX1 as one of the critical molecular targets to regulate both BCSCs and mesenchymal-like cell proliferation. MEOX1 was associated with poor survival, lymph node metastasis, and stage of breast cancer patients. These findings suggest that MEOX1 is a clinically relevant novel target in BCSCs and mesenchymal-like cancer cells in PTEN-deficient trastuzumab resistant breast cancer and may serve as target for future drug development. PMID:27285982

  15. Breast Cancer Detection by B7-H3-Targeted Ultrasound Molecular Imaging.

    PubMed

    Bachawal, Sunitha V; Jensen, Kristin C; Wilson, Katheryne E; Tian, Lu; Lutz, Amelie M; Willmann, Jürgen K

    2015-06-15

    Ultrasound complements mammography as an imaging modality for breast cancer detection, especially in patients with dense breast tissue, but its utility is limited by low diagnostic accuracy. One emerging molecular tool to address this limitation involves contrast-enhanced ultrasound using microbubbles targeted to molecular signatures on tumor neovasculature. In this study, we illustrate how tumor vascular expression of B7-H3 (CD276), a member of the B7 family of ligands for T-cell coregulatory receptors, can be incorporated into an ultrasound method that can distinguish normal, benign, precursor, and malignant breast pathologies for diagnostic purposes. Through an IHC analysis of 248 human breast specimens, we found that vascular expression of B7-H3 was selectively and significantly higher in breast cancer tissues. B7-H3 immunostaining on blood vessels distinguished benign/precursors from malignant lesions with high diagnostic accuracy in human specimens. In a transgenic mouse model of cancer, the B7-H3-targeted ultrasound imaging signal was increased significantly in breast cancer tissues and highly correlated with ex vivo expression levels of B7-H3 on quantitative immunofluorescence. Our findings offer a preclinical proof of concept for the use of B7-H3-targeted ultrasound molecular imaging as a tool to improve the diagnostic accuracy of breast cancer detection in patients.

  16. Targeting Breast Cancer Recurrence via Hedgehog-Mediated Sensitization of Breast Cancer Stem Cells

    DTIC Science & Technology

    2011-07-01

    force these cells back into the cell cycle, possibly sensitizing them to adjuvant cancer therapeutics. To test this hypothesis we developed three...force these cells back into the cell cycle, possibly sensitizing them to adjuvant cancer therapeutics. To test this hypothesis we developed three...canonical hedgehog target gene, Patched1, was not altered in response to oral-gavage of Smoothened agonists. In vitro testing of the compounds

  17. Tc-99m Labeled and VIP-Receptor Targeted Liposomes for Effective Imaging of Breast Cancer

    DTIC Science & Technology

    2006-09-01

    phospholipid mixed micelles to human breast cancer cells using quantum dots. CRS 2006. 15) Koo, O., Rubinstein, I., Onyuksel, H. Camptothecin in...Real time tracking of actively targeted phospholipid mixed micelles to human breast cancer cells using quantum dots. CRS 2006. 15) Koo, O... Shankar G, Townsend M, Fadeeva J, Betts V, et al. The role of cell derived oligomers of Ab in Alzheimers disease and avenues for therapeutic

  18. Targeting Sphingosine-1-Phosphate Axis in Obesity-Promoted Breast Cancer

    DTIC Science & Technology

    2015-05-01

    2011; 20: 454-63. 5. Pierobon M, Frankenfeld CL. Obesity as a risk factor for triple-negative breast cancers : a systematic review and meta-analysis...AWARD NUMBER: W81XWH-14-1-0071 TITLE: Targeting Sphingosine-1-Phosphate Axis in Obesity-Promoted Breast Cancer PRINCIPAL INVESTIGATOR...0704-0188 Public reporting burden for this collection of infoonation is esttmated to average 1 hour per response, including the time for reViewing

  19. Detecting and Targeting Oncogenic Myc in Breast Cancer

    DTIC Science & Technology

    2007-06-01

    androgen response genes in prostate cancer cells by coupling chromatin immunoprecipitation and genomic microarray analysis. Oncogene 2007. 18. Guo QM...have found that a non-coding RNA, H19, is a transcriptional target of MYC, and the inhibition of H19 transcription in cancer cells suppresses certain...morpholino oligomer (PMO), in the Le- wis lung carcinoma model [156]. AVI-4126 also inhibited growth of a murine prostate cancer xenograft by inducing

  20. 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

  1. Role of n-3 Polyunsaturated Fatty Acids and Exercise in Breast Cancer Prevention: Identifying Common Targets

    PubMed Central

    Abdelmagid, Salma A.; MacKinnon, Jessica L.; Janssen, Sarah M.; Ma, David W.L.

    2016-01-01

    Diet and exercise are recognized as important lifestyle factors that significantly influence breast cancer risk. In particular, dietary n-3 polyunsaturated fatty acids (PUFAs) have been shown to play an important role in breast cancer prevention. Growing evidence also demonstrates a role for exercise in cancer and chronic disease prevention. However, the potential synergistic effect of n-3 PUFA intake and exercise is yet to be determined. This review explores targets for breast cancer prevention that are common between n-3 PUFA intake and exercise and that may be important study outcomes for future research investigating the combined effect of n-3 PUFA intake and exercise. These lines of evidence highlight potential new avenues for research and strategies for breast cancer prevention. PMID:27812288

  2. Breast Cancer Overview

    MedlinePlus

    ... Cancer > Breast Cancer > Breast Cancer: Overview Request Permissions Breast Cancer: Overview Approved by the Cancer.Net Editorial Board , ... bean-shaped organs that help fight infection. About breast cancer Cancer begins when healthy cells in the breast ...

  3. Targeting Breast Cancers Featuring Activating Mutations in PIK3CA by Generating a Lethal Dose of PIP3

    DTIC Science & Technology

    2009-02-01

    AD_________________ AWARD NUMBER: W81XWH-06-1-0341 TITLE: Targeting Breast Cancers Featuring...ORGANIZATION: Dana-Farber Cancer Institute Boston, MA 02115 REPORT DATE...2006 – 31 Jan 2009 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Breast Cancers Featuring Activating Mutations in PIK3CA by Generating a

  4. Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells.

    PubMed

    Diessner, Joachim; Bruttel, Valentin; Becker, Kathrin; Pawlik, Miriam; Stein, Roland; Häusler, Sebastian; Dietl, Johannes; Wischhusen, Jörg; Hönig, Arnd

    2013-01-01

    Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of CD44(high)CD24(low)HER2(low) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells.

  5. Breast Cancer

    MedlinePlus

    Breast cancer affects one in eight women during their lives. No one knows why some women get breast cancer, but there are many risk factors. Risks that ... who have family members with breast or ovarian cancer may wish to be tested for the genes. ...

  6. Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells

    PubMed Central

    Guo, Shanchun; Liu, Mingli; Wang, Guangdi; Torroella-Kouri, Marta; Gonzalez-Perez, Ruben R.

    2012-01-01

    Significant correlations between obesity and incidence of various cancers have been reported. Obesity, considered a mild inflammatory process, is characterized by a high level of secretion of several cytokines from adipose tissue. These molecules have disparate effects, which could be relevant to cancer development. Among the inflammatory molecules, leptin, mainly produced by adipose tissue and overexpressed with its receptor (Ob-R) in cancer cells is the most studied adipokine. Mutations of leptin or Ob-R genes associated with obesity or cancer are rarely found. However, leptin is an anti-apoptotic molecule in many cell types, and its central roles in obesity-related cancers are based on its pro-angiogenic, pro-inflammatory and mitogenic actions. Notably, these leptin actions are commonly reinforced through entangled crosstalk with multiple oncogenes, cytokines and growth factors. Leptin-induced signals comprise several pathways commonly triggered by many cytokines (i.e, canonical: JAK2/STAT; MAPK/ERK1/2 and PI-3K/AKT1 and, non-canonical signaling pathways: PKC, JNK and p38 MAP kinase). Each of these leptin-induced signals is essential to its biological effects on food intake, energy balance, adiposity, immune and endocrine systems, as well as oncogenesis. This review is mainly focused on the current knowledge of the oncogenic role of leptin in breast cancer. Additionally, leptin pro-angiogenic molecular mechanisms and its potential role in breast cancer stem cells will be reviewed. Strict biunivocal binding-affinity and activation of leptin/Ob-R complex makes it a unique molecular target for prevention and treatment of breast cancer, particularly in obesity contexts. PMID:22289780

  7. Targeting the NFκB signaling pathways for breast cancer prevention and therapy.

    PubMed

    Wang, Wei; Nag, Subhasree A; Zhang, Ruiwen

    2015-01-01

    The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.

  8. Cancer Stem and Progenitor-Like Cells as Pharmacological Targets in Breast Cancer Treatment

    PubMed Central

    de Souza, Valéria B.; Schenka, André A.

    2015-01-01

    The present review is focused on the current role of neoplastic stem and progenitor-like cells as primary targets in the pharmacotherapy of cancer as well as in the development of new anticancer drugs. We begin by summarizing the main characteristics of these tumor-initiating cells and key concepts that support their participation in therapeutic failure. In particular, we discuss the differences between the major carcinogenesis models (ie, clonal evolution vs cancer stem cell (CSC) model) with emphasis on breast cancer (given its importance to the study of CSCs) and their implications for the development of new treatment strategies. In addition, we describe the main ways to target these cells, including the main signaling pathways that are more activated or altered in CSCs. Finally, we provide a comprehensive compilation of the most recently tested drugs. PMID:26609237

  9. Targeting of Breast Cancer through MT1-MMP/Tetraspanin Complexes

    DTIC Science & Technology

    2011-08-01

    breast cancer cells compared to normal breast cells, makes a major contribution towards breast cancer growth , invasion and metastasis. Another...that perturbation of tetraspanin proteins may provide an unconventional approach towards limiting the growth , invasion and metastasis of breast cancer...upregulated on the surface of breast cancer cells compared to normal breast cells, makes a major contribution towards breast cancer growth , invasion and

  10. Delineation of Supraclavicular Target Volumes in Breast Cancer Radiation Therapy

    SciTech Connect

    Brown, Lindsay C.; Diehn, Felix E.; Boughey, Judy C.; Childs, Stephanie K.; Park, Sean S.; Yan, Elizabeth S.; Petersen, Ivy A.; Mutter, Robert W.

    2015-07-01

    Purpose: To map the location of gross supraclavicular metastases in patients with breast cancer, in order to determine areas at highest risk of harboring subclinical disease. Methods and Materials: Patients with axial imaging of gross supraclavicular disease were identified from an institutional breast cancer registry. Locations of the metastatic lymph nodes were transferred onto representative axial computed tomography images of the supraclavicular region and compared with the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. Results: Sixty-two patients with 161 supraclavicular nodal metastases were eligible for study inclusion. At the time of diagnosis, 117 nodal metastases were present in 44 patients. Forty-four nodal metastases in 18 patients were detected at disease recurrence, 4 of whom had received prior radiation to the supraclavicular fossa. Of the 161 nodal metastases, 95 (59%) were within the RTOG consensus volume, 4 nodal metastases (2%) in 3 patients were marginally within the volume, and 62 nodal metastases (39%) in 30 patients were outside the volume. Supraclavicular disease outside the RTOG consensus volume was located in 3 regions: at the level of the cricoid and thyroid cartilage (superior to the RTOG volume), in the posterolateral supraclavicular fossa (posterolateral to the RTOG volume), and in the lateral low supraclavicular fossa (lateral to the RTOG volume). Only women with multiple supraclavicular metastases had nodal disease that extended superiorly to the level of the thyroid cartilage. Conclusions: For women with risk of harboring subclinical supraclavicular disease warranting the addition of supraclavicular radiation, coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted.

  11. A Target for Breast Cancer Prevention and Treatment

    DTIC Science & Technology

    2005-04-01

    by SXR activators, we treated MCF7 cells with 10 gM RIF, as well as the other SXR activators anadamide (ANA) and clotrimazole (CLO). Once again we...used CAMP as a positive control. As shown in Figure 2, we found that RIF, anandamide and clotrimazole were all able to induce apoptosis in MCF-7 cells...arrest. It is already known that the SXR activator clotrimazole can cause cell cycle arrest in the G1 phase and inhibit proliferation of breast cancer

  12. Brachyury promotes tamoxifen resistance in breast cancer by targeting SIRT1.

    PubMed

    Li, Kaichun; Ying, Mingzhen; Feng, Dan; Du, Jie; Chen, Shiyu; Dan, Bing; Wang, Cuihua; Wang, Yajie

    2016-12-01

    Tamoxifen is effective for treating estrogen receptor-alpha (ERα)-positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. In the present study, we determine the underlying roles of Brachyury in tamoxifen resistance. Loss- and gain-of-function assay are utilized to confirm the oncogenic roles of Brachyury in breast cancer. Compared with the normal MCF10A cells, Brachyury is commonly overexpressed in breast cancer cell lines. Knockdown of Brachyury inhibits tamoxifen resistance, whereas overexpression of Brachyury enhances tamoxifen resistance as demonstrated increased cell viability and reduced cell apoptosis. Mechanistically, we demonstrate for the first time that Brachyury mediates tamoxifen resistance by regulating Sirtuin-1 (SIRT1). Collectively, our data, as a proof of principle, indicate that Brachyury is a candidate marker for predicting the clinical efficacy of tamoxifen and targeting SIRT1 could overcome resistance to tamoxifen in breast cancer cells.

  13. Identification of vitamin D3 target genes in human breast cancer tissue.

    PubMed

    Sheng, Lei; Anderson, Paul H; Turner, Andrew G; Pishas, Kathleen I; Dhatrak, Deepak J; Gill, Peter G; Morris, Howard A; Callen, David F

    2016-11-01

    Multiple epidemiological studies have shown that high vitamin D3 status is strongly associated with improved breast cancer survival. To determine the molecular pathways influenced by 1 alpha, 25-dihydroxyvitamin D3 (1,25D) in breast epithelial cells we isolated RNA from normal human breast and cancer tissues treated with 1,25D in an ex vivo explant system. RNA-Seq revealed 523 genes that were differentially expressed in breast cancer tissues in response to 1,25D treatment, and 127 genes with altered expression in normal breast tissues. GoSeq KEGG pathway analysis revealed 1,25D down-regulated cellular metabolic pathways and enriched pathways involved with intercellular adhesion. The highly 1,25D up-regulated target genes CLMN, SERPINB1, EFTUD1, and KLK6were selected for further analysis and up-regulation by 1,25D was confirmed by qRT-PCR analysis in breast cancer cell lines and in a subset of human clinical samples from normal and cancer breast tissues. Ketoconazole potentiated 1,25D-mediated induction of CLMN, SERPINB1, and KLK6 mRNA through inhibition of 24-hydroxylase (CYP24A1) activity. Elevated expression levels of CLMN, SERPINB1, and KLK6 are associated with prolonged relapse-free survival for breast cancer patients. The major finding of the present study is that exposure of both normal and malignant breast tissue to 1,25D results in changes in cellular adhesion, metabolic pathways and tumor suppressor-like pathways, which support epidemiological data suggesting that adequate vitamin D3 levels may improve breast cancer outcome.

  14. Surgery for Breast Cancer

    MedlinePlus

    ... Pregnancy Breast Cancer Breast Cancer Treatment Surgery for Breast Cancer Surgery is a common treatment for breast cancer, ... Relieve symptoms of advanced cancer Surgery to remove breast cancer There are two main types of surgery to ...

  15. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    PubMed Central

    May, Felicity EB

    2014-01-01

    The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

  16. Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

    PubMed Central

    Segatto, Ilenia; Massarut, Samuele; Boyle, Robert; Baldassarre, Gustavo; Walker, David; Belletti, Barbara

    2016-01-01

    Breast cancer is a frequent and treatable disease. However, when recurrent, breast cancer often becomes refractory to therapy and progresses into metastatic forms that are typically incurable. Thus, understanding and targeting the critical pathways underlying breast cancer recurrence is urgently needed to eradicate primary disease and achieve better prognosis. Recently, we have demonstrated that the ribosomal protein p70S6K is activated in residual breast cancer cells as a result of post-surgical inflammation and that interfering with its activity in the peri-operative setting strongly suppresses recurrence in a mouse model. In order to develop clinically-exploitable treatments targeting p70S6K, we have tested a newly generated compound, called FS-115. FS-115 potently inhibited p70S6K1 (IC50 35nM) with high selectivity over other AGC kinases or PI3K pathway kinases. In vitro, treatment with FS-115 efficiently blocked p70S6K activity in breast cancer cell lines and impaired colony formation and anchorage independent growth. Pharmacokinetic profiling showed that FS-115 exhibited high oral bioavailability, optimal plasma distribution and high brain penetrance. In nude mice, FS-115 strongly suppressed tumor take-rate and primary tumor growth. Oral dosing with FS-115 in a peri-operative schedule was effective in decreasing local recurrence of breast cancer and a long-term treatment schedule was well tolerated and efficiently suppressed distant metastasis formation. Altogether, we propose that FS-115 might be a good candidate for the treatment of breast cancer patients at high risk to relapse. Summary Statement Our results confirm that inhibition of p70S6K represents a valuable opportunity for restraining loco-regional relapse and metastasis in breast cancer and identify in FS-115 a promising candidate-inhibitor to move from preclinical to clinical treatments. PMID:27155197

  17. SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases.

    PubMed

    Zhang, Siyuan; Huang, Wen-Chien; Zhang, Lin; Zhang, Chenyu; Lowery, Frank J; Ding, Zhaoxi; Guo, Hua; Wang, Hai; Huang, Suyun; Sahin, Aysegul A; Aldape, Kenneth D; Steeg, Patricia S; Yu, Dihua

    2013-09-15

    Despite better control of early-stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer and we show how Src-targeting combinatorial regimens can treat HER2(+) brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients' brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, an Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells through the induction of cell-cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat patients with breast cancer suffering from brain metastasis.

  18. Recent development of targeted approaches for the treatment of breast cancer.

    PubMed

    Maruthanila, V L; Elancheran, R; Kunnumakkara, A B; Kabilan, S; Kotoky, Jibon

    2017-03-01

    Breast cancer is the most prominent cause of cancer death in women worldwide. The highlights of this review are to provide an overview of the targeted therapeutic agents, challenges with metastatic breast cancer (MBCa), mechanisms of action through Hedgehog/Gli 1 signaling pathway and future prospective. Over a decade of success, several drugs have been approved and are in the advanced stages of clinical trials that target the receptors such as estrogen receptor, growth factor receptor, receptor activator of nuclear factor kappa-B, etc. Currently, several monoclonal antibodies are also used for the treatment of breast cancer. Advances in understanding tumor biology, particularly signaling pathways such as Notch signaling pathway, Hedgehog/Gli 1 signaling pathway, and inhibitors are considered to be important for bone metastasis. These studies may provide vital information for the design and development of new strategies with respect to efficacy, reduction of the side effects, and treatment strategies.

  19. Targeting the epigenetics of the DNA damage response in breast cancer

    PubMed Central

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

    2016-01-01

    Cancer is as much an epigenetic disease as it is a genetic disease, and epigenetic alterations in cancer often serve as potent surrogates for genetic mutations. Because the epigenetic factors involved in the DNA damage response are regulated by multiple elements, therapies to target specific components of the epigenetic machinery can be inefficient. In contrast, therapies aimed at inhibiting the methionine cycle can indirectly inhibit both DNA and protein methylation, and the wide variety of genes and pathways that are affected by these methylations make this global strategy very attractive. In the present study, we propose an adjuvant therapy that targets the epigenetics of the DNA damage response in breast cancer cells and that results in efficient apoptosis and a reduction in distant metastases in vivo. We observed that a combined therapy designed to uncouple adenosine metabolism using dipyridamole in the presence of a new synthetic antifolate, 3-O-(3,4,5-trimethoxybenzoyl)-(−)-catechin, simultaneously and efficiently blocked both the folic cycle and the methionine cycle in breast cancer cells and sensitized these cells to radiotherapy. The treatment impeded the recruitment of 53BP1 and BRCA1 to the chromatin regions flanking DNA double-strand breaks and thereby avoided the DNA damage responses in breast cancer cells that were exposed to ionizing radiation. In addition, this hypomethylating therapy was also efficient in reducing the self-renewal capability of breast cancer-initiating cells and induced reversion of mesenchymal phenotypes in breast cancer cells. PMID:27054335

  20. Recent developments and translational aspects in targeted therapy for metastatic breast cancer

    PubMed Central

    Marhold, Maximilian; Bartsch, Rupert; Zielinski, Christoph

    2016-01-01

    Biologically distinct subtypes of metastatic breast cancer (MBC) have been defined by multiple efforts in recent years, showing broad heterogeneity at the molecular level of disease. Throughout this endeavour, oncogenic drivers within MBC were identified as potential therapeutic targets. With recent results from clinical trials targeting these well-known cancer-promoting pathways, this review is trying to elucidate as well as summarise current new therapeutic aspects in MBC and shed light on translational aspects within this entity. PMID:27843605

  1. 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.

  2. A perspective on anti-EGFR therapies targeting triple-negative breast cancer

    PubMed Central

    Nakai, Katsuya; Hung, Mien-Chie; Yamaguchi, Hirohito

    2016-01-01

    Triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounts for about 15-20% of breast cancers and is the most aggressive breast cancer subtype. There are currently no effective therapies against metastatic TNBC. Compared with other breast cancer subtypes, EGFR is frequently overexpressed in TNBC and a potential therapeutic target for this disease. There are two types of EGFR inhibitors, small molecular tyrosine kinase inhibitor (TKI) and monoclonal antibody (mAb), for the treatment of cancers, such as non-small cell lung cancer and colorectal cancer. For breast cancer, however, the clinical trials of EGFR inhibitors have failed due to low response rates. Because a small portion of patients do demonstrate response to EGFR inhibitors, it may be necessary to stratify patients to enhance the efficacy of EGFR inhibitors in TNBC and to develop the effective combination therapy for this patient population. In this review, we describe some of the molecular mechanisms underlying EGFR inhibitor sensitivity and further discuss the possible therapeutic strategies to increase the efficacy of EGFR inhibitors in TNBC. PMID:27648353

  3. Concepts and targets in triple-negative breast cancer: recent results and clinical implications

    PubMed Central

    Saha, Poornima; Nanda, Rita

    2016-01-01

    Triple-negative breast cancer (TNBC) is a heterogeneous disease in which tumors are defined by lack of expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) receptor. No targeted therapies are available for the treatment of TNBC, and chemotherapy remains the standard of care. Gene expression profiling has identified six distinct molecular subtypes of TNBC. The identification of novel targets, coupled with the development of therapies for different subsets of TNBC, holds great promise for the future treatment of this aggressive form of breast cancer. This review focuses on novel therapies in development for the treatment of TNBC. PMID:27583027

  4. New Advances in Nanotechnology-Based Diagnosis and Therapeutics for Breast Cancer: An Assessment of Active-Targeting Inorganic Nanoplatforms.

    PubMed

    Falagan-Lotsch, Priscila; Grzincic, Elissa M; Murphy, Catherine J

    2017-01-18

    Breast cancer is a major cause of suffering and mortality among women. Limitations in the current diagnostic methods and treatment approaches have led to new strategies to positively impact the survival rates and quality of life of breast cancer patients. Nanotechnology offers a real possibility of mitigating breast cancer mortality by early-stage cancer detection and more precise diagnosis as well as more effective treatments with minimal side effects. The current nanoplatforms approved for breast cancer therapeutics are based on passive tumor targeting using organic nanoparticles and have not provided the expected significant improvements in the clinic. In this review, we present the emerging approaches in breast cancer nanomedicine based on active targeting using versatile inorganic nanoplatforms with biomedical relevance, such as gold, silica, and iron oxide nanoparticles, as well as their efficacy in breast cancer imaging, drug and gene delivery, thermal therapy, combinational therapy, and theranostics in preclinical studies. The main challenges for clinical translation and perspectives are discussed.

  5. Targeting apoptosis pathway with natural terpenoids: implications for treatment of breast and prostate cancer.

    PubMed

    Yang, Huanjie; Dou, Q Ping

    2010-06-01

    Terpenoids represent a large and diverse class of naturally occurring compounds found in a variety of fruits, vegetables and medicinal plants. Structurally some of the terpenoids are similar to human hormones. A diet rich in terpenoids is inversely related with the risk of chronic diseases including cancers. Breast and prostate cancers are hormone-related diseases and the second leading cause of female and male cancer mortality. Diterpenoid paclitaxel, and its semi-synthetic analogue docetaxel, have entered clinical use against established breast and prostate cancers. Here we reviewed potential molecular targets and biological properties of natural terpenoids, including monoterpenoids, diterpenoids, triterpenoids and tetraterpenoids, and their applications in treatment of human breast and prostate cancers. These terpenoids are able to inhibit tumor cell proliferation and induce tumor cell death by inhibiting multiple cancer-specific targets including the proteasome, NF-kappaB, and antiapoptotic protein Bcl-2. The efficacy of these terpenoids against breast or prostate cancer cells, as demonstrated in pre-clinical studies support clinical application of these naturally occurring terpenoids in treatment of hormone-related human cancers.

  6. Synthesis of a novel, sequentially active-targeted drug delivery nanoplatform for breast cancer therapy.

    PubMed

    Satsangi, Arpan; Roy, Sudipa S; Satsangi, Rajiv K; Tolcher, Anthony W; Vadlamudi, Ratna K; Goins, Beth; Ong, Joo L

    2015-08-01

    Breast cancer is the leading cause of cancer deaths among women. Paclitaxel (PTX), an important breast cancer medicine, exhibits reduced bioavailability and therapeutic index due to high hydrophobicity and indiscriminate cytotoxicity. PTX encapsulation in one-level active targeting overcomes such barriers, but enhances toxicity to normal tissues with cancer-similar expression profiles. This research attempted to overcome this challenge by increasing selectivity of cancer cell targeting while maintaining an ability to overcome traditional pharmacological barriers. Thus, a multi-core, multi-targeting construct for tumor specific delivery of PTX was fabricated with (i) an inner-core prodrug targeting the cancer-overexpressed cathepsin B through a cathepsin B-cleavable tetrapeptide that conjugates PTX to a poly(amidoamine) dendrimer, and (ii) the encapsulation of this prodrug (PGD) in an outer core of a RES-evading, folate receptor (FR)-targeting liposome. Compared to traditional FR-targeting PTX liposomes, this sequentially active-targeted dendrosome demonstrated better prodrug retention, an increased cytotoxicity to cancer cells (latter being true when FR and cathepsin B activities were both at moderate-to-high levels) and higher tumor reduction. This research may eventually evolve a product platform with reduced systemic toxicity inherent with traditional chemotherapy and localized toxicity inherent to single-target nanoplatforms, thereby allowing for better tolerance of higher therapeutic load in advanced disease states.

  7. Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

    DTIC Science & Technology

    2015-08-01

    oncogene activation or loss of tumor suppressor genes induces stalling and collapse of DNA replication forks, which in turn activates the replication...stress response (RSR) to maintain genome integrity [1-4]. RSR is a subset of the DNA damage response that safeguards the replication process [5]; defects...Taiwan, and one poster presentation by my postdoctoral fellow at the Conference of Exploring DNA Repair Pathways as Targets for Cancer at Cancun

  8. MicroRNA-495 induces breast cancer cell migration by targeting JAM-A.

    PubMed

    Cao, Minghui; Nie, Weiwei; Li, Jing; Zhang, Yujing; Yan, Xin; Guan, Xiaoxiang; Chen, Xi; Zen, Ke; Zhang, Chen-Yu; Jiang, Xiaohong; Hou, Dongxia

    2014-11-01

    MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression. The deregulated expression of miRNAs is associated with a variety of diseases, including breast cancer. In the present study, we found that miR-495 was markedly up-regulated in clinical breast cancer samples by quantitative real time-PCR (qRT-PCR). Junctional adhesion molecule A (JAM-A) was predicted to be a potential target of miR-495 by bioinformatics analysis and was subsequently verified by luciferase assay and Western blotting. JAM-A was found to be negatively correlated with the migration of breast cancer cells through loss-of-function and gain-of-function assays, and the inhibition of JAM-A by miR-495 promoted the migration of MCF-7 and MDA-MB-231 cells. Furthermore, overexpression of JAM-A could restore miR-495-induced breast cancer cell migration. Taken together, our findings suggest that miR-495 could facilitate breast cancer progression through the repression of JAM-A, making this miRNA a potential therapeutic target.

  9. FOXD1 promotes breast cancer proliferation and chemotherapeutic drug resistance by targeting p27

    SciTech Connect

    Zhao, Yi-Fan; Zhao, Jing-Yu; Yue, Hong; Hu, Ke-Shi; Shen, Hao; Guo, Zheng-Gang; Su, Xiao-Jun

    2015-01-02

    Highlights: • FOXD1 is up-regulated in breast cancer tissues. • FOXD1 promotes breast cancer cell proliferation and chemoresistance by inducing G1 to S transition. • FOXD1 transcriptionally suppresses p27 expression. - Abstract: Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. As a member of the forkhead family, FOXD1 is required during kidney development and its inactivation results in failure of nephron progenitor cells. However, the role of FOXD1 in carcinogenesis and progression is still limited. Here, we reported that FOXD1 is a potential oncogene in breast cancer. We found that FOXD1 is up-regulated in breast cancer tissues. Depletion of FOXD1 expression decreases the ability of cell proliferation and chemoresistance in MDA-MB-231 cells, whereas overexpression of FOXD1 increases the ability of cell proliferation and chemoresistance in MCF-7 cells. Furthermore, we observed that FOXD1 induces G1 to S phase transition by targeting p27 expression. Our results suggest that FOXD1 may be a potential therapy target for patients with breast cancer.

  10. CDK4 regulates cancer stemness and is a novel therapeutic target for triple-negative breast cancer

    PubMed Central

    Dai, Meiou; Zhang, Chenjing; Ali, Ayad; Hong, Xinyuan; Tian, Jun; Lo, Chieh; Fils-Aimé, Nadège; Burgos, Sergio A.; Ali, Suhad; Lebrun, Jean-Jacques

    2016-01-01

    Triple negative breast cancers exhibit very aggressive features and poor patient outcomes. These tumors are enriched in cancer stem cells and exhibit resistance to most treatments and chemotherapy. In this study, we found the cyclin-dependent kinase (CDK4) to act as a cancer stem cell regulator and novel prognostic marker in triple negative breast cancers. We found CDK4 to be highly expressed in these tumors and its expression to correlate with poor overall and relapse free survival outcomes, high tumor grade and poor prognostic features of triple negative breast cancer patients. Moreover, we found that blocking CDK4 expression or kinase activity, using a pharmacological inhibitor prevented breast cancer stem cell self-renewal. Interestingly, suppression of CDK4 expression or kinase activity reversed the basal-B TNBC mesenchymal phenotype to an epithelial- and luminal-like phenotype which correlates with better clinical prognosis. Finally, blocking CDK4 activity efficiently eliminated both normal and chemotherapy-resistant cancer cells in triple negative breast cancers, highlighting CDK4 as a promising novel therapeutic target for these aggressive breast tumors. PMID:27759034

  11. A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

    SciTech Connect

    Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young; Chun, Sung Hak; Han, Jeong Yun; Kim, Sung Dae; Lee, Janet; Lee, Chang-Woo; Yang, Kwangmo; Lee, Chang Geun

    2013-01-25

    Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24{sup −}/CD44{sup +}) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.

  12. miR-410-3p suppresses breast cancer progression by targeting Snail.

    PubMed

    Zhang, Ya-Feng; Yu, Yue; Song, Wang-Zhao; Zhang, Rui-Ming; Jin, Shan; Bai, Jun-Wen; Kang, Hong-Bin; Wang, Xin; Cao, Xu-Chen

    2016-07-01

    miR-410-3p acts as an oncogene or tumor-suppressor gene in various types of cancer. However, its role in breast cancer remains unknown. In the present study, expression of miR-410-3p in 30 breast cancer and paired adjacent normal tissues was detected by RT-qPCR. The expression of miR-410-3p was downregulated in 76.7% of the breast cancer samples. To further validate the expression of miR-410-3p in breast cancer, we analyzed miR-410-3p expression profiling data set from The Cancer Genome Atlas (TCGA) including 683 breast cancer and 87 normal breast tissues. We observed that the expression of miR-410-3p was downregulated in breast cancer tissues. Next, we investigated the influence of miR-410-3p on cell proliferation by transiently transfecting the miR-410-3p mimic or inhibitor, as well as their corresponding controls in the MDA-MB-231 and MCF7 cell lines. miR-410-3p overexpression reduced cell growth, colony formation and the number of EdU-positive cells in the MDA-MB-231 cells. In contrast, inhibition of miR-410-3p in the MCF7 cells resulted in a higher proliferation rate as assessed by MTT assay, plate colony formation and EdU assays. Furthermore, miR-410-3p inhibited epithelial-mesenchymal transition. In addition, Snail was found to be a direct target of miR-410-3p based on a luciferase assay. Overexpression of Snail was able to rescue the effect of miR-410-3p in breast cancer cells. Moreover, miR‑410-3p was inversely expressed with Snail in breast cancer samples. Our data provide new knowledge regarding the role of miR-410-3p in breast cancer progression.

  13. Natural Products as Promising Antitumoral Agents in Breast Cancer: Mechanisms of Action and Molecular Targets.

    PubMed

    Bonofiglio, Daniela; Giordano, Cinzia; De Amicis, Francesca; Lanzino, Marilena; Andò, Sebastiano

    2016-01-01

    Extensive research over the past several decades has identified numerous dietary and phytochemical compounds that have chemopreventive potential and could represent an important source of anti-cancer lead molecules. In this scenario several nutritional factors have attracted considerable attention as modifiable risk factor in the prevention of breast cancer, the most frequently diagnosed cancer and a major cause of death among women worldwide. There is an immediate need for more effective and less toxic therapeutic and preventive strategies for breast cancers able also to counteract the recurrent phenomenon of resistance to hormonal and targeted therapy that represent the first-line treatment in the management of breast cancer patients. The present review focuses on chemopreventive and anti-cancer activities of different bioactive compounds obtained from dietary sources such as Omega-3 fatty acids, naturally present in fish, Resveratrol (3,5,40-trihydroxy-transstilbene), a phytoalexin found in grapes and Epigallocatechin Gallate, a polyphenolic compound found in green tea, or purified from medicinal plant (Oldenlandia Diffusa) and fruits (Ziziphus Jujube) highlighting their potential use in breast cancer treatment. Herein, we discuss the molecular mechanisms by which the bioactive compounds can inhibit carcinogenesis by regulating antioxidant enzyme activities, and inducing antiproliferative and apoptotic effects in different breast cancer cell lines. Understanding the mechanism of action of dietary compounds or traditionally used herbs having potential preventive and therapeutic effects on cancer may provide a rationale for further translational studies. This review emphasizes the importance, in the next future, of a proper scientific validation of these natural bioactive compounds for clinical use in the therapeutic portfolio for breast cancer.

  14. MicroRNA-124 inhibits cellular proliferation and invasion by targeting Ets-1 in breast cancer.

    PubMed

    Li, Wentao; Zang, Wenqiao; Liu, Pei; Wang, Yuanyuan; Du, Yuwen; Chen, Xiaonan; Deng, Meng; Sun, Wencong; Wang, Lei; Zhao, Guoqiang; Zhai, Baoping

    2014-11-01

    MicroRNAs (miRNAs) are small non-coding RNAs that, by targeting certain messenger RNAs (mRNAs) for translational repression or cleavage, can regulate the expression of these genes. In addition, miRNAs may also function as oncogenes and tumor-suppressor genes, as the abnormal expression of miRNAs is associated with various human tumors. However, the effects of the expression of miR-124 in breast cancer remain unclear. The present study was conducted to study the expression of miR-124 in breast cancer, paying particular attention to miR-124's relation to the proliferation, invasion, and apoptosis in breast cancer cell MCF-7 and MDA-MB-231. Real-time quantitative RT-PCR (qRT-PCR) was performed to identify miR-124 that was down-regulated in breast cancer tissues. We also showed E26 transformation specific-1 (Ets-1) and miR-124 expression levels in breast cancer tissues that were associated with lymph node metastases. With transfected synthetic miR-124 agomir into MCF-7 and MDA-MB-231, a significant reduction (P < 0.05) in MCF-7 and MDA-MB-231 cell proliferation and colony forming potential was observed after treatment with miR-124. Apoptosis and migration rates were found to be significantly higher in two breast-derived cell lines transfected with a miR-124 agomir (P < 0.05). Luciferase reporter assay and Western blot were used to verify Ets-1 as a potential major target gene of miR-124, and the result showed that miR-124 can bind to putative binding sites within the Ets-1 mRNA 3' untranslated region (UTR) to reduce its expression. Based on these findings, we propose that miR-124 and Ets-1 may serve as a therapeutic agent in breast cancer.

  15. Mevalonate metabolism regulates Basal breast cancer stem cells and is a potential therapeutic target.

    PubMed

    Ginestier, Christophe; Monville, Florence; Wicinski, Julien; Cabaud, Olivier; Cervera, Nathalie; Josselin, Emmanuelle; Finetti, Pascal; Guille, Arnaud; Larderet, Gaelle; Viens, Patrice; Sebti, Said; Bertucci, François; Birnbaum, Daniel; Charafe-Jauffret, Emmanuelle

    2012-07-01

    There is increasing evidence that breast tumors are organized in a hierarchy, with a subpopulation of tumorigenic cancer cells, the cancer stem cells (CSCs), which sustain tumor growth. The characterization of protein networks that govern CSC behavior is paramount to design new therapeutic strategies targeting this subpopulation of cells. We have sought to identify specific molecular pathways of CSCs isolated from 13 different breast cancer cell lines of luminal or basal/mesenchymal subtypes. We compared the gene expression profiling of cancer cells grown in adherent conditions to those of matched tumorsphere cultures. No specific pathway was identified to be commonly regulated in luminal tumorspheres, resulting from a minor CSC enrichment in tumorsphere passages from luminal cell lines. However, in basal/mesenchymal tumorspheres, the enzymes of the mevalonate metabolic pathway were overexpressed compared to those in cognate adherent cells. Inhibition of this pathway with hydroxy-3-methylglutaryl CoA reductase blockers resulted in a reduction of breast CSC independent of inhibition of cholesterol biosynthesis and of protein farnesylation. Further modulation of this metabolic pathway demonstrated that protein geranylgeranylation (GG) is critical to breast CSC maintenance. A small molecule inhibitor of the geranylgeranyl transferase I (GGTI) enzyme reduced the breast CSC subpopulation both in vitro and in primary breast cancer xenografts. We found that the GGTI effect on the CSC subpopulation is mediated by inactivation of Ras homolog family member A (RHOA) and increased accumulation of P27(kip1) in the nucleus. The identification of protein GG as a major contributor to CSC maintenance opens promising perspectives for CSC targeted therapy in basal breast cancer.

  16. Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics.

    PubMed

    Bollig-Fischer, Aliccia; Michelhaugh, Sharon K; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

    2015-06-10

    Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.

  17. Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer

    PubMed Central

    Takai, Ken; Le, Annie; Weaver, Valerie M.; Werb, Zena

    2016-01-01

    Increased collagen expression in tumors is associated with increased risk of metastasis, and triple-negative breast cancer (TNBC) has the highest propensity to develop distant metastases when there is evidence of central fibrosis. Transforming growth factor-β (TGF-β) ligands regulated by cancer-associated fibroblasts (CAFs) promote accumulation of fibrosis and cancer progression. In the present study, we have evaluated TNBC tumors with enhanced collagen to determine whether we can reduce metastasis by targeting the CAFs with Pirfenidone (PFD), an anti-fibrotic agent as well as a TGF-β antagonist. In patient-derived xenograft models, TNBC tumors exhibited accumulated collagen and activated TGF-β signaling, and developed lung metastasis. Next, primary CAFs were established from 4T1 TNBC homograft tumors, TNBC xenograft tumors and tumor specimens of breast cancer patients. CAFs promoted primary tumor growth with more fibrosis and TGF-β activation and lung metastasis in 4T1 mouse model. We then examined the effects of PFD in vitro and in vivo. We found that PFD had inhibitory effects on cell viability and collagen production of CAFs in 2D culture. Furthermore, CAFs enhanced tumor growth and PFD inhibited the tumor growth induced by CAFs by causing apoptosis in the 3D co-culture assay of 4T1 tumor cells and CAFs. In vivo, PFD alone inhibited tumor fibrosis and TGF-β signaling but did not inhibit tumor growth and lung metastasis. However, PFD inhibited tumor growth and lung metastasis synergistically in combination with doxorubicin. Thus, PFD has great potential for a novel clinically applicable TNBC therapy that targets tumor-stromal interaction. PMID:27756881

  18. Trastuzumab-Conjugated Liposome-Coated Fluorescent Magnetic Nanoparticles to Target Breast Cancer

    PubMed Central

    Jang, Mijung; Yoon, Young Il; Kwon, Yong Soo; Yoon, Tae-Jong; Lee, Hak Jong; Hwang, Sung Il; Yun, Bo La

    2014-01-01

    Objective To synthesize mesoporous silica-core-shell magnetic nanoparticles (MNPs) encapsulated by liposomes (Lipo [MNP@m-SiO2]) in order to enhance their stability, allow them to be used in any buffer solution, and to produce trastuzumab-conjugated (Lipo[MNP@m-SiO2]-Her2Ab) nanoparticles to be utilized in vitro for the targeting of breast cancer. Materials and Methods The physiochemical characteristics of Lipo[MNP@m-SiO2] were assessed in terms of size, morphological features, and in vitro safety. The multimodal imaging properties of the organic dye incorporated into Lipo[MNP@m-SiO2] were assessed with both in vitro fluorescence and MR imaging. The specific targeting ability of trastuzumab (Her2/neu antibody, Herceptin®)-conjugated Lipo[MNP@m-SiO2] for Her2/neu-positive breast cancer cells was also evaluated with fluorescence and MR imaging. Results We obtained uniformly-sized and evenly distributed Lipo[MNP@m-SiO2] that demonstrated biological stability, while not disrupting cell viability. Her2/neu-positive breast cancer cell targeting by trastuzumab-conjugated Lipo[MNP@m-SiO2] was observed by in vitro fluorescence and MR imaging. Conclusion Trastuzumab-conjugated Lipo[MNP@m-SiO2] is a potential treatment tool for targeted drug delivery in Her2/neu-positive breast cancer. PMID:25053899

  19. Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

    PubMed Central

    Toss, Angela; Venturelli, Marta; Peterle, Chiara; Piacentini, Federico; Cascinu, Stefano; Cortesi, Laura

    2017-01-01

    In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer. PMID:28054957

  20. Antibody-Mediated BRCC36 Silencing: A Novel Approach for Targeted Breast Cancer Therapy

    DTIC Science & Technology

    2009-06-01

    complexes: new targets to overcome breast cancer radiation resistance. Expert Rev Anticancer Ther 6(2):187-96. Chen X, Arciero CA, Wang C, Broccoli D...1752s- 1756s. Chen X, Arciero CA, Wang C, Broccoli D, Godwin AK (2006). BRCC36 is essential for ionizing radiation-induced BRCA1 phosphorylation

  1. Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer.

    PubMed

    Merino, D; Lok, S W; Visvader, J E; Lindeman, G J

    2016-04-14

    The last three decades have seen significant progress in our understanding of the role of the pro-survival protein BCL-2 and its family members in apoptosis and cancer. BCL-2 and other pro-survival family members including Mcl-1 and BCL-XL have been shown to have a key role in keeping pro-apoptotic 'effector' proteins BAK and BAX in check. They also neutralize a group of 'sensor' proteins (such as BIM), which are triggered by cytotoxic stimuli such as chemotherapy. BCL-2 proteins therefore have a central role as guardians against apoptosis, helping cancer cells to evade cell death. More recently, an increasing number of BH3 mimetics, which bind and neutralize BCL-2 and/or its pro-survival relatives, have been developed. The utility of targeting BCL-2 in hematological malignancies has become evident in early-phase studies, with remarkable clinical responses seen in heavily pretreated patients. As BCL-2 is overexpressed in ~75% of breast cancer, there has been growing interest in determining whether this new class of drug could show similar promise in breast cancer. This review summarizes our current understanding of the role of BCL-2 and its family members in mammary gland development and breast cancer, recent progress in the development of new BH3 mimetics as well as their potential for targeting estrogen receptor-positive breast cancer.

  2. Breast cancer screening

    MedlinePlus

    Mammogram - breast cancer screening; Breast exam - breast cancer screening; MRI - breast cancer screening ... performed to screen women to detect early breast cancer when it is more likely to be cured. ...

  3. SF3B1 mutations constitute a novel therapeutic target in breast cancer.

    PubMed

    Maguire, Sarah L; Leonidou, Andri; Wai, Patty; Marchiò, Caterina; Ng, Charlotte Ky; Sapino, Anna; Salomon, Anne-Vincent; Reis-Filho, Jorge S; Weigelt, Britta; Natrajan, Rachael C

    2015-03-01

    Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes, chronic lymphocytic leukaemia, uveal melanoma, and pancreatic cancer, and at lower frequencies in breast cancer. To investigate whether dysfunction in RNA splicing is implicated in the pathogenesis of breast cancer, we performed a re-analysis of published exome and whole genome sequencing data. This analysis revealed that mutations in spliceosomal component genes occurred in 5.6% of unselected breast cancers, including hotspot mutations in the SF3B1 gene, which were found in 1.8% of unselected breast cancers. SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation. RNA sequencing identified differentially spliced events expressed in tumours with SF3B1 mutations including the protein coding genes TMEM14C, RPL31, DYNL11, UQCC, and ABCC5, and the long non-coding RNA CRNDE. Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3b complex inhibitor spliceostatin A and treatment resulted in perturbation of the splicing signature. Albeit rare, SF3B1 mutations result in alternative splicing events, and may constitute drivers and a novel therapeutic target in a subset of breast cancers.

  4. MiR-449a promotes breast cancer progression by targeting CRIP2.

    PubMed

    Shi, Wei; Bruce, Jeff; Lee, Matthew; Yue, Shijun; Rowe, Matthew; Pintilie, Melania; Kogo, Ryunosuke; Bissey, Pierre-Antoine; Fyles, Anthony; Yip, Kenneth W; Liu, Fei-Fei

    2016-04-05

    The identification of prognostic biomarkers and their underlying mechanisms of action remain of great interest in breast cancer biology. Using global miRNA profiling of 71 lymph node-negative invasive ductal breast cancers and 5 normal mammary epithelial tissues, we identified miR-449a to be highly overexpressed in the malignant breast tissue. Its expression was significantly associated with increased incidence of patient relapse, decreased overall survival, and decreased disease-free survival. In vitro, miR-449a promoted breast cancer cell proliferation, clonogenic survival, migration, and invasion. By utilizing a tri-modal in silico approach for target identification, Cysteine-Rich Protein 2 (CRIP2; a transcription factor) was identified as a direct target of miR-449a, corroborated using qRT-PCR, Western blot, and luciferase reporter assays. MDA-MB-231 cells stably transfected with CRIP2 demonstrated a significant reduction in cell viability, migration, and invasion, as well as decreased tumor growth and angiogenesis in mouse xenograft models. Our data revealed that overexpression of miR-449a suppresses CRIP2, which then affects the tumor vasculature, likely via NF-κB/p65 complex-mediated transcription of VEGF. These finding define an oncogenic function of miR-449a in human breast cancer, and highlight the importance of this pathway in driving aggressive behaviour.

  5. Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting.

    PubMed

    García-Teijido, Paula; Cabal, María Luque; Fernández, Ignacio Peláez; Pérez, Yolanda Fernández

    2016-01-01

    Triple negative breast cancer (TNBC) is a highly heterogeneous tumor. There is increasing evidence of the role of tumor lymphocytic immune infiltrates in this subtype of breast cancer. Robust levels of tumor infiltrating lymphocytes (TILs) have been associated with improved disease-free and overall survival rates in TNBC patients with and without any treatment. Recent efforts have been made to develop a standardized methodology for evaluating TILs. The presence of TILs in the breast tumor microenvironment can also predict responses not only to neoadjuvant but also to adjuvant chemotherapy treatments. High numbers of TILs correlate with increased pathological complete responses (pCR) in TNBC. TILs are prognostic and predictive of response to standard therapies; thus, the immune system appears to play an active role in a subgroup of breast cancer. There is an increasing interest in directly targeting the immune system as part of breast cancer therapy, mainly in patients with TNBC. New immune modulatory agents, including immune checkpoints inhibitors, have shown promising activity in a subgroup of metastatic TNBC. Increased programmed cell death protein 1 ligand (PD-L1) expression on the surface of TNBC provides the rationale for implementing therapeutic strategies targeting the PD-1/PD-L1 axis in TNBC. The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, and the PD-L1 inhibitor atezolizumab have shown promising results in clinical trials.

  6. Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting

    PubMed Central

    García-Teijido, Paula; Cabal, María Luque; Fernández, Ignacio Peláez; Pérez, Yolanda Fernández

    2016-01-01

    Triple negative breast cancer (TNBC) is a highly heterogeneous tumor. There is increasing evidence of the role of tumor lymphocytic immune infiltrates in this subtype of breast cancer. Robust levels of tumor infiltrating lymphocytes (TILs) have been associated with improved disease-free and overall survival rates in TNBC patients with and without any treatment. Recent efforts have been made to develop a standardized methodology for evaluating TILs. The presence of TILs in the breast tumor microenvironment can also predict responses not only to neoadjuvant but also to adjuvant chemotherapy treatments. High numbers of TILs correlate with increased pathological complete responses (pCR) in TNBC. TILs are prognostic and predictive of response to standard therapies; thus, the immune system appears to play an active role in a subgroup of breast cancer. There is an increasing interest in directly targeting the immune system as part of breast cancer therapy, mainly in patients with TNBC. New immune modulatory agents, including immune checkpoints inhibitors, have shown promising activity in a subgroup of metastatic TNBC. Increased programmed cell death protein 1 ligand (PD-L1) expression on the surface of TNBC provides the rationale for implementing therapeutic strategies targeting the PD-1/PD-L1 axis in TNBC. The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, and the PD-L1 inhibitor atezolizumab have shown promising results in clinical trials. PMID:27081325

  7. Targeting Alpha5 Beta1 Integrin to Prevent Metastatic Breast Cancer Cell Invasion: PhScN Target Site Definition and Plasma Stability

    DTIC Science & Technology

    2015-11-01

    Award Number: TITLE: “Targeting Alpha5 Beta1 Integrin to Prevent Metastatic Breast Cancer Cell Invasion: PhScN Target Site Definition and Plasma...SUBTITLE Targeting Alpha5 Beta1 Integrin to Prevent Metastatic Breast Cancer Cell Invasion: PhScN Target Site Definition and Plasma Stability 5a...desirable target. Our research tested definitively the hypothesis that both PHSCN and PhScN peptides inhibit α5β1 integrin fibronectin receptor

  8. Fetoprotein Derived Short Peptide Coated Nanostructured Amphiphilic Surfaces for Targeting Mouse Breast Cancer Cells

    NASA Astrophysics Data System (ADS)

    Brown, Alexandra M.; Miranda-Alarćon, Yoliem S.; Knoll, Grant A.; Santora, Anthony M.; Banerjee, Ipsita A.

    In this work, self-assembled tumor targeting nanostructured surfaces were developed from a newly designed amphiphile by conjugating boc protected isoleucine with 2,2‧ ethylenedioxy bis ethylamine (IED). To target mouse mammary tumor cells, a short peptide sequence derived from the human alpha-fetoprotein (AFP), LSEDKLLACGEG was attached to the self-assembled nanostructures. Tumor targeting and cell proliferation were examined in the presence of nanoscale assemblies. To further obliterate mouse breast tumor cells, the chemotherapeutic drug tamoxifen was then entrapped into the nanoassemblies. Our studies indicated that the targeting systems were able to efficiently encapsulate and release tamoxifen. Cell proliferation studies showed that IED-AFP peptide loaded with tamoxifen decreased the proliferation of breast cancer cells while in the presence of the IED-AFP peptide nanoassemblies alone, the growth was relatively slower. In the presence of human dermal fibroblasts however cell proliferation continued similar to controls. Furthermore, the nanoscale assemblies were found to induce apoptosis in mouse breast cancer cells. To examine live binding interactions, SPR analysis revealed that tamoxifen encapsulated IED-AFP peptide nanoassemblies bound to the breast cancer cells more efficiently compared to unencapsulated assemblies. Thus, we have developed nanoscale assemblies that can specifically bind to and target tumor cells, with increased toxicity in the presence of a chemotherapeutic drug.

  9. Detecting and Targeting Oncogenic Myc in Breast Cancer

    DTIC Science & Technology

    2006-06-01

    AP, Showe MK, et al. Analysis of genomic targets reveals complex functions of MYC. Nat Rev Cancer 2004, 4(7), 562–568. 30. Luscher B. Function and... Luscher -Firzlaff JM, Rottmann S, et al. Stimula- tion of c-MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. EMBO Rep...2005, 24(2), 336–346. 128. Austen M, Cerni C, Luscher -Firzlaff JM, et al. YY1 can inhibit c-Myc function through a mechanism requiring DNA binding of

  10. Endoscopic Breast Surgery in Treating Patients With Breast Cancer

    ClinicalTrials.gov

    2014-02-05

    Male Breast Cancer; Recurrent Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  11. RAD50 targeting impairs DNA damage response and sensitizes human breast cancer cells to cisplatin therapy

    PubMed Central

    Flores-Pérez, Ali; Rafaelli, Lourdes E; Ramírez-Torres, Nayeli; Aréchaga-Ocampo, Elena; Frías, Sara; Sánchez, Silvia; Marchat, Laurence A; Hidalgo-Miranda, Alfredo; Quintanar-Jurado, Valeria; Rodríguez-Cuevas, Sergio; Bautista-Piña, Verónica; Carlos-Reyes, Ángeles; López-Camarillo, César

    2014-01-01

    In tumor cells the effectiveness of anti-neoplastic agents that cause cell death by induction of DNA damage is influenced by DNA repair activity. RAD50 protein plays key roles in DNA double strand breaks repair (DSBs), which is crucial to safeguard genome integrity and sustain tumor suppression. However, its role as a potential therapeutic target has not been addressed in breast cancer. Our aim in the present study was to analyze the expression of RAD50 protein in breast tumors, and evaluate the effects of RAD50-targeted inhibition on the cytotoxicity exerted by cisplatin and anthracycline and taxane-based therapies in breast cancer cells. Immunohistochemistry assays on tissue microarrays indicate that the strong staining intensity of RAD50 was reduced in 14% of breast carcinomas in comparison with normal tissues. Remarkably, RAD50 silencing by RNA interference significantly enhanced the cytotoxicity of cisplatin. Combinations of cisplatin with doxorubicin and paclitaxel drugs induced synergistic effects in early cell death of RAD50-deficient MCF-7, SKBR3, and T47D breast cancer cells. Furthermore, we found an increase in the number of DSBs, and delayed phosphorylation of histone H2AX after cisplatin treatment in RAD50-silenced cells. These cellular events were associated to a dramatical increase in the frequency of chromosomal aberrations and a decrease of cell number in metaphase. In conclusion, our data showed that RAD50 abrogation impairs DNA damage response and sensitizes breast cancer cells to cisplatin-combined therapies. We propose that the development and use of inhibitors to manipulate RAD50 levels might represent a promising strategy to sensitize breast cancer cells to DNA damaging agents. PMID:24642965

  12. Targeting the mammalian target of rapamycin pathway with everolimus: implications for the management of metastatic breast cancer.

    PubMed

    Ng, Vin Cci; Johnson, Jeremy J; Cuellar, Sandra

    2015-12-01

    The inhibitors of mammalian target of rapamycin (mTOR) have documented antitumor activity via disruption of various signaling pathways leading to impaired cellular growth, proliferation, and survival. In preclinical studies, mTOR inhibitors use in combination with hormonal therapy has shown promising results in overcoming endocrine resistance in breast cancer cells. The role of everolimus in breast cancer was established in the Breast Cancer Trial of Oral Everolimus-2 (BOLERO-2) trial in combination with exemestane for patients with advanced metastatic hormone receptor-positive (HR+) breast cancer, who relapsed after initial hormonal manipulation. The study met its primary endpoint of significant improvement in progression free survival (PFS) with a median time to progression of 6.9 months in the combination group versus 2.8 months in exemestane group. Favorable improvements in PFS were reported across all patient subgroups regardless of age, Eastern Cooperative Oncology Group performance status, number of prior therapies, and presence of visceral metastases. Adverse events were mostly mild to moderate in severity and consistent with the known safety profile of everolimus. Major toxicities reported include stomatitis, non-infectious pneumonitis, and hyperglycemia. The purpose of this review is to discuss the role of everolimus as a valuable component in advanced metastatic breast cancer and delineate current strategies to prevent and manage the most common toxicities associated with this combination regimen.

  13. IDENTIFYING AND TARGETING TUMOR-INITIATING CELLS IN THE TREATMENT OF BREAST CANCER

    PubMed Central

    Wei, Wei; Lewis, Michael T.

    2015-01-01

    Breast cancer is the most common cancer in women (exclusive of skin cancer), and is the second leading cause of cancer-related deaths. Although conventional and targeted therapies have improved survival rates, there are still considerable challenges in treating breast cancer, including treatment resistance, disease recurrence, and metastasis. Treatment resistance can be either de novo - due to traits that tumor cells possess prior to treatment, or acquired, - due to traits that tumor cells gain in response to treatment. A recently proposed mechanism of de novo resistance invokes existence of a specialized subset of cancer cells defined as tumor-initiating cells (TICs), or cancer stem cells (CSC). TICs have the capacity to self-renew and regenerate new tumors that consist of all clonally-derived cell types present in the parental tumor. There are data to suggest that TICs are resistant to many conventional cancer therapies, and survive treatment in spite of dramatic shrinkage of the tumor. Residual TICs can then eventually regrow resulting in disease relapse. It is also hypothesized that TIC may be responsible for metastatic disease. If these hypotheses are correct, targeting TICs may be imperative to achieve cure. In this review, we discuss evidence for breast TICs and their apparent resistance to conventional chemotherapy and radiotherapy, as well as to various targeted therapies. We also address the potential impact of breast TIC plasticity and metastatic potential on therapeutic strategies. Finally, we describe several genes and signaling pathways that appear important for TIC function that may represent promising therapeutic targets. PMID:25876646

  14. A novel mouse monoclonal antibody targeting ErbB2 suppresses breast cancer growth.

    PubMed

    Kawa, Seiji; Matsushita, Hirohisa; Ohbayashi, Hirokazu; Semba, Kentaro; Yamamoto, Tadashi

    2009-07-03

    Overexpression of ErbB2 in breast cancer is associated with increased recurrence and worse prognosis. Accumulating evidences suggest that molecular targeted therapy is a promising anticancer strategy. In this study, we produced a novel anti-ErbB2 monoclonal antibody, 6G10, that recognized an epitope distinct from the trastuzumab binding site. 6G10 induced aggregation of BT474 breast cancer cells and inhibited proliferation of various breast cancer cell lines including BT474. A growth inhibition assay showed that 6G10 had EC(50) values comparable to trastuzumab, indicating that the drugs have a similar level of potency. Furthermore, intraperitoneal administration of 6G10 completely inhibited the growth of xenografted tumors derived from BT474 and SK-BR-3 cells. These data suggested that 6G10 has great therapeutic potential and could be administered to patients alternatively, or synergistically, with trastuzumab.

  15. Developmental windows of breast cancer risk provide opportunities for targeted chemoprevention

    PubMed Central

    Martinson, Holly A.; Lyons, Traci R.; Giles, Erin D.; Borges, Virginia F.; Schedin, Pepper

    2014-01-01

    The magnitude of the breast cancer problem implores researchers to aggressively investigate prevention strategies. However, several barriers currently reduce the feasibility of breast cancer prevention. These barriers include the inability to accurately predict future breast cancer diagnosis at the individual level, the need for improved understanding of when to implement interventions, uncertainty with respect to optimal duration of treatment, and negative side effects associated with currently approved chemoprevention therapies. None-the-less, the unique biology of the mammary gland, with its postnatal development and conditional terminal differentiation, may permit the resolution of many of these barriers. Specifically, lifecycle-specific windows of breast cancer risk have been identified that may be amenable to risk-reducing strategies. Here, we argue for prevention research focused on two of these lifecycle windows of risk: postpartum mammary gland involution and peri-menopause. We provide evidence that these windows are highly amenable to targeted, limited duration treatments. Such approaches could result in the prevention of postpartum and postmenopausal breast cancers, correspondingly. PMID:23664839

  16. Developmental windows of breast cancer risk provide opportunities for targeted chemoprevention.

    PubMed

    Martinson, Holly A; Lyons, Traci R; Giles, Erin D; Borges, Virginia F; Schedin, Pepper

    2013-07-01

    The magnitude of the breast cancer problem implores researchers to aggressively investigate prevention strategies. However, several barriers currently reduce the feasibility of breast cancer prevention. These barriers include the inability to accurately predict future breast cancer diagnosis at the individual level, the need for improved understanding of when to implement interventions, uncertainty with respect to optimal duration of treatment, and negative side effects associated with currently approved chemoprevention therapies. None-the-less, the unique biology of the mammary gland, with its postnatal development and conditional terminal differentiation, may permit the resolution of many of these barriers. Specifically, lifecycle-specific windows of breast cancer risk have been identified that may be amenable to risk-reducing strategies. Here, we argue for prevention research focused on two of these lifecycle windows of risk: postpartum mammary gland involution and peri-menopause. We provide evidence that these windows are highly amenable to targeted, limited duration treatments. Such approaches could result in the prevention of postpartum and postmenopausal breast cancers, correspondingly.

  17. A therapeutic target for hormone-independent estrogen receptor-positive breast cancers.

    PubMed Central

    Biswas, D. K.; Cruz, A.; Pettit, N.; Mutter, G. L.; Pardee, A. B.

    2001-01-01

    BACKGROUND: The action of the steroid hormone estradiol (E2) is mediated via interaction with a specific receptor (ER) that initiates a series of events downstream, leading to the modulation of hormone-responsive genes and cell proliferation. Antihormones also bind, but do not confer the active configuration to ER, thereby, blocking the transmission of E2-ER-initiated signals for cell proliferation. Although these compounds qualify for successful therapy of ER-positive [ER (+)] breast cancer patients, only a fraction of patients responds to antihormone treatment. In this study, the functional status of ER is determined to identify alternative targets for therapy of antihormone-resistant ER (+) breast cancers. METHOD: The interaction of ER with a specific DNA sequence, designated as E2 response element (ERE), was targeted to assess the functional state of ER. ER-ERE complex formation was measured by electrophoretic mobility shift assay (EMSA) and by a newly developed technique, based on the preferential binding of DNA-protein complex to a nitrocellulose membrane (NMBA) that measures both total and functional fraction of ER. RESULTS: The NMBA assay identified functional variants of ER among ER (+) breast cancer cell lines and breast tumor biopsy specimens. ER of (21PT) cells did not bind E2 and these cells were tamoxifen (TAM) resistant. However 21PT cells were sensitive to a calmodulin (CaM) antagonist, W7, that blocked ERE-ER complex formation. CONCLUSIONS: ER variants of the 21PT type were detected among breast cancer biopsy specimens, emphasizing the significance of an alternative therapeutic target for TAM-resistant ER (+) human breast cancers with compounds such as W7. PMID:11474128

  18. Correlation between molybdenum target mammography signs and pathological prognostic factors of breast cancer.

    PubMed

    Zhang, Y; Ma, A D; Jia, H X

    2016-01-01

    This study explores the correlation between molybdenum target (mo-target) mammography signs and pathological prognostic factors of breast cancer. We selected 320 breast cancer patients who were treated between January 2014 and January 2016; using single-factor and multiple-factor logistic regression method, we made correlation analysis on their clinical features, pathological features and mo-target mammography signs. Among mo-target mammography signs, lumps accompanied with calcification and blurry edge were associated with high histologic grades; lumps accompanied with calcification and clear edge were associated with Ki-67 positive; compared with the patients who had lumps with non-stellate edges, positive rates of estrogen receptor (ER) and progesterone receptor (PR) were significantly higher for the patients who had lumps with stellate edges (p < 0.01), while positive rate of human epidermal growth factor receptor-2 (HER-2) and tumor proliferative activity were significantly lower (p < 0.05, p < 0.01). According to the study, we can conclude that mo-target mammography signs mainly include lumps and calcification. Mo-target mammography can improve the accuracy of diagnosis and reduce misdiagnosis or missed diagnosis. Part of mo-target mammography signs are associated with clinical pathology prognostic factors; by grasping the relation, breast cancer patient conditions are expected to be relieved.

  19. Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer.

    PubMed

    LeBeau, Aaron M; Duriseti, Sai; Murphy, Stephanie T; Pepin, Francois; Hann, Byron; Gray, Joe W; VanBrocklin, Henry F; Craik, Charles S

    2013-04-01

    Components of the plasminogen activation system, which are overexpressed in aggressive breast cancer subtypes, offer appealing targets for development of new diagnostics and therapeutics. By comparing gene expression data in patient populations and cultured cell lines, we identified elevated levels of the urokinase plasminogen activation receptor (uPAR, PLAUR) in highly aggressive breast cancer subtypes and cell lines. Recombinant human anti-uPAR antagonistic antibodies exhibited potent binding in vitro to the surface of cancer cells expressing uPAR. In vivo these antibodies detected uPAR expression in triple negative breast cancer (TNBC) tumor xenografts using near infrared imaging and (111)In single-photon emission computed tomography. Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard (18)F-fluorodeoxyglucose at detecting non-glucose-avid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. In addition, a radioimmunotherapy study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope (177)Lu, found that they were effective at reducing tumor burden in vivo. Taken together, our results offer a preclinical proof of concept for uPAR targeting as a strategy for breast cancer diagnosis and therapy using this novel human antibody technology.

  20. The Mammalian target of rapamycin inhibitors in breast cancer: current evidence and future directions.

    PubMed

    Malaguti, Paola; Vari, Sabrina; Cognetti, Francesco; Fabi, Alessandra

    2013-01-01

    Mammalian target of rapamycin (mTOR) is a crucial mediator of tumor progression and may be a promising target in a significant proportion of patients with breast cancer. More specifically, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway plays a critical role in multiple cellular functions including metabolism, proliferation, growth and survival. This pathway is higly active in many types of cancer and is linked to resistance to many types of therapy. Direct blockade of the mTOR pathway is a new area in breast cancer therapy, with the potential to modulate growth factor- and estrogen-dependent and estrogen-independent pathways, which contribute to the pathogenesis and progression of tumors. Thus, inhibitors of mTOR are of interest as potential therapeutic agents for patients with breast cancer, everolimus and temsirolimus being the main representatives of this category. This review of the literature analyzes the available data emerging from trials and evaluates the efficacy and safety of mTOR inhibitors in all subtypes of breast cancer.

  1. Radiation binary targeted therapy for HER-2 positive breast cancers: assumptions, theoretical assessment and future directions

    NASA Astrophysics Data System (ADS)

    Mundy, Daniel W.; Harb, Wael; Jevremovic, Tatjana

    2006-03-01

    A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal antibodies (MABs) that would be used as vehicles to transport the nontoxic agent to cancer cells. The anti HER-2 MABs have been successful in targeting HER-2 positive breast cancers with high affinity. The proposed concept would utilize a neutral nontoxic boron-10 predicting that anti HER-2 MABs would assure its selective delivery to cancer cells. MABs against HER-2 have been a widely researched strategy in the clinical setting. The most promising antibody is Trastuzumab (Herceptin®). Targeting HER-2 with the MAB Trastuzumab has been proven to be a successful strategy in inducing tumour regression and improving patient survival. Unfortunately, these tumours become resistant and afflicted women succumb to breast cancer. In the proposed concept, when the tumour region is loaded with boron-10 it is irradiated with neutrons (treatment used for head and neck cancers, melanoma and glioblastoma for over 40 years in Japan and Europe). The irradiation process takes less than an hour producing minimal side effects. This paper summarizes our recent theoretical assessments of radiation binary targeted therapy for HER-2 positive breast cancers on: the effective drug delivery mechanism, the numerical model to evaluate the targeted radiation delivery and the survey study to find the neutron facility in the world that might be capable of producing the radiation effect as needed. A novel method of drug delivery utilizing Trastuzumab is described, followed by the description of a computational Monte Carlo based breast model used to determine radiation dose distributions. The total flux and neutron energy spectra of five currently available neutron

  2. Targeting Premalignant Lesions: Implications for Early Breast Cancer Detection and Intervention

    DTIC Science & Technology

    2016-04-01

    PRINCIPAL INVESTIGATOR: Aman Mann CONTRACTING ORGANIZATION: Sanford Burnham Prebys Medical Discovery Institute La Jolla, CA 92037-1005 REPORT DATE: April...2015 – 31 Mar 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-14-1-0032 Targeting Premalignant Lesions: Implications for Early Breast...identified a peptide CISQ that targets to the stroma in premalignant lesions and binds to cancer-associated fibroblasts (CAFs) in MMTV-PyMT mice

  3. Reduced Toxicity Breast Cancer Therapy: Changing the Or to And in Dual Targeted Therapeutics

    DTIC Science & Technology

    2010-10-01

    targeted breast cancer therapeutics with the potentia l to dra matically improve speci ficity, reducing unwanted side effects . Here, we review our...of this work wa s to propose a new type of therapy activate d only in tumors presenting both a first AND second molecular target. Chemotherapy ...design (Figu re 1). With our light trigger system, we should be able to con trol th e position and the tim e of siRNA rele ase, lim iting any unwanted

  4. Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer

    PubMed Central

    Hallett, Robin M.; Girgis-Gabardo, Adele; Gwynne, William D.; Giacomelli, Andrew O.; Bisson, Jennifer N.P.; Jensen, Jeremy E.; Dvorkin-Gheva, Anna; Hassell, John A.

    2016-01-01

    Accumulating data suggests that the initiation and progression of human breast tumors is fueled by a rare subpopulation of tumor cells, termed breast tumor-initiating cells (BTIC), which resist radiotherapy and chemotherapy. Consequently, therapies that abrogate BTIC activity are needed to achieve durable cures for breast cancer patients. To identify such therapies we used a sensitive assay to complete a high-throughput screen of small molecules, including approved drugs, with BTIC-rich mouse mammary tumor cell populations. We found that inhibitors of the serotonin reuptake transporter (SERT) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of mouse BTIC activity as determined by functional sphere-forming assays and the initiation of tumor formation by transplant of drug-exposed tumor cells into syngeneic mice. Moreover, sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), synergized with docetaxel (Taxotere) to shrink mouse breast tumors in vivo. Hence drugs targeting the serotonergic system might be repurposed to treat breast cancer patients to afford more durable breast cancer remissions. PMID:27447971

  5. Estrogen Receptor-Targeted Contrast Agents for Molecular Magnetic Resonance Imaging of Breast Cancer Hormonal Status

    PubMed Central

    Pais, Adi; Degani, Hadassa

    2016-01-01

    The estrogen receptor (ER) α is overexpressed in most breast cancers, and its level serves as a major prognostic factor. It is important to develop quantitative molecular imaging methods that specifically detect ER in vivo and assess its function throughout the entire primary breast cancer and in metastatic breast cancer lesions. This study presents the biochemical and molecular features, as well as the magnetic resonance imaging (MRI) effects of two novel ER-targeted contrast agents (CAs), based on pyridine-tetra-acetate-Gd(III) chelate conjugated to 17β-estradiol (EPTA-Gd) or to tamoxifen (TPTA-Gd). The experiments were conducted in solution, in human breast cancer cells, and in severe combined immunodeficient mice implanted with transfected ER-positive and ER-negative MDA-MB-231 human breast cancer xenografts. Binding studies with ER in solution and in human breast cancer cells indicated affinities in the micromolar range of both CAs. Biochemical and molecular studies in breast cancer cell cultures showed that both CAs exhibit estrogen-like agonistic activity, enhancing cell proliferation, as well as upregulating cMyc oncogene and downregulating ER expression levels. The MRI longitudinal relaxivity was significantly augmented by EPTA-Gd in ER-positive cells as compared to ER-negative cells. Dynamic contrast-enhanced studies with EPTA-Gd in vivo indicated specific augmentation of the MRI water signal in the ER-positive versus ER-negative xenografts, confirming EPTA-Gd-specific interaction with ER. In contrast, TPTA-Gd did not show increased enhancement in ER-positive tumors and did not appear to interact in vivo with the tumors’ ER. However, TPTA-Gd was found to interact strongly with muscle tissue, enhancing muscle signal intensity in a mechanism independent of the presence of ER. The specificity of EPTA-Gd interaction with ER in vivo was further verified by acute and chronic competition with tamoxifen. The chronic tamoxifen treatment also revealed that this

  6. Amine-modified hyaluronic acid-functionalized porous silicon nanoparticles for targeting breast cancer tumors

    NASA Astrophysics Data System (ADS)

    Almeida, Patrick V.; Shahbazi, Mohammad-Ali; Mäkilä, Ermei; Kaasalainen, Martti; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A.

    2014-08-01

    Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA+) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA+ nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of UnTHCPSi-HA+ relies on the capability of the conjugated HA+ to bind and consequently target CD44 receptors expressed on the surface of breast cancer cells, thus making the HA+-functionalized UnTHCPSi nanoparticles a suitable and promising nanoplatform for the targeting of CD44-overexpressing breast tumors and for drug delivery.Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA+) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA+ nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of Un

  7. MicroRNA-139 suppresses proliferation in luminal type breast cancer cells by targeting Topoisomerase II alpha

    SciTech Connect

    Hua, Wei; Sa, Ke-Di; Zhang, Xiang; Jia, Lin-Tao; Zhao, Jing; Yang, An-Gang; Zhang, Rui; Fan, Jing; Bian, Ka

    2015-08-07

    The classification of molecular subtypes of breast cancer improves the prognostic accuracy and therapeutic benefits in clinic. However, because of the complexity of breast cancer, more biomarkers and functional molecules need to be explored. Here, analyzing the data in a huge cohort of breast cancer patients, we found that Topoisomerase II alpha (TOP2a), an important target of chemotherapy is a biomarker for prognosis in luminal type breast cancer patients, but not in basal like or HER2 positive breast cancer patients. We identified that miR-139, a previous reported anti-metastatic microRNA targets 3’-untranslated region (3′UTR) of TOP2a mRNA. Further more, we revealed that the forced expression of miR-139 reduces the TOP2a expression at both mRNA and protein levels. And our functional experiments showed that the ectopic expression of miR-139 remarkably inhibits proliferation in luminal type breast cancer cells, while exogenous TOP2a expression could rescue inhibition of cell proliferation mediated by miR-139. Collectively, our present study demonstrates the miR-139-TOP2a regulatory axis is important for proliferation in luminal type breast cancer cells. This functional link may help us to further understand the specificity of subtypes of breast cancer and optimize the strategy of cancer treatment. - Highlights: • High levels of TOP2a expression are closely associated with poor prognosis in luminal type breast cancer patients. • TOP2a is a novel target of miR-139. • Overexpression of miR-139 inhibits proliferation in luminal type breast cancer cells. • TOP2a is essential for miR-139-induced growth arrest in luminal type breast cancer cells.

  8. Endoplasmic Reticulum-Associated Degradation Factor ERLIN2: Oncogenic Roles and Molecular Targeting of Breast Cancer

    DTIC Science & Technology

    2011-06-01

    phenotype. Oncogenes, such as Her2 , play important roles in uncontrolled proliferation and survival of breast cancer cells. However, cancer cells must...2 Figure 1. shRNA- mediated knockdown of ERLIN2 inhibits growth of breast cancer cells SUM-44 and SUM...1 Introduction Breast cancer cells contain a large number of genetic alterations that act in combination to create the malignant

  9. Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin.

    PubMed

    Kai, Masaya; Kanaya, Noriko; Wu, Shang V; Mendez, Carlos; Nguyen, Duc; Luu, Thehang; Chen, Shiuan

    2015-06-01

    The aim of this study is to investigate the efficacy of combining a histone deacetylase inhibitor (LBH589) and a breast cancer stem cells (BCSC)-targeting agent (salinomycin) as a novel combination therapy for triple-negative breast cancer (TNBC). We performed in vitro studies using the TNBC cell lines to examine the combined effect. We used the mammosphere and ALDEFLUOR assays to estimate BCSC self-renewal capacity and distribution of BCSCs, respectively. Synergistic analysis was performed using CalcuSyn software. For in vivo studies, aldehyde dehydrogenase 1 ALDH1-positive cells were injected into non-obese diabetic/severe combined immunodeficiency gamma (NSG) mice. After tumor formation, mice were treated with LBH589, salinomycin, or in combination. In a second mouse model, HCC1937 cells were first treated with each treatment and then injected into NSG mice. For mechanistic analysis, immunohistochemistry and Western blot analysis were performed using cell and tumor samples. HCC1937 cells displayed BCSC properties including self-renewal capacity, an ALDH1-positive cell population, and the ability to form tumors. Treatment of HCC1937 cells with LBH589 and salinomycin had a potent synergistic effect inhibiting TNBC cell proliferation, ALDH1-positive cells, and mammosphere growth. In xenograft mouse models treated with LBH589 and salinomycin, the drug combination effectively and synergistically inhibited tumor growth of ALDH1-positive cells. The drug combination exerted its effects by inducing apoptosis, arresting the cell cycle, and regulating epithelial-mesenchymal transition (EMT). Combination of LBH589 and salinomycin has a synergistic inhibitory effect on TNBC BCSCs by inducing apoptosis, arresting the cell cycle, and regulating EMT; with no apparent associated severe toxicity. This drug combination could therefore offer a new targeted therapeutic strategy for TNBC and warrants further clinical study in patients with TNBC.

  10. Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines

    SciTech Connect

    Vethakanraj, Helen Shiphrah; Babu, Thabraz Ahmed; Sudarsanan, Ganesh Babu; Duraisamy, Prabhu Kumar; Ashok Kumar, Sekar

    2015-08-28

    The sphingolipid ceramide is a pro apoptotic molecule of ceramide metabolic pathway and is hydrolyzed to proliferative metabolite, sphingosine 1 phosphate by the action of acid ceramidase. Being upregulated in the tumors of breast, acid ceramidase acts as a potential target for breast cancer therapy. We aimed at targeting this enzyme with a small molecule acid ceramidase inhibitor, Ceranib 2 in human breast cancer cell lines MCF 7 and MDA MB 231. Ceranib 2 effectively inhibited the growth of both the cell lines in dose and time dependant manner. Morphological apoptotic hallmarks such as chromatin condensation, fragmented chromatin were observed in AO/EtBr staining. Moreover, ladder pattern of fragmented DNA observed in DNA gel electrophoresis proved the apoptotic activity of Ceranib 2 in breast cancer cell lines. The apoptotic events were associated with significant increase in the expression of pro-apoptotic genes (Bad, Bax and Bid) and down regulation of anti-apoptotic gene (Bcl 2). Interestingly, increase in sub G1 population of cell cycle phase analysis and elevated Annexin V positive cells after Ceranib 2 treatment substantiated its apoptotic activity in MCF 7 and MDA MB 231 cell lines. Thus, we report Ceranib 2 as a potent therapeutic agent against both ER{sup +} and ER{sup −} breast cancer cell lines. - Highlights: • Acid Ceramidase inhibitor, Ceranib 2 induced apoptosis in Breast cancer cell lines (MCF 7 and MDA MB 231 cell lines). • Apoptosis is mediated by DNA fragmentation and cell cycle arrest. • Ceranib 2 upregulated the expression of pro-apoptotic genes and down regulated anti-apoptotic gene expression. • More potent compared to the standard drug Tamoxifen.

  11. Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity

    PubMed Central

    Sambi, Manpreet; Haq, Sabah; Samuel, Vanessa; Qorri, Bessi; Haxho, Fiona; Hill, Kelli; Harless, William; Szewczuk, Myron R

    2017-01-01

    One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current

  12. Comparison of Various Radiation Therapy Techniques in Breast Cancer Where Target Volume Includes Mammaria Interna Region

    SciTech Connect

    Dogan, Mehmet Hakan; Zincircioglu, Seyit Burhanedtin Zorlu, Faruk

    2009-04-01

    In breast cancer radiotherapy, the internal mammary lymphatic chain is treated in the target volume in a group of patients with high-risk criteria. Because of the variability of the anatomic region and structures in the irradiation field, there are a number of different techniques in breast radiotherapy. While irradiating the target volume, we also consider minimizing the dose to critical structures such as heart, lung, and contralateral breast tissue. In this study, we evaluated the dose distribution of different radiotherapy techniques in patients with left-sided breast cancer who had breast-conserving surgery. A three-dimensional computerized planning system (3DCPS) was used for each patient to compare wide-field, oblique photon-electron, and perpendicular photon-electron techniques in terms of dose homogeneities in the target volume; the doses received by the contralateral breast, heart, and lung; and the coverage of the internal mammary chain. Data from 3DCPS were controlled by the Rando-phantom and thermoluminescence dosimetry. Critical structures were irradiated with acceptable dose percentages in addition to the internal mammary chain with both wide-field and photon-electron techniques. We detected more frequent hot spots in the oblique photon-electron technique than in the other techniques, and this situation necessitated changing the junctions. The wide-field technique was easy to perform and exposed less radiation dose to the heart than photon-electron techniques. In conclusion, we suggest the use of the wide-field technique in breast irradiation when the internal mammary area is in the target volume.

  13. Id-1 gene and gene products as therapeutic targets for treatment of breast cancer and other types of carcinoma

    DOEpatents

    Desprez, Pierre-Yves; Campisi, Judith

    2014-08-19

    A method for treatment of breast cancer and other types of cancer. The method comprises targeting and modulating Id-1 gene expression, if any, for the Id-1 gene, or gene products in breast or other epithelial cancers in a patient by delivering products that modulate Id-1 gene expression. When expressed, Id-1 gene is a prognostic indicator that cancer cells are invasive and metastatic.

  14. MicroRNA-34a Suppresses Cell Proliferation by Targeting LMTK3 in Human Breast Cancer MCF-7 Cell Line

    PubMed Central

    Zhao, Guoqing; Guo, Jun; Li, Dong; Jia, Chengyou; Yin, Wanzhong; Sun, Ran; Lv, Zhongwei

    2013-01-01

    Breast cancer remains the leading cause of cancer mortality in females, and about 70% of the primary breast cancer patients are diagnosed ERα-positive, which is the most common type of breast cancer. MicroRNA-34a (miR-34a) has been shown to be a master regulator of tumor suppression in many types of cancers including breast cancer. However, the role of miR-34a in ERα-positive breast cancer has not been elucidated. Here, we find that in MCF-7, which is an ERα-positive breast cancer cell line, miR-34a is remarkably downregulated after E2 treatment. Overexpression of miR-34a by lentivirus suppresses cell proliferation, S phase ratio, and tumor formation in an E2-dependent manner in vitro. According to the mRNA sequence, lemur tyrosine kinase 3 (LMTK3), which is an important regulator of estrogen receptor alpha (ERα), is a predicted target of miR-34a. This is confirmed by dual luciferase reporter assay and the decrease of LMTK3 mRNA and protein levels after overexpression of miR-34a. Moreover, miR-34a overexpression decreases AKT signaling pathway and increases ERα phosphorylation status. Taken together, these results suggest that miR-34a inhibits breast cancer proliferation by targeting LMTK3 and might be used as an anti-ERα agent in breast cancer therapy. PMID:24050776

  15. In vivo photoacoustic imaging of breast cancer tumor with HER2-targeted nanodiamonds

    NASA Astrophysics Data System (ADS)

    Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Jo, Janggun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M. Laird

    2013-09-01

    Radiation-damaged nanodiamonds (NDs) are ideal optical contrast agents for photoacoustic (PA) imaging in biological tissues due to their good biocompatibility and high optical absorbance in the near-infrared (NIR) range. Acid treated NDs are oxidized to form carboxyl groups on the surface, functionalized with polyethylene glycol (PEG) and human epidermal growth factor receptor 2 (HER2) targeting ligand for breast cancer tumor imaging. Because of the specific binding of the ligand conjugated NDs to the HER2-overexpressing murine breast cancer cells (4T1.2 neu), the tumor tissues are significantly delineated from the surrounding normal tissue at wavelength of 820 nm under the PA imaging modality. Moreover, HER2 targeted NDs (HER2-PEG-NDs) result in higher accumulation in HER2 positive breast tumors as compared to non-targeted NDs after intravenous injection (i.v.). Longer retention time of HER-PEG-NDs is observed in HER2 overexpressing tumor model than that in negative tumor model (4T1.2). This demonstrates that targeting moiety conjugated NDs have great potential for the sensitive detection of cancer tumors and provide an attractive delivery strategy for anti-cancer drugs.

  16. In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

    PubMed Central

    Palmieri, Dario; De Luca, Luciana; Consiglio, Jessica; You, Jia; Rocci, Alberto; Talabere, Tiffany; Piovan, Claudia; Lagana, Alessandro; Cascione, Luciano; Guan, Jingwen; Gasparini, Pierluigi; Balatti, Veronica; Nuovo, Gerard; Coppola, Vincenzo; Hofmeister, Craig C.; Marcucci, Guido; Byrd, John C.; Volinia, Stefano; Shapiro, Charles L.; Freitas, Michael A.

    2013-01-01

    Numerous studies have described the altered expression and the causal role of microRNAs (miRNAs) in human cancer. However, to date, efforts to modulate miRNA levels for therapeutic purposes have been challenging to implement. Here we find that nucleolin (NCL), a major nucleolar protein, posttranscriptionally regulates the expression of a specific subset of miRNAs, including miR-21, miR-221, miR-222, and miR-103, that are causally involved in breast cancer initiation, progression, and drug resistance. We also show that NCL is commonly overexpressed in human breast tumors and that its expression correlates with that of NCL-dependent miRNAs. Finally, inhibition of NCL using guanosine-rich aptamers reduces the levels of NCL-dependent miRNAs and their target genes, thus reducing breast cancer cell aggressiveness both in vitro and in vivo. These findings illuminate a path to novel therapeutic approaches based on NCL-targeting aptamers for the modulation of miRNA expression in the treatment of breast cancer. PMID:23610125

  17. 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

  18. Somatostatin receptor targeted liposomes with Diacerein inhibit IL-6 for breast cancer therapy.

    PubMed

    Bharti, Rashmi; Dey, Goutam; Banerjee, Indranil; Dey, Kaushik Kumar; Parida, Sheetal; Kumar, B N Prashanth; Das, Chandan Kanta; Pal, Ipsita; Mukherjee, Manabendra; Misra, Mridula; Pradhan, Anjan K; Emdad, Luni; Das, Swadesh K; Fisher, Paul B; Mandal, Mahitosh

    2017-03-01

    Selective targeting to the tumor niche remains a major challenge in successful cancer therapy. Somatostatin receptor 2 (SSTR2) is overexpressed in breast cancer cells thus making this receptor an attractive target for selective guidance of ligand-conjugated drug liposomes to the tumor site. In this study, a synthetic somatostatin analogue (SST) was used as SSTR2 targeting agent and Diacerein was employed as therapeutic molecule. Diacerein loaded liposomes (DNL) were prepared and they were further decorated with the synthetic and stable analogue of somatostatin (SST-DNL). Fabricated liposomes were nano-size in range and biocompatible. SST-DNL displayed significantly better anti-tumor efficacy as compared to free Diacerein (DN) and DNL in breast cancer models. Enhanced apoptosis in breast cancer cells was detected in SST-DNL treated groups as monitored by cell cycle analysis and changes in expression level of apoptotic/anti-apoptotic proteins Bcl-2, Bax, cleaved Caspase 3 and PARP. SST-DNL more effectively inhibited the oncogenic IL-6/IL-6R/STAT3/MAPK/Akt signalling pathways as compared to DN or DNL in cancer cells. In addition, SST-DNL effectively suppressed angiogenesis and cancer cell invasion. In vivo tumor growth in a MDA-MB-231 mouse xenograft model was significantly suppressed following SST-DNL treatment. In xenograft model, immunohistochemistry of Ki-67 and CD-31 indicated that SST-DNL improved the anti-proliferative and anti-angiogenic impacts of Diacerein. In vivo pharmacokinetic studies in rats showed enhanced circulation time in the DNL or SST-DNL treated groups as compared to free DN. Considering all of these findings, we conclude that SST-DNL provides a novel strategy with better efficacy for breast cancer therapy.

  19. Identification of KLK10 as a therapeutic target to reverse trastuzumab resistance in breast cancer

    PubMed Central

    Jin, Yi; Zhang, Yulong; Li, Jiaqiu; Zhu, Liyuan; Xu, Wenxia; Feng, Lifeng; Jin, Hongchuan; Wang, Xian

    2016-01-01

    Trastuzumab, the first antibody widely used in anti-HER2 targeted therapy, dramatically improved the overall outcome of HER2 positive breast cancer patients. However, trastuzumab resistance emerged as a major problem in its clinical application. In order to explore mechanisms underlying trastuzumab resistance, we performed RNA-Seq to analyze the gene expression variation in trastuzumab resistant breast cancer cell line. The sequencing result was then combined with the relevant data in TCGA database to conduct a co-expression analysis. We found a series of differentially expressed genes with potential contributions to trastuzumab resistance. Among them, KLK10 was verified to be a potential therapeutic target for reversing trastuzumab resistance. In summary, this study provides a new clue to screen molecular targets and predictive biomarkers for trastuzumab resistance. PMID:27825132

  20. Suppressive role of myeloid-derived suppressor cells (MDSCs) in the microenvironment of breast cancer and targeted immunotherapies

    PubMed Central

    Sun, Qiming; Gong, Weihua

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) play a pivotal role in promoting tumor growth and metastasis and can even decrease the efficacy of immunotherapy. In breast cancer, MDSCs are recruited mainly by breast cancer cells to form a tumor-favoring microenvironment to suppress the anti-tumor immune response. In addition, MDSCs can react directly with breast cancer cells. In this paper, we describe several ways to recruit MDSCs in breast cancer, including breast cancer cell-derived cytokines and chemokines. The intracellular pathways in MDSCs during recruitment are classified as the STAT3-NF-κB-IDO pathway, the STAT3/IRF-8 pathway and the PTEN/Akt pathway. MDSCs act on T cells and NK cells to suppress the body's immunity, and via IL-6 trans-signaling, promote breast cancer directly. We further describe MDSC-targeted immune therapies for breast cancer, which are classified as: preventing the formation of MDSCs, eliminating MDSDCs, and reducing the products of MDSCs. Furthermore, MDSC-targeted immunotherapy potentiates the effect of the other immunotherapies. Based on the facts that MSDCs have significant roles in breast cancer malignant behaviors and can be suppressed by various strategies, we do believe MDSC-targeted immunotherapy presents a broad prospect in the future. PMID:27542274

  1. Suppressive role of myeloid-derived suppressor cells (MDSCs) in the microenvironment of breast cancer and targeted immunotherapies.

    PubMed

    Shou, Dawei; Wen, Liang; Song, Zhenya; Yin, Jian; Sun, Qiming; Gong, Weihua

    2016-09-27

    Myeloid-derived suppressor cells (MDSCs) play a pivotal role in promoting tumor growth and metastasis and can even decrease the efficacy of immunotherapy. In breast cancer, MDSCs are recruited mainly by breast cancer cells to form a tumor-favoring microenvironment to suppress the anti-tumor immune response. In addition, MDSCs can react directly with breast cancer cells. In this paper, we describe several ways to recruit MDSCs in breast cancer, including breast cancer cell-derived cytokines and chemokines. The intracellular pathways in MDSCs during recruitment are classified as the STAT3-NF-κB-IDO pathway, the STAT3/IRF-8 pathway and the PTEN/Akt pathway. MDSCs act on T cells and NK cells to suppress the body's immunity, and via IL-6 trans-signaling, promote breast cancer directly. We further describe MDSC-targeted immune therapies for breast cancer, which are classified as: preventing the formation of MDSCs, eliminating MDSDCs, and reducing the products of MDSCs. Furthermore, MDSC-targeted immunotherapy potentiates the effect of the other immunotherapies. Based on the facts that MSDCs have significant roles in breast cancer malignant behaviors and can be suppressed by various strategies, we do believe MDSC-targeted immunotherapy presents a broad prospect in the future.

  2. Nonlinear Growth Kinetics of Breast Cancer Stem Cells: Implications for Cancer Stem Cell Targeted Therapy

    NASA Astrophysics Data System (ADS)

    Liu, Xinfeng; Johnson, Sara; Liu, Shou; Kanojia, Deepak; Yue, Wei; Singn, Udai; Wang, Qian; Wang, Qi; Nie, Qing; Chen, Hexin

    2013-08-01

    Cancer stem cells (CSCs) have been identified in primary breast cancer tissues and cell lines. The CSC population varies widely among cancerous tissues and cell lines, and is often associated with aggressive breast cancers. Despite of intensive research, how the CSC population is regulated within a tumor is still not well understood so far. In this paper, we present a mathematical model to explore the growth kinetics of CSC population both in vitro and in vivo. Our mathematical models and supporting experiments suggest that there exist non-linear growth kinetics of CSCs and negative feedback mechanisms to control the balance between the population of CSCs and that of non-stem cancer cells. The model predictions can help us explain a few long-standing questions in the field of cancer stem cell research, and can be potentially used to predict the efficicacy of anti-cancer therapy.

  3. Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer.

    PubMed

    Song, Lingqin; Wang, Weifeng; Liu, Di; Zhao, Yang; He, Jianjun; Wang, Xijing; Dai, Zhijun; Zhang, Huimin; Li, Xiao

    2016-08-01

    Breast cancer is the most common malignant cancer among women. The Hedgehog (Hh) signaling pathway serves a key role in malignant cancer cell growth and migration. However, little is known with regard to the specific function of the Hh signaling pathway in human breast cancer. The current study investigated the specific role of Hh signaling in the human breast cancer cell line MDA-MB-231. Expression of components of Shh-Gli signaling, as well as the Gli-responsive genes B-cell lymphoma 2 (Bcl-2) and cyclin D1, were investigated in MDA-MB-231 cells using western blotting. The effects of Shh-Gli signaling on MDA-MB-231 proliferation were analyzed by MTT assay. The role of E-cadherin in the epithelial-mesenchymal transition process was determined by western blot while matrix metalloproteinase (MMP)-9/MMP-2 secretion was studied by enzyme-linked immunosorbent assay. The results indicated that Shh-Gli signaling was activated in MDA-MB-231 cells, significantly enhancing cell viability. Overexpression of Gli positively regulated the transcription of Bcl-2 and cyclin D1 thereby regulating MDA-MB-231 cell proliferation and survival. Treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus for 72 h significantly reduced E-cadherin protein levels and enhanced secretion of MMP-9 and MMP-2. These findings suggest that Shh-Gli signaling is significantly activated in human breast cancer cells, and is accompanied by enhanced cell viability, proliferation and migration capacities.

  4. Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

    PubMed Central

    Song, Lingqin; Wang, Weifeng; Liu, Di; Zhao, Yang; He, Jianjun; Wang, Xijing; Dai, Zhijun; Zhang, Huimin; Li, Xiao

    2016-01-01

    Breast cancer is the most common malignant cancer among women. The Hedgehog (Hh) signaling pathway serves a key role in malignant cancer cell growth and migration. However, little is known with regard to the specific function of the Hh signaling pathway in human breast cancer. The current study investigated the specific role of Hh signaling in the human breast cancer cell line MDA-MB-231. Expression of components of Shh-Gli signaling, as well as the Gli-responsive genes B-cell lymphoma 2 (Bcl-2) and cyclin D1, were investigated in MDA-MB-231 cells using western blotting. The effects of Shh-Gli signaling on MDA-MB-231 proliferation were analyzed by MTT assay. The role of E-cadherin in the epithelial-mesenchymal transition process was determined by western blot while matrix metalloproteinase (MMP)-9/MMP-2 secretion was studied by enzyme-linked immunosorbent assay. The results indicated that Shh-Gli signaling was activated in MDA-MB-231 cells, significantly enhancing cell viability. Overexpression of Gli positively regulated the transcription of Bcl-2 and cyclin D1 thereby regulating MDA-MB-231 cell proliferation and survival. Treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus for 72 h significantly reduced E-cadherin protein levels and enhanced secretion of MMP-9 and MMP-2. These findings suggest that Shh-Gli signaling is significantly activated in human breast cancer cells, and is accompanied by enhanced cell viability, proliferation and migration capacities. PMID:27446389

  5. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice.

    PubMed

    Sarkar, Devanand; Su, Zao-Zhong; Vozhilla, Nicolaq; Park, Eun Sook; Gupta, Pankaj; Fisher, Paul B

    2005-09-27

    Limitations of current viral-based gene therapies for malignant tumors include lack of cancer-specific targeting and insufficient tumor delivery. To ameliorate these problems and develop a truly effective adenovirus gene-based therapy for cancer, we constructed a conditionally replication competent adenovirus (CRCA) manifesting the unique properties of tumor-specific virus replication in combination with production of a cancer-selective cytotoxic cytokine, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), which embodies potent bystander antitumor activity. Cancer cell selective tropism was ensured by engineering the expression of the adenoviral E1A protein, necessary for viral replication, under the control of a minimal promoter region of progression elevated gene-3 (PEG-3), which functions selectively in diverse cancer cells with minimal activity in normal cells. In the E3 region of this CRCA, we introduced the mda-7/IL-24 gene, thereby mediating robust production of this cytokine as a function of adenovirus replication. Infection of this CRCA (designated Ad.PEG-E1A-mda-7) in normal mammary epithelial cells and breast cancer cells confirmed cancer cell selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 into human breast cancer xenografts in athymic nude mice completely eradicated not only the primary tumor but also distant tumors (established on the opposite flank of the animal) thereby implementing a cure. This dual cancer-specific targeting strategy provides an effective approach for treating breast and other human neoplasms with the potential for eradicating both primary tumors and metastatic disease. Additionally, these studies support the potential use of mda-7/IL-24 in the therapy of malignant cancers.

  6. Molecular photoacoustic tomography of breast cancer using receptor targeted magnetic iron oxide nanoparticles as contrast agents.

    PubMed

    Xi, Lei; Grobmyer, Stephen R; Zhou, Guangyin; Qian, Weiping; Yang, Lily; Jiang, Huabei

    2014-06-01

    In this report, we present a breast imaging technique combining high-resolution near-infrared (NIR) light induced photoacoustic tomography (PAT) with NIR dye-labeled amino-terminal fragments of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (NIR830-ATF-IONP) for breast cancer imaging using an orthotopic mouse mammary tumor model. We show that accumulation of the targeted nanoparticles in the tumor led to photoacoustic contrast enhancement due to the high absorption of iron oxide nanoparticles (IONP). NIR fluorescence images were used to validate specific delivery of NIR830-ATF-IONP to mouse mammary tumors. We found that systemic delivery of the targeted IONP produced 4- and 10-fold enhancement in photoacoustic signals in the tumor, compared to the tumor of the mice that received non-targeted IONP or control mice. The use of targeted nanoparticles allowed imaging of tumors located as deep as 3.1 cm beneath the normal tissues. Our study indicates the potential of the combination of photoacoustic tomography and receptor-targeted NIR830-ATF-IONP as a clinical tool that can provide improved specificity and sensitivity for breast cancer detection.

  7. MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase.

    PubMed

    Zhang, Lixin; Sullivan, Peggy S; Goodman, Jerry C; Gunaratne, Preethi H; Marchetti, Dario

    2011-02-01

    Heparanase (HPSE) is a potent protumorigenic, proangiogenic, and prometastatic enzyme that is overexpressed in brain metastatic breast cancer (BMBC). However, little is known about the regulation of this potential therapeutic target in BMBC, which remains very poorly managed in the clinic. We hypothesized that HPSE gene expression might be regulated by micro RNA that might be exploited therapeutically. Using miRanda and RNAhybrid, we identified miR-1258 as a candidate micro RNA that may directly target HPSE and suppress BMBC. In support of our hypothesis, we found that miR-1258 levels inversely correlated with heparanase expression, enzymatic activity, and cancer cell metastatic propensities, being lowest in highly aggressive BMBC cell variants compared with either nontumorigenic or nonmetastatic human mammary epithelial cells. These findings were validated by analyses of miR-1258 and heparanase content in paired clinical specimens of normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. In regulatory experiments, miR-1258 inhibited the expression and activity of heparanase in BMBC cells, whereas modulating heparanase blocked the phenotypic effects of miR-1258. In functional experiments, stable expression of miR-1258 in BMBC cells inhibited heparanase in vitro cell invasion and experimental brain metastasis. Together, our findings illustrate how micro RNA mechanisms are linked to brain metastatic breast cancer through heparanase control, and they offer a strong rationale to develop heparanase-based therapeutics for treatment of cancer patients with brain metastases, BMBC in particular.

  8. Learning about Breast Cancer

    MedlinePlus

    ... genetic terms used on this page Learning About Breast Cancer What do we know about heredity and breast ... Cancer What do we know about heredity and breast cancer? Breast cancer is a common disease. Each year, ...

  9. Amine-modified hyaluronic acid-functionalized porous silicon nanoparticles for targeting breast cancer tumors

    PubMed Central

    Almeida, Patrick V.; Shahbazi, Mohammad-Ali; Mäkilä, Ermei; Kaasalainen, Martti; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A.

    2014-01-01

    Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA+) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi–HA+ nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of UnTHCPSi–HA+ relies on the capability of the conjugated HA+ to bind and consequently target CD44 receptors expressed on the surface of breast cancer cells, thus making the HA+-functionalized UnTHCPSi nanoparticles a suitable and promising nanoplatform for the targeting of CD44-overexpressing breast tumors and for drug delivery. PMID:25074521

  10. Enriched transcription factor signatures in triple negative breast cancer indicates possible targeted therapies with existing drugs

    PubMed Central

    Willis, Scooter; De, Pradip; Dey, Nandini; Long, Bradley; Young, Brandon; Sparano, Joseph A.; Wang, Victoria; Davidson, Nancy E.; Leyland-Jones, Brian R.

    2015-01-01

    Purpose Triple negative (TN) breast cancers which lack expression of the estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors convey a poor prognosis due in part to a lack of targeted therapies. Methods To identify viable targets for the treatment of TN disease, we have conducted a gene set enrichment analysis (GSEA) on seven different breast cancer whole genome gene expression cohorts comparing TN vs. ER + HER2 − to identify consistently enriched genes that share a common promoter motif. The seven cohorts were profiled on three different genome expression platforms (Affymetrix, Illumina and RNAseq) consisting in total of 2088 samples with IHC metadata. Results GSEA identified enriched gene expression patterns in TN samples that share common promoter motifs associated with SOX9, E2F1, HIF1A, HMGA1, MYC BACH2, CEBPB, and GCNF/NR6A1. Unexpectedly, NR6A1 an orphan nuclear receptor normally expressed in germ cells of gonads is highly expressed in TN and ER + HER2 − samples making it an ideal drug target. Conclusion With the increasing number of large sample size breast cancer cohorts, an exploratory analysis of genes that are consistently enriched in TN sharing common promoter motifs allows for the identification of possible therapeutic targets with extensive validation in patient derived data sets. PMID:26005638

  11. 6 Common Cancers - Breast Cancer

    MedlinePlus

    ... Bar Home Current Issue Past Issues 6 Common Cancers - Breast Cancer Past Issues / Spring 2007 Table of Contents For ... her down. Photo: AP Photo/Brett Flashnick Breast Cancer Breast cancer is a malignant (cancerous) growth that ...

  12. FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance.

    PubMed

    Nestal de Moraes, Gabriela; Delbue, Deborah; Silva, Karina L; Robaina, Marcela Cristina; Khongkow, Pasarat; Gomes, Ana R; Zona, Stefania; Crocamo, Susanne; Mencalha, André Luiz; Magalhães, Lídia M; Lam, Eric W-F; Maia, Raquel C

    2015-12-01

    Drug resistance is a major hurdle for successful treatment of breast cancer, the leading cause of deaths in women throughout the world. The FOXM1 transcription factor is a potent oncogene that transcriptionally regulates a wide range of target genes involved in DNA repair, metastasis, cell invasion, and migration. However, little is known about the role of FOXM1 in cell survival and the gene targets involved. Here, we show that FOXM1-overexpressing breast cancer cells display an apoptosis-resistant phenotype, which associates with the upregulation of expression of XIAP and Survivin antiapoptotic genes. Conversely, FOXM1 knockdown results in XIAP and Survivin downregulation as well as decreased binding of FOXM1 to the promoter regions of XIAP and Survivin. Consistently, FOXM1, XIAP, and Survivin expression levels were higher in taxane and anthracycline-resistant cell lines when compared to their sensitive counterparts and could not be downregulated in response to drug treatment. In agreement with our in vitro findings, we found that FOXM1 expression is significantly associated with Survivin and XIAP expression in samples from patients with IIIa stage breast invasive ductal carcinoma. Importantly, patients co-expressing FOXM1, Survivin, and nuclear XIAP had significantly worst overall survival, further confirming the physiological relevance of the regulation of Survivin and XIAP by FOXM1. Together, these findings suggest that the overexpression of FOXM1, XIAP, and Survivin contributes to the development of drug-resistance and is associated with poor clinical outcome in breast cancer patients.

  13. Novel approaches to target HER2-positive breast cancer: trastuzumab emtansine

    PubMed Central

    Recondo, Gonzalo; de la Vega, Maximo; Galanternik, Fernando; Díaz-Cantón, Enrique; Leone, Bernardo Amadeo; Leone, José Pablo

    2016-01-01

    The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast carcinomas. Prior to the development of targeted therapies, HER2-positive breast cancer was associated with more aggressive disease and poor prognosis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that results from the combination of trastuzumab and DM1, a derivative of the antimicrotubule agent maytansine. This molecule has the ability to enhance cytotoxic drug delivery to specifically targeted cells that overexpress HER2, therefore, maximizing efficacy while sparing toxicity. In recent years, T-DM1 has shown to improve outcomes in metastatic HER2-positive breast cancer that is resistant to trastuzumab. In addition, T-DM1 is currently being tested in the neoadjuvant and adjuvant settings to identify patients who may benefit from this therapy. This review focuses on the mechanism of action, early and late-phase clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer. PMID:27274311

  14. Neural cell adhesion molecule 2 as a target molecule for prostate and breast cancer gene therapy.

    PubMed

    Takahashi, Shu; Kato, Kazunori; Nakamura, Kiminori; Nakano, Rika; Kubota, Kazuishi; Hamada, Hirofumi

    2011-04-01

    In adenovirus-derived gene therapy, one of the problems is the difficulty in specific targeting. We have recently demonstrated that monoclonal antibody (mAb) libraries screened by fiber-modified adenovirus vector (Adv-FZ33), which is capable of binding to immunoglobulin-G (IgG), provide a powerful approach for the identification of suitable target antigens for prostate cancer therapy. Hybridoma libraries from mice immunized with androgen-dependent prostate cancer cell line LNCaP were screened and mAb were selected. Through this screening, we obtained one mAb, designated LNI-29, that recognizes a glycoprotein with an apparent molecular mass of 100 kD. It was identified as neural cell adhesion molecule 2 (NCAM2). Some prostate and breast cancer cell lines highly expressed NCAM2 whereas normal prostate cell lines expressed NCAM2 at low levels. In contrast to the low efficiency of gene transduction by Adv-FZ33 with a control antibody, LNI-29-mediated Adv-FZ33 infection induces high rates of gene delivery in NCAM2-positive cancers. NCAM2-mediated therapeutic gene transduction of uracil phosphoribosyltransferase (UPRT) had a highly effective cytotoxic effect on NCAM2-positive cancer cells, whereas it had less of an effect in cases with a control antibody. In conclusion, NCAM2 should be a novel gene therapy target for the treatment of prostate and breast cancer.

  15. DNA Topoisomerase I-Targeted Therapy for Breast Cancer

    DTIC Science & Technology

    1999-06-01

    DNA cleavage. Our results indicate that the 10,11- methylenedioxy CPT analog was effective in all three tests. Further, this analog was effective...against MX-1 and MDA-231 human breast xenografts growing in nude mice. The 10, 11- methylenedioxy analog appears to be the best choice among the analogs examined, and we are currently pursuing moving this compound into clinical trials.

  16. Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion

    PubMed Central

    Xie, Yan; Abel, Peter W.; Kirui, Joseph K.; Deng, Caishu; Sharma, Poonam; Wolff, Dennis W.; Toews, Myron L.; Tu, Yaping

    2013-01-01

    Metastasis is the major cause of breast cancer mortality. We recently reported that aberrant G-protein coupled receptor (GPCR) signaling promotes breast cancer metastasis by enhancing cancer cell migration and invasion. Phosphatidylinositol 3-kinase γ (PI3Kγ) is specifically activated by GPCRs. The goal of the present study was to determine the role of PI3Kγ in breast cancer cell migration and invasion. Immunohistochemical staining showed that the expression of PI3Kγ protein was significantly increased in invasive human breast carcinoma when compared to adjacent benign breast tissue or ductal carcinoma in situ. PI3Kγ was also detected in metastatic breast cancer cells, but not in normal breast epithelial cell line or in non-metastatic breast cancer cells. In contrast, PI3K isoforms α, β and δ were ubiquitously expressed in these cell lines. Overexpression of recombinant PI3Kγ enhanced the metastatic ability of non-metastatic breast cancer cells. Conversely, migration and invasion of metastatic breast cancer cells were inhibited by a PI3Kγ inhibitor or by siRNA knockdown of PI3Kγ but not by inhibitors or siRNAs of PI3Kα or PI3Kβ. Lamellipodia formation is a key step in cancer metastasis, and PI3Kγ blockade disrupted lamellipodia formation induced by the activation of GPCRs such as CXC chemokine receptor 4 and protease-activated receptor 1, but not by the epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that upregulated PI3Kγ conveys the metastatic signal initiated by GPCRs in breast cancer cells, and suggest that PI3Kγ may be a novel therapeutic target for development of chemotherapeutic agents to prevent breast cancer metastasis. PMID:23500535

  17. miR-155 drives telomere fragility in human breast cancer by targeting TRF1.

    PubMed

    Dinami, Roberto; Ercolani, Cristiana; Petti, Eleonora; Piazza, Silvano; Ciani, Yari; Sestito, Rosanna; Sacconi, Andrea; Biagioni, Francesca; le Sage, Carlos; Agami, Reuven; Benetti, Roberta; Mottolese, Marcella; Schneider, Claudio; Blandino, Giovanni; Schoeftner, Stefan

    2014-08-01

    Telomeres consist of DNA tandem repeats that recruit the multiprotein complex shelterin to build a chromatin structure that protects chromosome ends. Although cancer formation is linked to alterations in telomere homeostasis, there is little understanding of how shelterin function is limited in cancer cells. Using a small-scale screening approach, we identified miR-155 as a key regulator in breast cancer cell expression of the shelterin component TERF1 (TRF1). miR-155 targeted a conserved sequence motif in the 3'UTR of TRF1, resulting in its translational repression. miR-155 was upregulated commonly in breast cancer specimens, as associated with reduced TRF1 protein expression, metastasis-free survival, and relapse-free survival in estrogen receptor-positive cases. Modulating miR-155 expression in cells altered TRF1 levels and TRF1 abundance at telomeres. Compromising TRF1 expression by elevating miR-155 increased telomere fragility and altered the structure of metaphase chromosomes. In contrast, reducing miR-155 levels improved telomere function and genomic stability. These results implied that miR-155 upregulation antagonizes telomere integrity in breast cancer cells, increasing genomic instability linked to poor clinical outcome in estrogen receptor-positive disease. Our work argued that miRNA-dependent regulation of shelterin function has a clinically significant impact on telomere function, suggesting the existence of "telo-miRNAs" that have an impact on cancer and aging.

  18. Contextual Refinement of Regulatory Targets Reveals Effects on Breast Cancer Prognosis of the Regulome

    PubMed Central

    Andrews, Erik; Wang, Yue; Xia, Tian; Cheng, Wenqing; Cheng, Chao

    2017-01-01

    Gene expression regulators, such as transcription factors (TFs) and microRNAs (miRNAs), have varying regulatory targets based on the tissue and physiological state (context) within which they are expressed. While the emergence of regulator-characterizing experiments has inferred the target genes of many regulators across many contexts, methods for transferring regulator target genes across contexts are lacking. Further, regulator target gene lists frequently are not curated or have permissive inclusion criteria, impairing their use. Here, we present a method called iterative Contextual Transcriptional Activity Inference of Regulators (icTAIR) to resolve these issues. icTAIR takes a regulator’s previously-identified target gene list and combines it with gene expression data from a context, quantifying that regulator’s activity for that context. It then calculates the correlation between each listed target gene’s expression and the quantitative score of regulatory activity, removes the uncorrelated genes from the list, and iterates the process until it derives a stable list of refined target genes. To validate and demonstrate icTAIR’s power, we use it to refine the MSigDB c3 database of TF, miRNA and unclassified motif target gene lists for breast cancer. We then use its output for survival analysis with clinicopathological multivariable adjustment in 7 independent breast cancer datasets covering 3,430 patients. We uncover many novel prognostic regulators that were obscured prior to refinement, in particular NFY, and offer a detailed look at the composition and relationships among the breast cancer prognostic regulome. We anticipate icTAIR will be of general use in contextually refining regulator target genes for discoveries across many contexts. The icTAIR algorithm can be downloaded from https://github.com/icTAIR. PMID:28103241

  19. Targeting Androgen Receptor in Breast Cancer: Enzalutamide as a Novel Breast Cancer Therapeutic

    DTIC Science & Technology

    2014-09-01

    sponsored by our Pharma partners, Medivation and Astellas. Clinical Aim 1: To identify pretreatment molecular characteristics associated with lack of...2Karmanos Cancer Institute, Detroit, MI; 3Medivation, Inc., San Francisco, CA; 4Astellas Global Pharma Development, Deerfield, IL; 5Memorial Sloan

  20. Targeting Epidermal Growth Factor Receptor in triple negative breast cancer: New discoveries and practical insights for drug development.

    PubMed

    Costa, Ricardo; Shah, Ami N; Santa-Maria, Cesar A; Cruz, Marcelo R; Mahalingam, Devalingam; Carneiro, Benedito A; Chae, Young Kwang; Cristofanilli, Massimo; Gradishar, William J; Giles, Francis J

    2017-02-01

    Triple negative breast cancer (TNBC) accounts for 10-20% of cases in breast cancer. Despite recent advances in the treatment of hormonal receptor+ and HER2+ breast cancers, there are no targeted therapies available for TNBC. Evidence supports that most patients with TNBC express the transmembrane Epidermal Growth Factor Receptor (EGFR). However, early phase clinical trials failed to demonstrate significant activity of EGFR-targeted monoclonal antibodies and/or tyrosine kinase inhibitors. Here, we review the recent discoveries related to the underlying biology of the EGFR pathway in TNBC, clinical progress to date and suggest rational future approaches for investigational therapies in TNBC.

  1. 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.

  2. A Partnership Training Program: Studying Targeted Drug Delivery Using Nanoparticles in Breast Cancer Diagnosis and Therapy

    DTIC Science & Technology

    2012-10-01

    Yuan H, He R, Gao X, Jing L, Zhao F, et al. The strong MRI relaxivity of paramagnetic nanoparticles . J Phys Chem B 2008;112: 6288-91. 10. Shu CY...Delivery Using Nanoparticles In Breast Cancer Diagnosis and Therapy Paul C. Wang, Ph.D. Howard University Washington, DC 20059 15 September...undergraduate students from 6 departments at the Howard University have been trained in the use of nanoparticles as targeted drug delivery vehicles for

  3. The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

    PubMed Central

    Makvandi, Mehran; Tilahun, Estifanos D.; Lieberman, Brian P.; Anderson, Redmond-Craig; Zeng, Chenbo; Xu, Kuiying; Hou, Catherine; McDonald, Elizabeth S.; Pryma, Daniel A.; Mach, Robert H.

    2015-01-01

    Background Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC. Methods Three TNBC cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 hours. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points. Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134. Conclusion Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC. PMID:26453012

  4. Mesenchymal Stem Cells for Vascular Target Discovery in Breast Cancer-Associated Angiogenesis

    DTIC Science & Technology

    2005-09-01

    investigative gene discovery program to identify new genes involved in blood vessel formation. MSCs, a normal cell type from the bone marrow, can spontaneously...34antiangiogenesis" targets for either a classic pharmacological approach or for cell and gene therapy therapeutic strategies. The utilization of...compounds. 15. SUBJECT TERMS Marrow stroma, breast cancer, angiogenesis gene therapy, gene discovery 16. SECURITY CLASSIFICATION OF: 17. LIMITATION 18

  5. Targeting Breast Cancer with T Cells Redirected to the Vasculature. Addendum

    DTIC Science & Technology

    2012-10-01

    validated a panel of multivalent antibodies for binding to recombinant proteins by ELISA assays.. We have generated CIRs against PSMA using scFv (PZ1) and T...tracer for PET imaging. 15. SUBJECT TERMS Chimeric Immune Receptor(CIR), tumor vascular targeting, PET, TEM1, PSMA , scFv 16. SECURITY...recognizing prostate specific membrane antigen ( PSMA ), which will carry CD28 and/or 4-1BB (costimulatory). 3) Test T-bodies against breast cancer

  6. Targets and mechanisms of berberine, a natural drug with potential to treat cancer with special focus on breast cancer.

    PubMed

    Jabbarzadeh Kaboli, Parham; Rahmat, Asmah; Ismail, Patimah; Ling, King-Hwa

    2014-10-05

    Breast cancer is the most common cancer among women worldwide and novel therapeutic agents are needed to treat this disease. The plant-based alkaloid berberine has potential therapeutic applications for breast cancer, although a better understanding of the genes and cellular pathways regulated by this compound is needed to define the mechanism of its action in cancer treatment. In this review, the molecular targets of berberine in various cancers, particularly breast cancer, are discussed. Berberine was shown to be effective in inhibiting cell proliferation and promoting apoptosis in various cancerous cells. Some signaling pathways affected by berberine, including the MAP (mitogen-activated protein) kinase and Wnt/β-catenin pathways, are critical for reducing cellular migration and sensitivity to various growth factors. This review will discuss recent studies and consider the application of new prospective approaches based on microRNAs and other crucial regulators for use in future studies to define the action of berberine in cancer. The effects of berberine on cancer cell survival and proliferation are also outlined.

  7. CCN1, a candidate target for zoledronic acid treatment in breast cancer.

    PubMed

    Espinoza, Ingrid; Liu, Hong; Busby, Robert; Lupu, Ruth

    2011-05-01

    CCN1, also known as CYR61, is a survival and proangiogenic factor overexpressed in about 30% of invasive breast carcinomas, and particularly in triple-negative breast carcinomas (TNBC). CCN1 expression in breast cancer promotes tumorigenicity, metastasis, antihormone, and chemoresistance. TNBCs often develop bone metastasis, thus the vast majority of patients receive bisphosphonate treatment as a companion to chemotherapy. Zoledronic acid (ZOL), a bisphosphonate currently in use, inhibits bone resorption, prevents development of new osteolytic lesions induced by tumor metastasis, and has a direct antitumor activity in breast cancer cells and tumors. We have shown that ZOL inhibits anchorage independent growth as well as branching and morphogenesis in CCN1 overexpressing cells. However, the mechanism is not yet well understood. In this study, we investigate the effect of ZOL in breast cancer cells with high and undetectable CCN1 expression levels. We show that CCN1-expressing cells are more sensitive to ZOL, that ZOL induces downregulation of the CCN1 promoter activity and CCN1 protein expression in a dose-dependent manner, and that ZOL is associated with a decrease in phosphorylated Akt and translocation of FOXO3a, a negative regulator of CCN1 expression, to the nucleus. Deletion of the FOXO3a binding site in the CCN1 promoter prevents ZOL inhibition of the CCN1 promoter activity showing that FOXO3a transcriptional activation is necessary for ZOL to induce CCN1 inhibition. This study provides evidence that ZOL targets the proangiogenic factor (CCN1) through FOXO3a and reveals a new mechanism of ZOL action in breast cancer cells.

  8. Targeting Breast Cancer Recurrence via Hedgehog-Mediated Sensitization of Breast Cancer Stem Cells

    DTIC Science & Technology

    2012-07-01

    epithelium is carried out via symmetric mitosis that is parallel to the outer surface of the sphere. By contrast the elaboration and expansion of...Nature  439,  84  (Jan  5,  2006).   12.   J.  Debnath,  J.  S.  Brugge,  Modelling   glandular  epithelial  cancers  in

  9. Cisplatin Prodrug-Conjugated Gold Nanocluster for Fluorescence Imaging and Targeted Therapy of the Breast Cancer

    PubMed Central

    Zhou, Fangyuan; Feng, Bing; Yu, Haijun; Wang, Dangge; Wang, Tingting; Liu, Jianping; Meng, Qingshuo; Wang, Siling; Zhang, Pengcheng; Zhang, Zhiwen; Li, Yaping

    2016-01-01

    Theranostic nanomedicine has emerged as a promising modality for cancer diagnosis and treatment. In this study, we report the fabrication of fluorescence gold nanoclusters (GNC) conjugated with a cisplatin prodrug and folic acid (FA) (FA-GNC-Pt) for fluorescence imaging and targeted chemotherapy of breast cancer. The physio-chemical properties of FA-GNC-Pt nanoparticles are thoroughly characterized by fluorescence/UV-Vis spectroscopic measurement, particle size and zeta-potential examination. We find that FA-modification significantly accelerated the cellular uptake and increased the cytotoxicity of GNC-Pt nanoparticles in murine 4T1 breast cancer cells. Fluorescence imaging in vivo using 4T1 tumor bearing nude mouse model shows that FA-GNC-Pt nanoparticles selectively accumulate in the orthotopic 4T1 tumor and generate strong fluorescence signal due to the tumor targeting effect of FA. Moreover, we demonstrate that FA-GNC-Pt nanoparticles significantly inhibit the growth and lung metastasis of the orthotopically implanted 4T1 breast tumors. All these data imply a good potential of the GNC-based theranostic nanoplatform for fluorescence tumor imaging and cancer therapy. PMID:27022415

  10. Cisplatin Prodrug-Conjugated Gold Nanocluster for Fluorescence Imaging and Targeted Therapy of the Breast Cancer.

    PubMed

    Zhou, Fangyuan; Feng, Bing; Yu, Haijun; Wang, Dangge; Wang, Tingting; Liu, Jianping; Meng, Qingshuo; Wang, Siling; Zhang, Pengcheng; Zhang, Zhiwen; Li, Yaping

    2016-01-01

    Theranostic nanomedicine has emerged as a promising modality for cancer diagnosis and treatment. In this study, we report the fabrication of fluorescence gold nanoclusters (GNC) conjugated with a cisplatin prodrug and folic acid (FA) (FA-GNC-Pt) for fluorescence imaging and targeted chemotherapy of breast cancer. The physio-chemical properties of FA-GNC-Pt nanoparticles are thoroughly characterized by fluorescence/UV-Vis spectroscopic measurement, particle size and zeta-potential examination. We find that FA-modification significantly accelerated the cellular uptake and increased the cytotoxicity of GNC-Pt nanoparticles in murine 4T1 breast cancer cells. Fluorescence imaging in vivo using 4T1 tumor bearing nude mouse model shows that FA-GNC-Pt nanoparticles selectively accumulate in the orthotopic 4T1 tumor and generate strong fluorescence signal due to the tumor targeting effect of FA. Moreover, we demonstrate that FA-GNC-Pt nanoparticles significantly inhibit the growth and lung metastasis of the orthotopically implanted 4T1 breast tumors. All these data imply a good potential of the GNC-based theranostic nanoplatform for fluorescence tumor imaging and cancer therapy.

  11. Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer

    PubMed Central

    Yoo, Byunghee; Kavishwar, Amol; Wang, Ping; Ross, Alana; Pantazopoulos, Pamela; Dudley, Michael; Moore, Anna; Medarova, Zdravka

    2017-01-01

    Treatment of stage IV metastatic breast cancer patients is limited to palliative options and represents an unmet clinical need. Here, we demonstrate that pharmacological inhibition of miRNA-10b - a master regulator of metastatic cell viability – leads to elimination of distant metastases in a mouse model of metastatic breast cancer. This was achieved using the miRNA-10b inhibitory nanodrug, MN-anti-miR10b, which consists of magnetic nanoparticles, conjugated to LNA-based miR-10b antagomirs. Intravenous injection of MN-anti-miR10b into mice bearing lung, bone, and brain metastases from breast cancer resulted in selective accumulation of the nanodrug in metastatic tumor cells. Weekly treatments of mice with MN-anti-miR-10b and low-dose doxorubicin resulted in complete regression of pre-existing distant metastases in 65% of the animals and a significant reduction in cancer mortality. These observations were supported by dramatic reduction in proliferation and increase in apoptosis in metastatic sites. On a molecular level, we observed a significant increase in the expression of HOXD10, which is a known target of miRNA-10b. These results represent first steps into the uncharted territory of therapy targeted to the metastatic niche. PMID:28322342

  12. Characterization of the Role of Breast Tumor Kinase (BRK) in Breast Cancer Cells Non-responsive to EGFR-targeted Agents

    DTIC Science & Technology

    2006-07-01

    Epidermal growth factor (EGF) receptor tyrosine kinases (erbB family), EGFR (erbB1) and HER2, are highly expressed in breast cancer and are associated...utilizing microRNA ( miRNA ) instead of shRNA approach. Three different miRNA sequences targeting Brk and one scramble miRNA control were generated and...Tumor Kinase (BRK) in Breast Cancer Cells Non-responsive to EGFR-targeted Agents PRINCIPAL INVESTIGATOR: Anjaruwee Nimnual, Ph.D

  13. miR-145 sensitizes breast cancer to doxorubicin by targeting multidrug resistance-associated protein-1

    PubMed Central

    Gao, Man; Miao, Lingling; Liu, Mingxia; Li, Chenggang; Yu, Cunzhi; Yan, Hong; Yin, Yongxiang; Wang, Yizheng; Qi, Xinming; Ren, Jin

    2016-01-01

    Multidrug resistance-associated protein 1 (MRP1) is an important efflux transporter and overexpression of MRP1 usually leads to chemoresistance in breast cancer. Here, we found MRP1 overexpressed in human breast cancer tissues and breast cancer cell lines (compared with normal breast tissues and cell line, respectively). And MRP1 level increased in doxorubicin resistant MCF-7 cells compared with parental MCF-7 cells. Increasing evidences suggest microRNAs (miRNAs) influence chemotherapy response. We found miR-145 level decreased in human breast cancer tissues, breast cancer cell lines and doxorubicin resistant MCF-7 cells, and inversely correlated with MRP1 expression level. In the process of constructing MCF-7 doxorubicin resistant cell line, escalating doxorubicin markedly decreased miR-145 level, following by increased MRP1 level. Further study showed, miR-145 suppressed MRP1 expression by directly targeting MRP1 3′-untranslated regions. Overexpression of miR-145 sensitized breast cancer cells to doxorubicin in vitro and enhanced to doxorubicin chemotherapy in vivo through inducing intracellular doxorubicin accumulation via inhibiting MRP1. Taken together, our study revealed miR-145 sensitizes breast cancer to doxorubicin by targeting MRP1 and indicated the potential application in developing MRP1 inhibitor. PMID:27487127

  14. Downregulated miR-45 Inhibits the G1-S Phase Transition by Targeting Bmi-1 in Breast Cancer

    PubMed Central

    Wang, Lan; Liu, Jun-Ling; Yu, Liang; Liu, Xiang-Xia; Wu, Hong-Mei; Lei, Fang-Yong; Wu, Shu; Wang, Xi

    2015-01-01

    Abstract Bmi-1 (B cell-specific Moloney murine leukemia virus integration site 1) is upregulated in breast cancer and was involved in many malignant progressions of breast cells, including cell proliferation, stem cell pluripotency, and cancer initiation. However, the epigenetic regulatory mechanism of Bmi-1 in breast cancer remains unclear. After analysis of the ArrayExpress dataset GSE45666, we comparatively detected the expression levels of miR-495 in 9 examined breast cancer cell lines, normal breast epithelial cells and 8 pairs of fresh clinical tumor samples. Furthermore, to evaluate the effect of miR-495 on the progression of breast cancer, MCF-7 and MDA-MB-231 were transduced to stably overexpress miR-495. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, colony formation assays, 5-Bromo-2-deoxyUridine labeling and immunofluorescence, anchorage-independent growth ability assay, flow cytometry analysis, and luciferase assays were used to test the effect of miR-495 in MCF-7 and MDA-MB-231 cells in vitro. Xenografted tumor model was also used to evaluate the effect of miR-495 in breast cancer. Herein, we found that miR-495, a predicted regulator of Bmi-1, was frequently downregulated in malignant cells and tissues of breast. Upregulation of miR-495 significantly suppressed breast cancer cell proliferation and tumorigenicity via G1-S arrest. Further analysis revealed that miR-495 targeted Bmi-1 through its 3′ untranslated region. Moreover, Bmi-1 could neutralize the suppressive effect of miR-495 on cell proliferation and tumorigenicity of breast cancer in vivo. These data suggested that miR-495 could inhibit the G1-S phase transition that leads to proliferation and tumorigenicity inhibition by targeting and suppressing Bmi-1 in breast cancer. PMID:26020378

  15. DNA methylation data for identification of epigenetic targets of resveratrol in triple negative breast cancer cells.

    PubMed

    Medina-Aguilar, Rubiceli; Pérez-Plasencia, Carlos; Gariglio, Patricio; Marchat, Laurence A; Flores-Pérez, Ali; López-Camarillo, César; García Mena, Jaime

    2017-04-01

    Previous studies revealed that some bioactive food components have anti-cancer effects. However epigenetic effects of dietary compound resveratrol are largely unknown in breast cancer cells (M.A. Dawson, T. Kouzarides, 2012) [1]. Here we provide novel data and comparisons of DNA methylation status of promoter gene regions in response to resveratrol treatment at 24 h and 48 h versus untreated MDA-MB-231 breast cancer cells. DNA methylation changes were measured using Array-PRIMES method (aPRIMES) followed by whole-genome hybridization using human DNA methylation promoter microarray NimbleGen HG18 Refseq Promoter 3×720 K array. Our data were associated to corresponding changes in mRNA expression in a set of cancer-related genes. Using gene ontology analysis we also identify cancer-related cellular processes and pathways that can be epigenetically reprogramed by resveratrol. Data in this article are associated to the research articles "Methylation Landscape of Human Breast Cancer Cells in Response to Dietary Compound Resveratrol". Medina Aguilar et al., PLoS ONE 11(6): e0157866. doi:10.1371/journal.pone.0157866 2016 (A.R. Medina, P.C. Pérez, L.A. Marchat, P. Gariglio, M.J. García, C.S. Rodríguez, G.E. Ruíz, et al., 2016) [2]; and "Resveratrol inhibits cell cycle progression by targeting Aurora kinase A and Polo-like kinase 1 in breast cancer cells" in Oncology Reports. Medina Aguilar et al., 2016 Jun; 35(6):3696-704. doi: 10.3892/or.2016.4728 (A.R. Medina, P. Gariglio, M.J. García, O.E. Arechaga, S.N. Villegas, C.M. Martínez et al., 2016) [3].

  16. Breast cancer as photodynamic therapy target: Enhanced therapeutic efficiency by overview of tumor complexity

    PubMed Central

    Lamberti, María Julia; Vittar, Natalia Belén Rumie; Rivarola, Viviana Alicia

    2014-01-01

    Photodynamic therapy is a minimally invasive and clinically approved procedure for eliminating selected malignant cells with specific light activation of a photosensitizer agent. Whereas interstitial and intra-operative approaches have been investigated for the ablation of a broad range of superficial or bulky solid tumors such as breast cancer, the majority of approved photodynamic therapy protocols are for the treatment of superficial lesions of skin and luminal organs. This review article will discuss recent progress in research focused mainly on assessing the efficacies of various photosensitizers used in photodynamic therapy, as well as the combinatory strategies of various therapeutic modalities for improving treatments of parenchymal and/or stromal tissues of breast cancer solid tumors. Cytotoxic agents are used in cancer treatments for their effect on rapidly proliferating cancer cells. However, such therapeutics often lack specificity, which can lead to toxicity and undesirable side effects. Many approaches are designed to target tumors. Selective therapies can be established by focusing on distinctive intracellular (receptors, apoptotic pathways, multidrug resistance system, nitric oxide-mediated stress) and environmental (glucose, pH) differences between tumor and healthy tissue. A rational design of effective combination regimens for breast cancer treatment involves a better understanding of the mechanisms and molecular interactions of cytotoxic agents that underlie drug resistance and sensitivity. PMID:25493228

  17. Hormonally up-regulated neu-associated kinase: A novel target for breast cancer progression.

    PubMed

    Zambrano, Joelle N; Neely, Benjamin A; Yeh, Elizabeth S

    2017-02-09

    Hormonally up-regulated neu-associated Kinase (Hunk) is a protein kinase that was originally identified in the murine mammary gland and has been shown to be highly expressed in Human Epidermal Growth Factor Receptor 2 positive (HER2(+)/ErbB2(+)) breast cancer cell lines as well as MMTV-neu derived mammary tumor cell lines. However, the physiological role of Hunk has been largely elusive since its identification. Though Hunk is predicted to be a Serine/Threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK family of protein kinases, there are no known Hunk substrates that have been identified to date. Recent work demonstrates a role for Hunk in HER2(+)/ErbB2(+) breast cancer progression, including drug resistance to HER2/ErbB2 inhibitors, with Hunk potentially acting downstream of HER2/ErbB2 and the PI3K/Akt pathway. These studies have collectively shown that Hunk plays a vital role in promoting mammary tumorigenesis, as Hunk knockdown via shRNA in xenograft tumor models or crossing MMTV-neu or Pten-deficient genetically engineered mouse models into a Hunk knockout (Hunk-/-) background impairs mammary tumor growth in vivo. Because the majority of HER2(+)/ErbB2(+) breast cancer patients acquire drug resistance to HER2/ErbB2 inhibitors, the characterization of novel drug targets like Hunk that have the potential to simultaneously suppress tumorigenesis and potentially enhance efficacy of current therapeutics is an important facet of drug development. Therefore, work aimed at uncovering specific regulatory functions for Hunk that could contribute to this protein kinase's role in both tumorigenesis and drug resistance will be informative. This review focuses on what is currently known about this under-studied protein kinase, and how targeting Hunk may prove to be a potential therapeutic target for the treatment of breast cancer.

  18. Therapeutic Targeting of Alternative Translation Initiation in Breast Cancer

    DTIC Science & Technology

    2009-04-01

    investigation within the next 6 months. Cell type specific cancer cell killing of the prototype oncolytic poliovirus , PVS-RIPO, depends on selective...demanded by FDA. 15. SUBJECT TERMS Translation, eIF4E, eIF4G, IRES, Cancer, Poliovirus 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18...genetically recombinant poliovirus . Moreover, my work has laid the groundwork for correlative testing and efficacy studies of a vast array of protein kinase

  19. Targeting Breast Cancers Featuring Activating Mutations in PIK3CA by Generating a Lethal Dose of PIP3

    DTIC Science & Technology

    2008-02-01

    2003). Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma. Int J Cancer 104, 318-327...AD_________________ Award Number: W81XWH-06-1-0341 TITLE: Targeting Breast Cancers Featuring...ORGANIZATION: Dana-Farber Cancer Institute Boston, MA 02115 REPORT DATE: February 2008 TYPE OF REPORT: Annual Summary

  20. A glucose-targeted mixed micellar formulation outperforms Genexol in breast cancer cells.

    PubMed

    Moretton, Marcela A; Bernabeu, Ezequiel; Grotz, Estefanía; Gonzalez, Lorena; Zubillaga, Marcela; Chiappetta, Diego A

    2017-05-01

    Breast cancer represents the top cancer among women, accounting 521.000 deaths per year. Development of targeted nanomedicines to breast cancer tissues represents a milestone to reduce chemotherapy side effects. Taking advantage of the over-expression of glucose (Glu) membrane transporters in breast cancer cells, we aim to expand the potential of a paclitaxel (PTX)-loaded mixed micellar formulation based on polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) by its surface decoration with Glu moieties. The glycopolymer (Soluplus(Glu)) was obtained by microwave-assisted ring opening reaction of δ-gluconolactone initiated by Soluplus®. The glycosylation was confirmed by (1)H NMR and by agglutination assays employing Concanavalin A. The hydrodynamic diameter of Soluplus(Glu) micelles was characterized by dynamic light scattering (100.3±3.8nm) as well as the critical micellar concentration value (0.0151% w/v). Then, a mixed micelle formulation employing Soluplus®, Soluplus(Glu) and TPGS (3:1:1wt ratio) loaded with PTX (4mg/mL) was developed as a multifunctional nanocarrier. Its in vitro anticancer performance in MCF-7 (1.6-fold) and MDA-MB-231 (14.1-fold) was significantly enhanced (p<0.05) versus the unique commercially available micellar-based PTX-nanoformulation (Genexol®). Furthermore, the in vitro PTX cellular uptake assays revealed that the drug intracellular/cell content was significantly (p<0.05) higher for the Glu-containing mixed micelles versus Genexol® after 6h of incubation with MCF-7 (30.5-fold) and MDA-MB-231 (5-fold). Overall, results confirmed the potential of our Glu-decorated mixed colloidal formulation as an intelligent nanocarrier for PTX-targeted breast cancer chemotherapy.

  1. MUC1 Functions as an Oncogene by Targeting the Nucleus of Human Breast Cancer Cells

    DTIC Science & Technology

    2005-09-01

    Donald Kufe, M.D. CONTRACTING ORGANIZATION: Dana-Farber Cancer Institute Boston, MA 02115 REPORT DATE: September 2005 TYPE OF REPORT: Annual PREPARED...TITLE AND SUBTITLE 5a. CONTRACT NUMBER MUCI Functions as an Oncogene by Targeting the Nucleus of Human Breast Cancer Cells 5b. GRANT NUMBER DAMD17-03-1...5. MUC1 increases ERa occupancy of EREs and ERa-mediated transactivation. A. MCF-7/CsiRNA and MCF-7/ MUCl siRNA-A cells were treated with 100 nM E2 for

  2. Targeting breast cancer stem cells by dendritic cell vaccination in humanized mice with breast tumor: preliminary results

    PubMed Central

    Pham, Phuc Van; Le, Hanh Thi; Vu, Binh Thanh; Pham, Viet Quoc; Le, Phong Minh; Phan, Nhan Lu-Chinh; Trinh, Ngu Van; Nguyen, Huyen Thi-Lam; Nguyen, Sinh Truong; Nguyen, Toan Linh; Phan, Ngoc Kim

    2016-01-01

    Background Breast cancer (BC) is one of the leading cancers in women. Recent progress has enabled BC to be cured with high efficiency. However, late detection or metastatic disease often renders the disease untreatable. Additionally, relapse is the main cause of death in BC patients. Breast cancer stem cells (BCSCs) are considered to cause the development of BC and are thought to be responsible for metastasis and relapse. This study aimed to target BCSCs using dendritic cells (DCs) to treat tumor-bearing humanized mice models. Materials and methods NOD/SCID mice were used to produce the humanized mice by transplantation of human hematopoietic stem cells. Human BCSCs were injected into the mammary fat pad to produce BC humanized mice. Both hematopoietic stem cells and DCs were isolated from the human umbilical cord blood, and immature DCs were produced from cultured mononuclear cells. DCs were matured by BCSC-derived antigen incubation for 48 hours. Mature DCs were vaccinated to BC humanized mice with a dose of 106 cells/mice, and the survival percentage was monitored in both treated and untreated groups. Results The results showed that DC vaccination could target BCSCs and reduce the tumor size and prolong survival. Conclusion These results suggested that targeting BCSCs with DCs is a promising therapy for BC. PMID:27499638

  3. miR-103 regulates triple negative breast cancer cells migration and invasion through targeting olfactomedin 4.

    PubMed

    Xiong, Bin; Lei, Xuefeng; Zhang, Lei; Fu, Jia

    2017-03-18

    Our previous study showed olfactomedin 4 (OLFM4) suppressed triple-negative breast cancer cells migration, invasion and metastasis-associated protein MMP 9 expression. OLFM4 was identified as a potential target of miR-103 according to microRNA target databases and published studies. The aim of this study is to validate the relationship between miR-103 and OLFM4, and explore the function and clinical significance of miR-103 in triple-negative breast cancer patients. In our results, miR-103 negatively regulated OLFM4 expression by directly targeting its 3'-UTR. OLFM4 was a functional target of miR-103 to regulate triple-negative breast cancer cells migration, invasion and MMP 9 expression. Moreover, miR-103 overexpression was observed in triple-negative breast cancer tissues and cell lines, and associated with lymph node metastasis, distant metastasis and clinical stage. Univariate and multivariate analyses suggested that miR-103 overexpression was a poor independent prognostic factor for triple-negative breast cancer patients. In conclusion, miR-103 acts as an oncogene miRNA to promote triple-negative breast cancer cells migration and invasion through targeting OLFM4.

  4. Systematic Identification and Assessment of Therapeutic Targets for Breast Cancer Based on Genome-Wide RNA Interference Transcriptomes

    PubMed Central

    Liu, Yang; Yin, Xiaoyao; Zhong, Jing; Guan, Naiyang; Luo, Zhigang; Min, Lishan; Yao, Xing; Bo, Xiaochen; Dai, Licheng; Bai, Hui

    2017-01-01

    With accumulating public omics data, great efforts have been made to characterize the genetic heterogeneity of breast cancer. However, identifying novel targets and selecting the best from the sizeable lists of candidate targets is still a key challenge for targeted therapy, largely owing to the lack of economical, efficient and systematic discovery and assessment to prioritize potential therapeutic targets. Here, we describe an approach that combines the computational evaluation and objective, multifaceted assessment to systematically identify and prioritize targets for biological validation and therapeutic exploration. We first establish the reference gene expression profiles from breast cancer cell line MCF7 upon genome-wide RNA interference (RNAi) of a total of 3689 genes, and the breast cancer query signatures using RNA-seq data generated from tissue samples of clinical breast cancer patients in the Cancer Genome Atlas (TCGA). Based on gene set enrichment analysis, we identified a set of 510 genes that when knocked down could significantly reverse the transcriptome of breast cancer state. We then perform multifaceted assessment to analyze the gene set to prioritize potential targets for gene therapy. We also propose drug repurposing opportunities and identify potentially druggable proteins that have been poorly explored with regard to the discovery of small-molecule modulators. Finally, we obtained a small list of candidate therapeutic targets for four major breast cancer subtypes, i.e., luminal A, luminal B, HER2+ and triple negative breast cancer. This RNAi transcriptome-based approach can be a helpful paradigm for relevant researches to identify and prioritize candidate targets for experimental validation. PMID:28245581

  5. Mesoporous silica nanoparticles as a breast-cancer targeting ultrasound contrast agent

    PubMed Central

    Milgroom, Andrew; Intrator, Miranda; Madhavan, Krishna; Mazzaro, Luciano; Shandas, Robin; Liu, Bolin; Park, Daewon

    2014-01-01

    Ultrasound (US) is used widely in the context of breast cancer. While it is advantageous for a number of reasons, it has low specificity and requires the use of a contrast agent. Its use as a standalone diagnostic and real-time imaging modality could be achieved by development of a tumor-targeted ultrasound contrast agent (UCA); functionalizing the UCA with a tumor-targeting agent would also allow the targeted administration of anti-cancer drugs at the tumor site. In this article, clinical US techniques are used to show that mesoporous silica nanoparticles (MSNs), functionalized with the monoclonal antibody Herceptin®, can be used as an effective UCA by increasing US image contrast. Furthermore, in vitro assays show the successful localization and binding of the MSN-Herceptin conjugate to HER2+ cancer cells, resulting in tumor-specific cytotoxicity. These results demonstrate the potential of MSNs as a stable, biocompatible, and effective therapeutic and diagnostic (“theranostic”) agent for US-based breast cancer imaging, diagnosis, and treatment. PMID:24269054

  6. Effective treatment of HER2-amplified breast cancer by targeting HER3 and β1 integrin

    PubMed Central

    Campbell, Marcia R.; Zhang, Hui; Ziaee, Shabnam; Ruiz-Saenz, Ana; Gulizia, Nathaniel; Oeffinger, Julie; Amin, Dhara N.; Ahuja, Deepika; Moasser, Mark M.; Park, Catherine C.

    2016-01-01

    The central role of HER2 as the disease driver and HER3 as its essential partner has made them rational targets for the treatment of HER2-amplifed breast cancers, and there is considerable interest in developing highly effective treatment regimens for this disease that consist of targeted therapies alone. Much of these efforts are focused on dual targeting approaches, particularly dual targeting of the HER2-HER3 tumor driver complex itself, or vertical combinations that target downstream PI3K or Akt in addition to HER2. There is also potential in lateral combinations based on evidence implicating cross-talk with other membrane receptor systems, particularly integrins, and such lateral combinations can potentially involve either HER2 or HER3. We established a preclinical model of targeting HER3 using doxycycline-inducible shRNA and determined the efficacy of a β1 integrin inhibitor in combination with targeting HER3. We report that targeting HER3 and β1 integrin provides a particularly effective combination therapy approach for HER2-amplified cancers, surpassing the combination of HER2 and β1 integrin targeting, and evading some of the safety concerns associated with direct HER2-targeting. This further validates HER3 as a major hub mediating the tumorigenic functions of HER2 and identifies it as a high value target for lateral combination therapy strategies. PMID:26860947

  7. Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

    DTIC Science & Technology

    2014-08-01

    Ohtani S, Deng WG, Ravoori M, Bankson J, et al. (2006) The 3p21.3 tumor suppressor NPRL2 plays an important role in cisplatin -induced resistance in human...non-small cell lung cancer (NSCLC) cells to cisplatin treatment by regulating key components in the DNA repair pathway. PLoS One; 5; 8, e11994. 9. Wu

  8. Endoplasmic Reticulum-Associated Degradation Factor ERLIN2: Oncogenic Roles and Molecular Targeting of Breast Cancer

    DTIC Science & Technology

    2011-06-01

    phenotype. Oncogenes, such as Her2 , play important roles in uncontrolled proliferation and survival of breast cancer cells. However, cancer cells must...transforming roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast cancer have not been elucidated. In this... signaling in aggressive forms of human breast cancer . Accordingly, we propose that ERLIN2 represents a novel class of oncogenic factors and that

  9. Targeting the Psychosexual Challenges Faced by Couples with Breast Cancer: Can Couples Group Psychotherapy Help?

    PubMed Central

    Lagana, Luciana; Fobair, Patricia; Spiegel, David

    2016-01-01

    The need for the psychosexual rehabilitation of breast cancer survivors and their intimate partners is underscored by the high prevalence of multiple psychosexual difficulties encountered by this patient population. Concerns about health, sexuality, and emotional distress are common among women with breast cancer and are often related to the side effects of cancer treatment. Additionally, both intimate relationship problems and partners’ distress are likely to influence patients’ psychosexual health. A clearer understanding of these complex clinical issues is needed in order to implement effective psychosexual rehabilitation interventions. In this article, we extended the use of the manualized and empirically validated Supportive-Expressive Group Therapy (SEGT) model to target the specific psychosexual needs of couples with breast (as well as other types of) cancer. In view of the pertinent literature in this area and based on our clinical experience utilizing this group therapy model with different patient populations, we have discussed how clinicians involved in the psychosexual care of oncology patients could apply such a model within a couples group therapy format. PMID:27239398

  10. Breast cancer photothermal therapy based on gold nanorods targeted by covalently-coupled bombesin peptide

    NASA Astrophysics Data System (ADS)

    Heidari, Zahra; Salouti, Mojtaba; Sariri, Reyhaneh

    2015-05-01

    Photothermal therapy, a minimally invasive treatment method for killing cancers cells, has generated a great deal of interest. In an effort to improve treatment efficacy and reduce side effects, better targeting of photoabsorbers to tumors has become a new concept in the battle against cancer. In this study, a bombesin (BBN) analog that can bind to all gastrin-releasing peptide (GRP) receptor subtypes was bound covalently with gold nanorods (GNRs) using Nanothinks acid as a link. The BBN analog was also coated with poly(ethylene glycol) to increase its stability and biocompatibility. The interactions were confirmed by ultraviolet-visible and Fourier transform infrared spectroscopy. A methylthiazol tetrazolium assay showed no cytotoxicity of the PEGylated GNR-BBN conjugate. The cell binding and internalization studies showed high specificity and uptake of the GNR-BBN-PEG conjugate toward breast cancer cells of the T47D cell line. The in vitro study revealed destruction of the T47D cells exposed to the new photothermal agent combined with continuous-wave near-infrared laser irradiation. The biodistribution study showed significant accumulation of the conjugate in the tumor tissue of mice with breast cancer. The in vivo photothermal therapy showed the complete disappearance of xenographted breast tumors in the mouse model.

  11. miR-96 promotes cell proliferation, migration and invasion by targeting PTPN9 in breast cancer

    PubMed Central

    Hong, Yeting; Liang, Hongwei; Uzair-ur-Rehman; Wang, Yanbo; Zhang, Weijie; Zhou, Yong; Chen, Song’an; Yu, Mengchao; Cui, Sufang; Liu, Minghui; Wang, Nan; Ye, Chao; Zhao, Chihao; Liu, Yanqing; Fan, Qian; Zhang, Chen-Yu; Sang, Jianfeng; Zen, Ke; Chen, Xi

    2016-01-01

    microRNAs (miRNAs) have emerged as major regulators of the initiation and progression of human cancers, including breast cancer. The aim of this study is to determine the expression pattern of miR-96 in breast cancer and to investigate its biological role during tumorigenesis. We showed that miR-96 was significantly upregulated in breast cancer. We then investigated its function and found that miR-96 significantly promoted cell proliferation, migration and invasion in vitro and enhanced tumor growth in vivo. Furthermore, we explored the molecular mechanisms by which miR-96 contributes to breast cancer progression and identified PTPN9 (protein tyrosine phosphatase, non-receptor type 9) as a direct target gene of miR-96. Finally, we showed that PTPN9 had opposite effects to those of miR-96 on breast cancer cells, suggesting that miR-96 may promote breast tumorigenesis by silencing PTPN9. Taken together, this study highlights an important role for miR-96 in the regulation of PTPN9 in breast cancer cells and may provide insight into the molecular mechanisms of breast carcinogenesis. PMID:27857177

  12. Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers

    DTIC Science & Technology

    2015-10-01

    chosen for its intrinsic inhibitory activity against fungi , bacteria, and malignant cancer.230–232 One com- pound synthesized in the series (27; Figure 7...We subsequently attributed this stability to protection by LSD1 binding, since in a CoREST siRNA knockdown normally LSD1 is unstable and rapidly...Peptide Science) might protect the cell from potentially toxic formaldehyde or regulate access of the substrate to the FAD within the active site. It is not

  13. Targeting Histone Abnormality in Triple-Negative Breast Cancer

    DTIC Science & Technology

    2015-08-01

    1985 Medical or other Professional Licensure: State of Maryland 1982 Commonwealth of Pennsylvania 2009 MEMBERSHIPS IN PROFESSIONAL SCIENTIFIC...inhibition of glucocorticoid binding capacity of rat liver nuclei. Biochim. Biophys. Acta 473:200-10, 1976. PMID 181075 2. Kensler TW, Busby WF, Davidson NE...and Wogan GN. Effect of hepatocarcinogens on the binding of glucocorticoid-receptor complex in rat liver nuclei. Cancer Res. 36:4647-51, 1976. PMID

  14. Detection of breast cancer cells using targeted magnetic nanoparticles and ultra-sensitive magnetic field sensors

    PubMed Central

    2011-01-01

    Introduction Breast cancer detection using mammography has improved clinical outcomes for many women, because mammography can detect very small (5 mm) tumors early in the course of the disease. However, mammography fails to detect 10 - 25% of tumors, and the results do not distinguish benign and malignant tumors. Reducing the false positive rate, even by a modest 10%, while improving the sensitivity, will lead to improved screening, and is a desirable and attainable goal. The emerging application of magnetic relaxometry, in particular using superconducting quantum interference device (SQUID) sensors, is fast and potentially more specific than mammography because it is designed to detect tumor-targeted iron oxide magnetic nanoparticles. Furthermore, magnetic relaxometry is theoretically more specific than MRI detection, because only target-bound nanoparticles are detected. Our group is developing antibody-conjugated magnetic nanoparticles targeted to breast cancer cells that can be detected using magnetic relaxometry. Methods To accomplish this, we identified a series of breast cancer cell lines expressing varying levels of the plasma membrane-expressed human epidermal growth factor-like receptor 2 (Her2) by flow cytometry. Anti-Her2 antibody was then conjugated to superparamagnetic iron oxide nanoparticles using the carbodiimide method. Labeled nanoparticles were incubated with breast cancer cell lines and visualized by confocal microscopy, Prussian blue histochemistry, and magnetic relaxometry. Results We demonstrated a time- and antigen concentration-dependent increase in the number of antibody-conjugated nanoparticles bound to cells. Next, anti Her2-conjugated nanoparticles injected into highly Her2-expressing tumor xenograft explants yielded a significantly higher SQUID relaxometry signal relative to unconjugated nanoparticles. Finally, labeled cells introduced into breast phantoms were measured by magnetic relaxometry, and as few as 1 million labeled cells

  15. Targeting Energy Metabolic Pathways as Therapeutic Intervention for Breast Cancer

    DTIC Science & Technology

    2014-12-01

    observed that the cells with knockdown of eEF-2K expression exhibited a decreased glucose consumption (Fig. 1B), as measured by flow cytometric analysis of......3. DATES COVERED 30 Sep 2011 - 20 Sep 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Energy Metabolic Pathways as Therapeutic

  16. Understanding and Targeting Cell Growth Networks in Breast Cancer

    DTIC Science & Technology

    2012-04-01

    recombinase  (Figure  1d...with   adenoviruses   encoding   Cre   recombinase   or   a  β-­‐galactosidase   (LacZ)   control.     Enhanced   levels...target   effect   of   Cre   recombinase   or   adenoviral   infection   protocol   (Fig.   4E).   Additionally,  

  17. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2013-10-01

    www.paneuropeannetworks.com/ST9/#163/z 7 Stafford JH, Hao G, Best AM, Sun X, Thorpe PE. Highly specific PET imaging of prostate tumors in mice with an iodine - 124 ...vascular endothelial cells. • Autoradiography and PET imaging of radioactive iodine labeled PGN635 confirmed the targeting specificity of PGN635 and

  18. Development of a Vaccine Targeting Triple-Negative Breast Cancer

    DTIC Science & Technology

    2012-09-01

    Society of Clinical Oncology 27, 4685-4692 (2009). 26. Kantoff, P.W., et al. Sipuleucel - T immunotherapy for castration-resistant prostate cancer. N Engl...specific aims of this proposal are to: (1) To identify putative Class II epitopes, derived from IGF-IR, that stimulate IGF-IR-specific T cells in...model of TNBC. BODY Aim 1. To identify putative Class II epitopes, derived from IGF-IR, that stimulate IGF-IR-specific T cells in patients with

  19. Targeting of miR9/NOTCH1 interaction reduces metastatic behavior in triple-negative breast cancer.

    PubMed

    Mohammadi-Yeganeh, Samira; Mansouri, Ardalan; Paryan, Mahdi

    2015-11-01

    Many reports have indicated deregulation of a variety of microRNAs (miRNAs) in human cancers. In this study, we appraised miR-9 correlation with NOTCH1 involved in Notch signaling in metastatic breast cancer. The Notch signaling pathway has been approved to be associated with the development and progression of many human cancers, including breast cancer, but the precise mechanism has remained unknown. To the best of our knowledge, this is the first study that introduces miR-9 and NOTCH1 correlation as an effective factor in breast cancer. We found that miR-9 expression was decreased in MDA-MB-231 breast cancer cells compared with MCF-10A normal breast cell line. However, NOTCH1 was upregulated in the metastatic breast cancer cells. Furthermore, luciferase assay revealed a significant inverse correlation between miR-9 and NOTCH1. Overexpression of Notch signaling via Notch1 intracellular domain in MDA-MB-231 cell line was suppressed by lentiviruses expressing miR-9. Taken together, the results obtained by MTT, flow cytometry, migration, and wound healing assays showed that it is possible to inhibit metastasis and induce pro-apoptotic state by induction of miR-9 expression in MDA-MB-231 cells but with no effect on cell proliferation. These results shows that miR-9, by direct targeting of NOTCH1, can reveal a suppressor-like activity in metastatic breast cancer cells.

  20. Death receptor pathways mediate targeted and non-targeted effects of ionizing radiations in breast cancer cells

    PubMed Central

    Luce, Audrey; Courtin, Aurélie; Levalois, Céline; Altmeyer-Morel, Sandrine; Romeo, Paul-Henri; Lebeau, Jérôme

    2009-01-01

    Delayed cell death by mitotic catastrophe is a frequent mode of solid tumor cell death after γ-irradiation, a widely used treatment of cancer. Whereas the mechanisms that underlie the early γ-irradiation-induced cell death are well documented, those that drive the delayed cell death are largely unknown. Here we show that the Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor (TNF)-α death receptor pathways mediate the delayed cell death observed after γ-irradiation of breast cancer cells. Early after irradiation, we observe the increased expression of Fas, TRAIL-R and TNF-R that first sensitizes cells to apoptosis. Later, the increased expression of FasL, TRAIL and TNF-α permit the apoptosis engagement linked to mitotic catastrophe. Treatments with TNF-α, TRAIL or anti-Fas antibody, early after radiation exposure, induce apoptosis, whereas the neutralization of the three death receptors pathways impairs the delayed cell death. We also show for the first time that irradiated breast cancer cells excrete soluble forms of the three ligands that can induce the death of sensitive bystander cells. Overall, these results define the molecular basis of the delayed cell death of irradiated cancer cells and identify the death receptors pathways as crucial actors in apoptosis induced by targeted as well as non-targeted effects of ionizing radiation. PMID:19126655

  1. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2013-10-01

    3                          4                  Stack    Autoradiograph a b c I‐ 124 ‐PGN635 PET/CT 231BR normal d d. Detection and...in mice bearing brain metastases. PGN635F(ab’)2 were successfully labeled with I- 124 or I-125 to study its specific targeting of brain metastases...brain metastases in mice. 9 Fig. 4 Autoradiography and PET imaging of I- 124 /125 labeled PGN635 in targeting brain metastases. a

  2. Targeting siRNA Missiles to Her2+ Breast Cancer

    DTIC Science & Technology

    2009-06-01

    Nagai, H., Oniki, S., Oka, M., Horikawa, T., and Nishigori, C. (2006). Induction of cellular immunity against hair follicle melanocyte causes alopecia...Principal Investigator: Medina-Kauwe, Lali K. 4 INTRODUCTION: The purpose of this research is to test the hypothesis that recombinant Ad5 capsid...delivered the most potent cytotoxicity in order to incorporate it into the targeted complex and test it in vivo. We compared HER2- silencing siRNA

  3. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-12-01

    INVESTIGATOR: Dawen Zhao, M.D., Ph.D. CONTRACTING ORGANIZATION: University of Texas Southwestern Medical Center at Dallas Dallas, TX 75390 REPORT DATE...a fully human monoclonal antibody, was used to target exposed PS in the brain metastases. Our data show that PGN635 binds specifically to tumor...Furthermore, pretreatment with 10Gy of whole brain radiation significantly increased PGN635 binding to tumor vascular endothelial cells and tumor

  4. Targeting the Synthetic Essential Kinases of Breast Cancers

    DTIC Science & Technology

    2016-05-01

    test the role of enzymatic activities of COASY in the multi-nucleation phenotypes, we transfect wild type and enzymatic dead mutant (R499C) of COASY...and enzymatic dead mutant of COASY could completely rescue the multinucleation phenotypes (Fig 9E). COASY encode the last protein in the multi-step...acetylation (Fig 12A). To determine whether TPX2 is a target protein of CBP, we co-transfected wildtype (CBP WT) and enzymatic dead mutant (CBP Mut) CBP with

  5. Enhanced noscapine delivery using estrogen-receptor-targeted nanoparticles for breast cancer therapy.

    PubMed

    Madan, Jitender; Gundala, Sushma R; Kasetti, Yoganjaneyulu; Bharatam, Prasad V; Aneja, Ritu; Katyal, Anju; Jain, Upendra K

    2014-07-01

    Noscapine (Nos), an orally available plant-derived antitussive alkaloid, is in phase II clinical trials for cancer chemotherapy. It has extensively been shown to inhibit tumor growth in nude mice bearing human xenografts of hematopoietic, breast, lung, ovarian, brain, and prostate origin. However, high tumor-suppressive Nos dosages encumber the development of oral controlled-release formulations because of a short biological half-life (<2 h), poor absorption, low aqueous solubility, and extensive first-pass metabolism. Here, we present the design, fabrication, optimization, characterization, and biological evaluation of estrone-conjugated noscapine-loaded gelatin nanoparticles (Nos-ES-GN) for targeting estrogen-receptor-positive breast cancer MCF-7 cells. Gelatin nanoparticles (GN) were a uniformly compact size, stable at physiological pH, and showed a drug entrapment efficiency of 66.1±5.9 and 65.2±5.6% for Nos-GN and Nos-ES-GN, respectively. The secondary structure of gelatin nanocoacervates was predicted using circular dichroism and in-silico molecular modeling. Our data suggest that ethanol-fabricated GN retained the α-helical content of gelatin, whereas acetone favored the formation of random coils. The conjugation of estrone to Nos-GN did not affect the release rate of the drug, and both formulations followed first-order release kinetics with an initial burst, followed by a slow release. The IC50 value of Nos-ES-GN was 21.2 μmol/l, which was ∼50% lower than the free drug (43.3 μmol/l), suggesting targeted drug delivery. Our cell uptake study carried out in an estrogen-receptor-positive (MCF-7) and negative (MDA-MB-231) cancer cell lines showed greater accumulation of Nos-ES-GN in MCF-7 cells instead of MDA-MB-231 cells. Our data indicated that estrone-conjugated nanoparticles may potentially be used for targeting breast cancer cells.

  6. Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model.

    PubMed

    Meng, Mingyao; Wang, Wenju; Yan, Jun; Tan, Jing; Liao, Liwei; Shi, Jianlin; Wei, Chuanyu; Xie, Yanhua; Jin, Xingfang; Yang, Li; Jin, Qing; Zhu, Huirong; Tan, Weiwei; Yang, Fang; Hou, Zongliu

    2016-08-01

    Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP(+) stromal cells which mimicked the FAP(+) CAF in vivo. We immunized a breast cancer mouse model with FAP(+) stromal cells to perform immunotherapy against FAP(+) cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP(+) stromal cells whose phenotype was CD11b(+)/CD34(+)/Sca-1(+)/FSP-1(+)/MHC class I(+). Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP(+) stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4(+) and CD8(+) T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP(+) CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP(+) stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.

  7. MiR-153 promotes breast cancer cell apoptosis by targeting HECTD3

    PubMed Central

    Wu, Xiaowei; Li, Lin; Li, Yi; Liu, Zhihua

    2016-01-01

    Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) is an E3 ubiquitin ligase which ubiquitinates caspase-8, caspase-9 and promotes cancer cell survival. Aberrant HECTD3 expression is frequently involved in various types of cancer progression. However, to date, the regulation of HECTD3 remains unclear. Here, we demonstrated that miR-153 functions as a negative regulator of HECTD3 and sensitizes cisplatin-induced apoptosis in triple-negative breast cancer cells MDA-MB-231 and BT-549. Luciferase reporter assay demonstrated that miR-153 suppresses HECTD3 expression through directly targeting its mRNA within the 3’-Untranslated Region (3’UTR). Additionally, the expression levels of miR-153 and HECTD3 are inversely correlated in breast cancer cell lines. Furthermore, ectopic expression of miR-153 promotes apoptosis in MDA-MB-231 and BT-549 cells treated with cisplatin or TNF-α, and miR-153 inhibitor treatment inhibits cisplatin induced apoptosis in MDA-MB-231 and BT-549 cells. Moreover, stable overexpression of HECTD3 abrogates the sensitization effect of miR-153 to cisplatin treatment in MDA-MB-231 cells, and miR-153 inhibitor protects cells against cisplatin cytotoxicity in control cells, but not in the stable knockdown HECTD3 MDA-MB-231 cells. More importantly, breast cancer patients with higher expression levels of miR-153 had significant higher 5-year survival rate in PROGmiR database (P<0.05). Taken together, our study indicated that miR-153 inhibits TNBC survival by targeting HECTD3 and functions as a potent tumor suppressor. PMID:27508098

  8. 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.

  9. Targeting GPR110 in HER2-Overexpressing Breast Cancers

    DTIC Science & Technology

    2015-10-01

    trastuzumab (T) (L+T)), which is effective in a larger group of patients. Drugs targeting G protein-coupled receptors (GPCRs) have low toxicity because of... effects of GPR110 overexpression or knockdown on cell growth in the context of drug resistance will also be determined to understand the possible role...HER2   drug   resistance            CONCLUSIONS    REFERENCES   Figure  8.   Effects  of  GPR110

  10. mir-101-3p is a key regulator of tumor metabolism in triple negative breast cancer targeting AMPK

    PubMed Central

    Li, Xing; Tang, Hailin; Li, Shuaijie; Huang, Xiaojia; Song, Cailu; Wei, Weidong; Xie, Xiaoming

    2016-01-01

    mir-101-3p has been reported to be a tumor suppressor and a promising therapeutic target in cancer. Recently, AMPK dysfunction has been highlighted in cancers, including breast cancer. The aim of this study is to investigate the biological roles of mir-101-3p and AMPK in breast cancer. Our research demonstrated that AMPK was up-regulated in breast cancer tissues and cell lines, especially in triple negative breast cancer (TNBC). High-expression of AMPK correlated with poor outcome in both total breast cancer and TNBC patients. Ectopic expression of AMPK improved glucose uptake, glycolysis, proliferation of TNBC cells in vitro and its tumorigenicity in vivo. AMPK was predicted to be a direct target of mir-101-3p. The luciferase reporter assay was performed to certificate this prediction. The expression of AMPK was suppressed by transfection of mir-101-3p in TNBC cells. Over-expression of mir-101-3p or knock-down of AMPK inhibited glucose metabolism and proliferation of TNBC cells in vitro. Our study provides evidence that mir-101-3p- AMPK axis could be a promising therapeutic target in TNBC targeting tumor metabolism. PMID:27145268

  11. Understanding a Breast Cancer Diagnosis

    MedlinePlus

    ... Category Cancer A-Z Breast Cancer Understanding a Breast Cancer Diagnosis If you’ve been diagnosed with breast ... cancer or how fast it’s growing. Types of Breast Cancer There are several types of breast cancer. The ...

  12. A review of HER2-targeted therapy in breast and ovarian cancer: lessons from antiquity - CLEOPATRA and PENELOPE.

    PubMed

    Hodeib, Melissa; Serna-Gallegos, Tasha; Tewari, Krishnansu S

    2015-01-01

    Although breast and ovarian cancer have notable distinctions, there may exist parallel pathways that can be exploited for therapeutic gain. For example, the therapeutic arena in breast cancer has benefited greatly from available endocrine therapies as well as novel drugs designed to target the HER2 receptor, including trastuzumab, lapatinib, T-DM1 and pertuzumab. CLEOPATRA, a Phase III randomized clinical trial studying pertuzumab in women with HER2-amplified metastatic breast cancer, was practice-changing in 2014. Its counterpart, the Phase III randomized PENELOPE trial, was activated following promising Phase II data and studied pertuzumab in an enriched ovarian cancer patient population with low HER3 mRNA. This review will trace the development of anti-HER2 therapies in breast and ovarian cancer.

  13. Comprehensive molecular characterization of salivary duct carcinoma reveals actionable targets and similarity to apocrine breast cancer

    PubMed Central

    Dalin, Martin G.; Desrichard, Alexis; Katabi, Nora; Makarov, Vladimir; Walsh, Logan A.; Lee, Ken-Wing; Wang, Qingguo; Armenia, Joshua; West, Lyndsay; Dogan, Snjezana; Wang, Lu; Ramaswami, Deepa; Ho, Alan L.; Ganly, Ian; Solit, David B.; Berger, Michael F.; Schultz, Nikolaus D.; Reis-Filho, Jorge S.; Chan, Timothy A.; Morris, Luc G.T.

    2016-01-01

    Purpose Salivary duct carcinoma (SDC) is an aggressive salivary malignancy which is resistant to chemotherapy and has high mortality rates. We investigated the molecular landscape of SDC, focusing on genetic alterations and gene expression profiles. Experimental Design We performed whole-exome sequencing, RNA sequencing and immunohistochemical analyses in 16 SDC tumors, and examined selected alterations via targeted sequencing of 410 genes in a second cohort of 15 SDCs. Results SDCs harbored a higher mutational burden than many other salivary carcinomas (1.7 mutations/megabase). The most frequent genetic alterations were mutations in TP53 (55%), HRAS (23%), PIK3CA (23%), and amplification of ERBB2 (35%). Most (74%) tumors had alterations in either MAP kinase (BRAF/HRAS/NF1) genes or ERBB2. Potentially targetable alterations based on supportive clinical evidence were present in 61% of tumors. Androgen receptor (AR) was overexpressed in 75%; several potential resistance mechanisms to androgen deprivation therapy (ADT) were identified, including the AR-V7 splice variant (present in 50%, often at low ratios compared to full length AR) and FOXA1 mutations (10%). Consensus clustering and pathway analyses in transcriptome data revealed striking similarities between SDC and molecular apocrine breast cancer. Conclusions This study illuminates the landscape of genetic alterations and gene expression programs in SDC, identifying numerous molecular targets and potential determinants of response to AR antagonism. This has relevance for emerging clinical studies of ADT and other targeted therapies in SDC. The similarities between SDC and apocrine breast cancer indicate that clinical data in breast cancer may generate useful hypotheses for SDC. PMID:27103403

  14. Targeting insulin and insulin-like growth factor signaling in breast cancer

    PubMed Central

    Yang, Yuzhe; Yee, Douglas

    2012-01-01

    The insulin and insulin like growth factor (IGF) signaling systems are implicated in breast cancer biology. Thus, disrupting IGF/insulin signaling has been shown to have promise in a number of preclinical models. However, human clinical trials have been less promising. Despite evidence of some activity in early phase trials, randomized phase III studies have thus far been unable to show a benefit of blocking IGF signaling in combination with conventional strategies. In breast cancer, combination anti IGF/insulin signaling agents with hormone therapy has not yet proven to have benefit. This inability to translate the preclinical findings into useful clinical strategies calls attention to the need for a deeper understanding of this complex pathway. Development of predictive biomarkers and optimal inhibitory strategies of the IGF/insulin system should yield better clinical strategies. Furthermore, unraveling the interaction between the IGF/insulin pathway and other critical signaling pathways in breast cancer biology, namely estrogen receptor-α (ERα) and epidermal growth factor receptor (EGFR) pathways, provides additional new concepts in designing combination therapies. In this review, we will briefly summarize the current strategies targeting the IGF/insulin system, discuss the possible reasons of success or failure of the existing therapies, and provide potential future direction for research and clinical trials. PMID:23054135

  15. Jab1 is a target of EGFR signaling in ERα-negative breast cancer

    PubMed Central

    Wang, Jiaxu; Barnes, Rebecca O; West, Nathan R; Olson, Melanie; Chu, Jenny E; Watson, Peter H

    2008-01-01

    Introduction c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional signaling protein that previously has been shown to be a master regulator of a poor prognostic gene signature in invasive breast cancer and to mediate the action of S100A7. Since epidermal growth factor receptor (EGFR), like S100A7, is often expressed in estrogen receptor-alpha-negative (ERα-) breast cancer, we set out to investigate the role of Jab1 in mediating EGFR signaling, another facet of the ERα- phenotype. Methods MDA-MB-231 and MDA-MB-468 ERα-/EGFR+ cell lines were assessed for localization of Jab1 and levels of downstream genes by immunofluorescence and nuclear protein extract assay following treatment with epidermal growth factor (EGF) and extracellular signal-regulated kinase (ERK) pathway inhibitor. A cohort of 424 human breast tumors was also assessed by immunohistochemistry. Results EGF treatment of cell lines resulted in increased Jab1 nuclear expression. This effect was inhibited by the ERK pathway inhibitor, PD98059. EGF treatment was also associated with colocalization of pERK (phosphorylated ERK) and Jab1 as well as regulation of the Jab1 downstream target gene, p27. When Jab1 activity was knocked down, p27 levels were restored to pre-EGF treatment level. Analysis of EGFR and Jab1 expression in a cohort of invasive breast tumors by tissue microarray and immunohistochemistry confirmed a relationship between EGFR and increased nuclear Jab1 within the ERα- subset (n = 154, P = 0.019). The same association was also confirmed for S100A7 and Jab1 (P = 0.036), and high Jab1 nuclear expression was most frequent in tumors that were positive for both EGFR and S100A7 (P = 0.004). Conclusion Jab1 is a target of EGFR signaling in ERα- cell lines and breast tumors and therefore may be a common central factor and potential therapeutic target for important cell signaling pathways in ERα- breast cancer. PMID:18534028

  16. "Blind" targeting in action: From phage display to breast cancer cell targeting with peptide-gold nanoconjugates.

    PubMed

    Galbiati, Elisabetta; Gambini, Luca; Civitarese, Viola; Bellini, Michela; Ambrosini, Dario; Allevi, Raffaele; Avvakumova, Svetlana; Romeo, Sergio; Prosperi, Davide

    2016-09-01

    Tumor homing peptides (THPs) specific for a representative breast cancer cell line (MCF-7) were carefully selected basing on a phage-displayed peptide library freely available on the web, namely the "TumorHoPe: A Database of Tumor Homing Peptides". The selected THPs were synthesized and evaluated in terms of their affinity toward MCF-7 cells. Out of 5 tested THPs, 3 best-performing peptide sequences and 1 scrambled sequence were separately conjugated to spherical gold nanoparticles yielding stable nanoconjugates. THP nanoconjugates were examined for their ability to actively target MCF-7 cells in comparison to noncancerous 3T3-L1 fibroblast cells. These THP-gold nanoconjugates exhibited good selectivity and binding affinity by flow cytometry, and low cytotoxicity as assayed by cell death experiments. The uptake of targeted nanoconjugates by the breast cancer cells was confirmed by transmission electron microscopy analysis. This work demonstrates that it is possible to exploit the conjugation of short peptides selected from phage-displayed libraries to develop nanomaterials reliably endowed with tumor targeting potential irrespective of a specific knowledge of the target cell biology.

  17. MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1.

    PubMed

    Sun, Quanquan; Liu, Tongxin; Yuan, Yawei; Guo, Zhenli; Xie, Guozhu; Du, Shasha; Lin, Xiaoshan; Xu, Zhixin; Liu, Minfeng; Wang, Wei; Yuan, Quan; Chen, Longhua

    2015-03-01

    Radioresistance is a major challenge during the treatment of breast cancer. A further understanding of the mechanisms of radioresistance could provide strategies to address this challenge. In our study, we compared the expression of miR-200c in four distinct breast cancer cell lines: two representative basal cancer cells (MDA-MB-231 and BT549) vs. two representative luminal cancer cells (MCF-7 and BT474). The results revealed practically lower expression of miR-200c in the two basal cancer cell lines and higher expression of miR-200c in luminal cancer cells compared to the normal breast epithelial cell line MCF-10A. Ectopic expression of miR-200c in MDA-MB-231 cells inhibited irradiation-induced autophagy and sensitized the breast cancer cells to irradiation. We also identified UBQLN1 as a direct functional target of miR-200c involved in irradiation-induced autophagy and radioresistance. In 35 human breast cancer tissue samples, we detected an inverse correlation between the expression of miR-200c vs. UBQLN1 and LC3. These results indicate that the identified miR-200c/UBQLN1-mediated autophagy pathway may help to elucidate radioresistance in human breast cancer and might represent a therapeutic strategy.

  18. Mesoporous silica nanoparticles as a breast cancer targeting contrast agent for ultrasound imaging

    NASA Astrophysics Data System (ADS)

    Milgroom, Andrew Carson

    Current clinical use of ultrasound for breast cancer diagnostics is strictly limited to a role as a supplementary detection method to other modalities, such as mammography or MRI. A major reason for ultrasound’s role as a secondary method is its inability to discern between cancerous and non-cancerous bodies of similar density, like dense calcifications or benign fibroadenomas. Its detection capabilities are further diminished by the variable density of the surrounding breast tissue with the progression of age. Preliminary studies suggest that mesoporous silica nanoparticles (MSNs) are a good candidate as an in situ contrast agent for ultrasound. By tagging the silica particle surface with the cancer-targeting antibody trastuzumab (Herceptin), suspect regions of interest can be better identified in real time with standard ultrasound equipment. Once the silica-antibody conjugate is injected into the bloodstream and enters the cancerous growth’s vasculature, the antibody arm will bind to HER2, a cell surface receptor known to be dysfunctional or overexpressed in certain types of breast cancer. As more particles aggregate at the cell surface, backscatter of the ultrasonic waves increases as a result of the higher porous silica concentration. This translates to an increased contrast around the lesion boundary. Tumor detection through ultrasound contrast enhancement provides a tremendous advantage over current cancer diagnostics because is it significantly cheaper and can be monitored in real time. Characterization of MCM-41 type MSNs suggests that these particles have sufficient stability and particle size distribution to penetrate through fenestrated tumor vasculature and accumulate in HER2+ breast cancer cells through the enhanced permeation and retention (EPR) effect. A study of acoustic properties showed that particle concentration is linearly correlated to image contrast in clinical frequency-range ultrasound, although less pronounced than typical microbubble

  19. Integrative exploration of genomic profiles for triple negative breast cancer identifies potential drug targets

    PubMed Central

    Wang, Xiaosheng; Guda, Chittibabu

    2016-01-01

    Abstract Background: Triple negative breast cancer (TNBC) is high-risk due to its rapid drug resistance and recurrence, metastasis, and lack of targeted therapy. So far, no molecularly targeted therapeutic agents have been clinically approved for TNBC. It is imperative that we discover new targets for TNBC therapy. Objectives: A large volume of cancer genomics data are emerging and advancing breast cancer research. We may integrate different types of TNBC genomic data to discover molecular targets for TNBC therapy. Data sources: We used publicly available TNBC tumor tissue genomic data in the Cancer Genome Atlas database in this study. Methods: We integratively explored genomic profiles (gene expression, copy number, methylation, microRNA [miRNA], and gene mutation) in TNBC and identified hyperactivated genes that have higher expression, more copy numbers, lower methylation level, or are targets of miRNAs with lower expression in TNBC than in normal samples. We ranked the hyperactivated genes into different levels based on all the genomic evidence and performed functional analyses of the sets of genes identified. More importantly, we proposed potential molecular targets for TNBC therapy based on the hyperactivated genes. Results: Some of the genes we identified such as FGFR2, MAPK13, TP53, SRC family, MUC family, and BCL2 family have been suggested to be potential targets for TNBC treatment. Others such as CSF1R, EPHB3, TRIB1, and LAD1 could be promising new targets for TNBC treatment. By utilizing this integrative analysis of genomic profiles for TNBC, we hypothesized that some of the targeted treatment strategies for TNBC currently in development are more likely to be promising, such as poly (ADP-ribose) polymerase inhibitors, while the others are more likely to be discouraging, such as angiogenesis inhibitors. Limitations: The findings in this study need to be experimentally validated in the future. Conclusion: This is a systematic study that combined 5

  20. Breast Cancer -- Male

    MedlinePlus

    ... Home > Types of Cancer > Breast Cancer in Men Breast Cancer in Men This is Cancer.Net’s Guide to Breast Cancer in Men. Use the menu below to choose ... social workers, and patient advocates. Cancer.Net Guide Breast Cancer in Men Introduction Statistics Risk Factors and Prevention ...

  1. shRNA kinome screen identifies TBK1 as a therapeutic target for HER2+ breast cancer.

    PubMed

    Deng, Tao; Liu, Jeff C; Chung, Philip E D; Uehling, David; Aman, Ahmed; Joseph, Babu; Ketela, Troy; Jiang, Zhe; Schachter, Nathan F; Rottapel, Robert; Egan, Sean E; Al-Awar, Rima; Moffat, Jason; Zacksenhaus, Eldad

    2014-04-01

    HER2(+) breast cancer is currently treated with chemotherapy plus anti-HER2 inhibitors. Many patients do not respond or relapse with aggressive metastatic disease. Therefore, there is an urgent need for new therapeutics that can target HER2(+) breast cancer and potentiate the effect of anti-HER2 inhibitors, in particular those that can target tumor-initiating cells (TIC). Here, we show that MMTV-Her2/Neu mammary tumor cells cultured as nonadherent spheres or as adherent monolayer cells select for stabilizing mutations in p53 that "immortalize" the cultures and that, after serial passages, sphere conditions maintain TICs, whereas monolayer cells gradually lose these tumorigenic cells. Using tumorsphere formation as surrogate for TICs, we screened p53-mutant Her2/Neu(+) tumorsphere versus monolayer cells with a lentivirus short hairpin RNA kinome library. We identified kinases such as the mitogen-activated protein kinase and the TGFβR protein family, previously implicated in HER2(+) breast cancer, as well as autophagy factor ATG1/ULK1 and the noncanonical IκB kinase (IKK), TANK-binding kinase 1 (TBK1), which have not been previously linked to HER2(+) breast cancer. Knockdown of TBK1 or pharmacologic inhibition of TBK1 and the related protein, IKKε, suppressed growth of both mouse and human HER2(+) breast cancer cells. TBK1/IKKε inhibition promoted cellular senescence by suppressing p65-NF-κB and inducing p16(Ink4a). In addition, TBK1/IKKε inhibition cooperated with lapatinib, a HER2/EGFR1-targeted drug, to accelerate apoptosis and kill HER2(+) breast cancer cells both in culture and in xenografts. Our results suggest that patients with HER2(+) breast cancer may benefit from anti-TBK1/IKKε plus anti-HER2 combination therapies and establish conditions that can be used to screen for additional TIC-specific inhibitors of HER2(+) breast cancer.

  2. Transcription Factor Networks as Targets for Therapeutic Intervention of Cancer: The Breast Cancer Paradigm

    PubMed Central

    Karamouzis, Michalis V; Papavassiliou, Athanasios G

    2011-01-01

    It has long been shown that many of the presently used anticancer drugs exert their effects partly through modulating the activity of vital transcription factors. The intricacy of transcriptional regulation still represents the main obstacle for the design of transcription factor–directed agents. Systematic mapping of tumor-specific transcriptional networks and application of new molecular tools have reinforced research interest and efforts in this venue. The case of breast cancer is discussed as a representative example. PMID:21912809

  3. Targeted Therapy of Human Breast Cancer by 2-5A-Antisense Directed Against Telomerase RNA

    DTIC Science & Technology

    1999-09-01

    results in chromosome instability and cell death . To overcome this problem most cancer cells re-express the telomerase enzyme which prevents telomere...selectively destroy the target RNA. Using this system we have shown that targeting telomerase causes rapid cell death in several different breast cancer...cell lines in vitro. This cell death is not seen when the cells are treated with control oligos carrying mismatches in the target sequence. Cell death is due to apoptosis.

  4. TTK/hMPS1 Is an Attractive Therapeutic Target for Triple-Negative Breast Cancer

    PubMed Central

    Maire, Virginie; Baldeyron, Céline; Richardson, Marion; Tesson, Bruno; Vincent-Salomon, Anne; Gravier, Eléonore; Marty-Prouvost, Bérengère; De Koning, Leanne; Rigaill, Guillem; Dumont, Aurélie; Gentien, David; Barillot, Emmanuel; Roman-Roman, Sergio; Depil, Stéphane; Cruzalegui, Francisco; Pierré, Alain; Tucker, Gordon C.; Dubois, Thierry

    2013-01-01

    Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In order to discover potential therapeutic targets, we searched for protein kinases that are overexpressed in human TNBC biopsies and whose silencing in TNBC cell lines causes cell death. A cohort including human BC biopsies obtained at Institut Curie as well as normal tissues has been analyzed at a gene-expression level. The data revealed that the human protein kinase monopolar spindle 1 (hMPS1), also known as TTK and involved in mitotic checkpoint, is specifically overexpressed in TNBC, compared to the other BC subgroups and healthy tissues. We confirmed by immunohistochemistry and reverse phase protein array that TNBC expressed higher levels of TTK protein compared to the other BC subgroups. We then determined the biological effects of TTK depletion by RNA interference, through analyses of tumorigenic capacity and cell viability in different human TNBC cell lines. We found that RNAi-mediated depletion of TTK in various TNBC cell lines severely compromised their viability and their ability to form colonies in an anchorage-independent manner. Moreover, we observed that TTK silencing led to an increase in H2AX phosphorylation, activation of caspases 3/7, sub-G1 cell population accumulation and high annexin V staining, as well as to a decrease in G1 phase cell population and an increased aneuploidy. Altogether, these data indicate that TTK depletion in TNBC cells induces apoptosis. These results point out TTK as a protein kinase overexpressed in TNBC that may represent an attractive therapeutic target specifically for this poor prognosis associated subgroup of breast cancer. PMID:23700430

  5. Scanning the Human Genome for Novel Therapeutic Targets for Breast Cancer

    DTIC Science & Technology

    2005-04-01

    polymorphisms, as well as a be applied to mammals until the discovery that short knowledge of all potentially expressed genes. The dsRNA duplexes, processed...Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author( s ) and should not be construed as an official...for Novel Therapeutic Targets for DAMD17-02-1-0346 Breast Cancer 6. AUTHOR( S ) Gregory J. Hannon, Ph.D. 7. PERFORMING ORGANIZA TION NAME( S ) AND ADDRESS

  6. MiR-221 promotes stemness of breast cancer cells by targeting DNMT3b.

    PubMed

    Roscigno, Giuseppina; Quintavalle, Cristina; Donnarumma, Elvira; Puoti, Ilaria; Diaz-Lagares, Angel; Iaboni, Margherita; Fiore, Danilo; Russo, Valentina; Todaro, Matilde; Romano, Giulia; Thomas, Renato; Cortino, Giuseppina; Gaggianesi, Miriam; Esteller, Manel; Croce, Carlo M; Condorelli, Gerolama

    2016-01-05

    Cancer stem cells (CSCs) are a small part of the heterogeneous tumor cell population possessing self-renewal and multilineage differentiation potential as well as a great ability to sustain tumorigenesis. The molecular pathways underlying CSC phenotype are not yet well characterized. MicroRNAs (miRs) are small noncoding RNAs that play a powerful role in biological processes. Early studies have linked miRs to the control of self-renewal and differentiation in normal and cancer stem cells. We aimed to study the functional role of miRs in human breast cancer stem cells (BCSCs), also named mammospheres. We found that miR-221 was upregulated in BCSCs compared to their differentiated counterpart. Similarly, mammospheres from T47D cells had an increased level of miR-221 compared to differentiated cells. Transfection of miR-221 in T47D cells increased the number of mammospheres and the expression of stem cell markers. Among miR-221's targets, we identified DNMT3b. Furthermore, in BCSCs we found that DNMT3b repressed the expression of various stemness genes, such as Nanog and Oct 3/4, acting on the methylation of their promoters, partially reverting the effect of miR-221 on stemness. We hypothesize that miR-221 contributes to breast cancer tumorigenicity by regulating stemness, at least in part through the control of DNMT3b expression.

  7. Aptamer-conjugated Magnetic Nanoparticles as Targeted Magnetic Resonance Imaging Contrast Agent for Breast Cancer

    PubMed Central

    Keshtkar, Mohammad; Shahbazi-Gahrouei, Daryoush; Khoshfetrat, Seyyed Mehdi; Mehrgardi, Masoud A.; Aghaei, Mahmoud

    2016-01-01

    Early detection of breast cancer is the most effective way to improve the survival rate in women. Magnetic resonance imaging (MRI) offers high spatial resolution and good anatomic details, and its lower sensitivity can be improved by using targeted molecular imaging. In this study, AS1411 aptamer was conjugated to Fe3O4@Au nanoparticles for specific targeting of mouse mammary carcinoma (4T1) cells that overexpress nucleolin. In vitro cytotoxicity of aptamer-conjugated nanoparticles was assessed on 4T1 and HFFF-PI6 (control) cells. The ability of the synthesized nanoprobe to target specifically the nucleolin overexpressed cells was assessed with the MRI technique. Results show that the synthesized nanoprobe produced strongly darkened T2-weighted magnetic resonance (MR) images with 4T1 cells, whereas the MR images of HFFF-PI6 cells incubated with the nanoprobe are brighter, showing small changes compared to water. The results demonstrate that in a Fe concentration of 45 μg/mL, the nanoprobe reduced by 90% MR image intensity in 4T1 cells compared with the 27% reduction in HFFF-PI6 cells. Analysis of MR signal intensity showed statistically significant signal intensity difference between 4T1 and HFFF-PI6 cells treated with the nanoprobe. MRI experiments demonstrate the high potential of the synthesized nanoprobe as a specific MRI contrast agent for detection of nucleolin-expressing breast cancer cells. PMID:28028501

  8. A review of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer

    PubMed Central

    Diaby, Vakaramoko; Xiao, Hong; Montero, Alberto J.

    2015-01-01

    Breast cancer is a global health concern. In fact, breast cancer is the primary cause of death among women worldwide and constitutes the most expensive malignancy to treat. As health care resources are finite, decisions regarding the adoption and coverage of breast cancer treatments are increasingly being based on “value for money,” i.e., cost-effectiveness. As the evidence about the cost-effectiveness of breast cancer treatments is abundant, therefore difficult to navigate, systematic reviews of published systematic reviews offer the advantage of bringing together the results of separate systematic reviews in a single report. As a consequence, this paper presents an overview of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer to inform policy and reimbursement decision-making. A systematic review was conducted of published systematic reviews documenting cost-effectiveness analyses of breast cancer treatments from 2000 to 2014. Systematic reviews identified through a literature search of health and economic databases were independently assessed against inclusion and exclusion criteria. Systematic reviews of original evaluations were included only if they targeted breast cancer patients and specific breast cancer treatments (hormone therapy, chemotherapy, and targeted therapy only), documented incremental cost-effectiveness ratios, and were reported in the English language. The search strategy used a combination of these key words: “breast cancer,” “systematic review/meta-analysis,” and “cost-effectiveness/economics.” Data were extracted using predefined extraction forms and qualitatively appraised using the assessment of multiple systematic reviews (AMSTAR) tool. The literature search resulted in 511 bibliographic records, of which ten met our inclusion criteria. Five reviews were conducted in the early-stage breast cancer setting and five reviews in the metastatic setting. In

  9. Patients' satisfaction in early breast cancer treatment: Change in treatment over time and impact of HER2-targeted therapy.

    PubMed

    Spano, Jean-Philippe; Azria, David; Gonçalves, Anthony

    2015-06-01

    Although breast cancer remains a major cause of cancer death, its related death rate has dropped in the last years through early tumor detection and better available treatments. With the development of innovative techniques and new molecules as well as new routes of administration, local treatment and adjuvant therapy of early breast cancer have evolved, from mutilating, time-consuming and/or painful procedures to breast-conservative ones, sparing healthy tissues, reducing the total dose of treatment and the treatment time which in turn reduce the occurrence and severity of toxicity. In parallel with these improvements leading to an increase in survival rate, patients' health-related quality of life has become a major concern. This review aims at describing the evolution of early breast cancer treatment, and its impact on patients' quality of life, convenience, and satisfaction, including a special insight into emerging human epidermal growth factor receptor 2 (HER2)-targeted therapy.

  10. A review of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer.

    PubMed

    Diaby, Vakaramoko; Tawk, Rima; Sanogo, Vassiki; Xiao, Hong; Montero, Alberto J

    2015-05-01

    Breast cancer is a global health concern. In fact, breast cancer is the primary cause of death among women worldwide and constitutes the most expensive malignancy to treat. As health care resources are finite, decisions regarding the adoption and coverage of breast cancer treatments are increasingly being based on "value for money," i.e., cost-effectiveness. As the evidence about the cost-effectiveness of breast cancer treatments is abundant, therefore difficult to navigate, systematic reviews of published systematic reviews offer the advantage of bringing together the results of separate systematic reviews in a single report. As a consequence, this paper presents an overview of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer to inform policy and reimbursement decision-making. A systematic review was conducted of published systematic reviews documenting cost-effectiveness analyses of breast cancer treatments from 2000 to 2014. Systematic reviews identified through a literature search of health and economic databases were independently assessed against inclusion and exclusion criteria. Systematic reviews of original evaluations were included only if they targeted breast cancer patients and specific breast cancer treatments (hormone therapy, chemotherapy, and targeted therapy only), documented incremental cost-effectiveness ratios, and were reported in the English language. The search strategy used a combination of these key words: "breast cancer," "systematic review/meta-analysis," and "cost-effectiveness/economics." Data were extracted using predefined extraction forms and qualitatively appraised using the assessment of multiple systematic reviews (AMSTAR) tool. The literature search resulted in 511 bibliographic records, of which ten met our inclusion criteria. Five reviews were conducted in the early-stage breast cancer setting and five reviews in the metastatic setting. In early-stage breast

  11. Targeting Signal Transduction Pathways in Metastatic Breast Cancer: A Comprehensive Review

    PubMed Central

    Rosen, Lee S.; Ashurst, Helen Louise

    2010-01-01

    Greater understanding of the underlying etiology and biology of breast cancer is enabling the clinical development of targeted therapies for metastatic breast cancer (MBC). Following the successful introduction of trastuzumab, the first human epidermal growth factor receptor (HER) biologically targeted therapy to become widely used in MBC patients, other agents have been developed. Novel agents include monoclonal antibodies such as pertuzumab, which bind to receptors on the cell surface, and tyrosine kinase inhibitors (TKIs) such as lapatinib, which target intracellular pathways such as that of the epidermal growth factor receptor. There is also growing clinical experience with antiangiogenic agents, particularly in combination with chemotherapy. These include the monoclonal antibody bevacizumab, which targets vascular endothelial growth factor receptor, and multitargeted TKIs with antiangiogenic and antiproliferative activities, such as sunitinib. Combination treatment with multiple agents targeting both the HER family and angiogenic pathways (e.g., trastuzumab plus bevacizumab) is also showing activity in the clinical setting. Despite recent advances, there are unanswered questions regarding the management of MBC with targeted agents. Future studies are necessary to determine the optimal combinations, doses, and schedules required to maximize clinical activity while minimizing toxicity. Despite the temptation to use a targeted agent in all patients, identification of patient subgroups most likely to benefit must be a key goal and will be critical to the successful future use of these treatments. The aim of this review is to summarize some of the key signaling pathways involved in tumor progression and some of the novel therapies that are in development for MBC. PMID:20200040

  12. Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity

    PubMed Central

    Bao, Bin; Mitrea, Cristina; Wijesinghe, Priyanga; Marchetti, Luca; Girsch, Emily; Farr, Rebecca L.; Boerner, Julie L; Mohammad, Ramzi; Dyson, Greg; Terlecky, Stanley R.; Bollig-Fischer, Aliccia

    2017-01-01

    Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30–60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL—a re-engineered protein form of the antioxidant enzyme catalase—inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c. PMID:28281569

  13. Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity.

    PubMed

    Bao, Bin; Mitrea, Cristina; Wijesinghe, Priyanga; Marchetti, Luca; Girsch, Emily; Farr, Rebecca L; Boerner, Julie L; Mohammad, Ramzi; Dyson, Greg; Terlecky, Stanley R; Bollig-Fischer, Aliccia

    2017-03-10

    Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL-a re-engineered protein form of the antioxidant enzyme catalase-inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c.

  14. Transcription factor Fos-related antigen 1 is an effective target for a breast cancer vaccine

    NASA Astrophysics Data System (ADS)

    Luo, Yunping; Zhou, He; Mizutani, Masato; Mizutani, Noriko; Reisfeld, Ralph A.; Xiang, Rong

    2003-07-01

    Protection against breast cancer was achieved with a DNA vaccine against murine transcription factor Fos-related antigen 1, which is overexpressed in aggressively proliferating D2F2 murine breast carcinoma. Growth of primary s.c. tumor and dissemination of pulmonary metastases was markedly suppressed by this oral DNA vaccine, carried by attenuated Salmonella typhimurium, encoding murine Fos-related antigen 1, fused with mutant polyubiquitin, and cotransformed with secretory murine IL-18. The life span of 60% of vaccinated mice was tripled in the absence of detectable tumor growth after lethal tumor cell challenge. Immunological mechanisms involved activation of T, natural killer, and dendritic cells, as indicated by up-regulation of their activation markers and costimulatory molecules. Markedly increased specific target cell lysis was mediated by both MHC class I-restricted CD8+ T cells and natural killer cells isolated from splenocytes of vaccinated mice, including a significant release of proinflammatory cytokines IFN- and IL-2. Importantly, fluorescence analysis of fibroblast growth factor 2 and tumor cell-induced vessel growth in Matrigel plugs demonstrated marked suppression of angiogenesis only in vaccinated animals. Taken together, this multifunctional DNA vaccine proved effective in protecting against growth and metastases of breast cancer by combining the action of immune effector cells with suppression of tumor angiogenesis. vaccine | tumor | metastases | antiangiogenesis

  15. 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

  16. AECHL-1 targets breast cancer progression via inhibition of metastasis, prevention of EMT and suppression of Cancer Stem Cell characteristics

    PubMed Central

    Dasgupta, Aparajita; Sawant, Mithila A.; Kavishwar, Gayatri; Lavhale, Manish; Sitasawad, Sandhya

    2016-01-01

    Triple negative breast cancer (TNBC) features among the most aggressive manifestations of cancer due to its enhanced metastatic potential and immunity to therapeutics which target hormone receptors. Under such scenarios, anti-cancer compounds with an ability to influence multiple targets, or an entire process, will have an advantage over specific signal transduction inhibitors. To counter the metastatic threat it is essential to target cellular components central to the processes of cancer cell migration and adaptation. Our previous work on a novel triterpenoid, AECHL-1, explored its anti-cancer potential, and linked it to elevated ER stress in cancer cells, while its anti-angiogenic potential was credited for its ability to manipulate the cytoskeleton. Here, we broaden its range of action by showing that it curbs the metastatic ability of TNBC cells, both in vitro in MDA-MB-231 cell line and in vivo, in mouse models of metastasis. AECHL-1 does so by disrupting the cytoskeletal network, and also suppressing NF-κB and β-Catenin mediated key molecular pathways. These activities also contributed to AECHL-1 mediated suppression of TGF-β/TNF-α induced Epithelial to Mesenchymal Transition (EMT) and cancer stem cell characteristic. Thus, we present AECHL-1 as a promising therapeutic inhibitor of metastatic disease. PMID:27974826

  17. MicroRNA-154 inhibits growth and invasion of breast cancer cells through targeting E2F5.

    PubMed

    Xu, Hui; Fei, Dan; Zong, Shan; Fan, Zhimin

    2016-01-01

    Accumulating evidence suggested that microRNA-154 (miR-154) might play important roles in the development of various cancer types. However, the role of miR-154 in breast cancer progression remains largely unknown. Here, miR-154 expression level was measured via quantitative real-time RT-PCR (qRT-PCR) in 36 pairs of human breast cancer tissues and adjacent normal breast tissues and in a panel of human breast cancer cell lines. Cell proliferation, cycle, migration, and invasion were assessed by CCK8 assay, flow cytometer assay, wound healing assay and transwell invasion assay, respectively. Luciferase reporter assay and Western blot was used to verify E2F transcription factor 5 protein (E2F5) as a novel target gene of miR-154. Our results showed that miR-154 was frequently downregulated in breast cancer tissues and cell lines. Overexpression of miR-154 in MCF-7 cells significantly inhibited cell proliferation, migration, and invasion, and increased cell arrest at G0/G1 stage in vitro. E2F5 was identified as a target of miR-154, and its expression was inversely correlated with miR-154 expression in clinical breast cancer tissues. In addition, downregulation of E2F5 in MCF7 cells had similar effect on cell proliferation, cycle, migration and invasion by miR-154 induced. These findings indicate that miR-154 acts as a tumor suppressor by targeting E2F5, suggesting miR-154 as a potential therapeutic target for the treatment of breast cancer.

  18. Dietary targeting of tumor suppressors and oncogenes for breast cancer prevention

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Breast cancer is a complex disease that arises from genetic and epigenetic changes in molecules that are critical for growth control, DNA repair, apoptosis, and differentiation. The incidence of breast cancer varies worldwide, implicating diet and lifestyle disparities among the general population a...

  19. Breast Cancer In Women

    Cancer.gov

    This infographic shows the Breast Cancer Subtypes in Women. It’s important for guiding treatment and predicting survival. Know the Science: HR = Hormone receptor. HR+ means tumor cells have receptors for the hormones estrogen or progesterone, which can promote the growth of HR+ tumors. Hormone therapies like tamoxifen can be used to treat HR+ tumors. HER2 = Human epidermal growth Factor receptor, HER2+ means tumor cells overexpress (make high levels of) a protein, called HE2/neu, which has been shown to be associated with certain aggressive types of breast cancer. Trastuzumab and some other therapies can target cells that overexpress HER2. HR+/HER2, aka “LuminalA”. 73% of all breast cancer cases: best prognosis, most common subtype for every race, age, and poverty level. HR-/HER2, aka “Triple Negative”: 13% of all breast cancer cases, Worst prognosis, Non-Hispanic blacks have the highest rate of this subtype at every age and poverty level. HR+/HER2+, aka “Luminal B”, 10% of all breast cancer cases, little geographic variation by state. HR-/HER2+, aka”HER2-enriched”, 5% of all breast cancer cases, lowest rates for all races and ethnicities. www.cancer.gov Source: Special section of the Annual Report to the Nation on the Status of Cancer, 1975-2011.

  20. Male Breast Cancer

    MedlinePlus

    Although breast cancer is much more common in women, men can get it too. It happens most often to men between ... 60 and 70. Breast lumps usually aren't cancer. However, most men with breast cancer have lumps. ...

  1. Breast Cancer (For Kids)

    MedlinePlus

    ... de los dientes Video: Getting an X-ray Breast Cancer KidsHealth > For Kids > Breast Cancer Print A A ... for it when they are older. What Is Breast Cancer? The human body is made of tiny building ...

  2. Breast Cancer Trends

    MedlinePlus

    ... Breast Cancer Funding: Young Breast Cancer Survivors Funding: Breast Cancer Genomics Statistics Rates by Race and Ethnicity Rates by State Risk by Age Trends What CDC Is Doing Research African American Women and Mass Media Campaign Public Service Announcements Print ...

  3. Identification of Breast Cancer Specific Proteolytic Activities for Targeted Prodrug Activation

    DTIC Science & Technology

    2006-05-01

    overexpress hK2 to generate models that can be used for in vivo testing. Studies with Human Breast Cancer extracts Our original intention was to...microsomes for detection by fluorescence based cell sorting. Once we have optimized the system we will begin to analyze extracts from breast...tested for hydrolysis in breast cancer ECF extracts to determine best peptide sequence for further development 10 DAMD17-03-1-0304 P.I. Denmeade

  4. Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer

    PubMed Central

    Upreti, Meenakshi; Jyoti, Amar; Johnson, Sara E.; Swindell, Elden P.; Napier, Dana; Sethi, Pallavi; Chan, Ryan; Feddock, Jonathan M.; Weiss, Heidi L.; O'Halloran, Thomas V.; Mark Evers, B.

    2016-01-01

    Currently there are no FDA approved targeted therapies for Triple Negative Breast Cancer (TNBC). Ongoing clinical trials for TNBC have focused primarily on targeting the epithelial cancer cells. However, targeted delivery of cytotoxic payloads to the non-transformed tumor associated-endothelium can prove to be an alternate approach that is currently unexplored. The present study is supported by recent findings on elevated expression of stromal galectin-1 in clinical samples of TNBC and our ongoing findings on stromal targeting of radiation induced galectin-1 by the anginex-conjugated arsenic-cisplatin loaded liposomes using a novel murine tumor model. We demonstrate inhibition of tumor growth and metastasis in response to the multimodal nanotherapeutic strategy using a TNBC model with orthotopic tumors originating from 3D tumor tissue analogs (TTA) comprised of tumor cells, endothelial cells and fibroblasts. The ‘rigorous’ combined treatment regimen of radiation and targeted liposomes is also shown to be well tolerated. More importantly, the results presented provide a means to exploit clinically relevant radiation dose for concurrent receptor mediated enhanced delivery of chemotherapy while limiting overall toxicity. The proposed study is significant as it falls in line with developing combinatorial therapeutic approaches for stroma-directed tumor targeting using tumor models that have an appropriate representation of the TNBC microenvironment. PMID:27223428

  5. Targeting Innate Immunity with dsRNA-Conjugated Mesoporous Silica Nanoparticles Promotes Antitumor Effects on Breast Cancer Cells.

    PubMed

    Ultimo, Amelia; Giménez, Cristina; Bartovsky, Pavel; Aznar, Elena; Sancenón, Félix; Marcos, M Dolores; Amorós, Pedro; Bernardo, Ana R; Martínez-Máñez, Ramón; Jiménez-Lara, Ana M; Murguía, José R

    2016-01-26

    We describe herein a Toll-like receptor 3 (TLR3) targeting delivery system based on mesoporous silica nanoparticles capped with the synthetic double stranded RNA polyinosinic-polycytidylic acid (poly(I:C)) for controlled cargo delivery in SK-BR-3 breast carcinoma cells. Our results show that poly(I:C)-conjugated nanoparticles efficiently targeted breast cancer cells due to dsRNA-TLR3 interaction. Such interaction also triggered apoptotic pathways in SK-BR-3, significantly decreasing cells viability. Poly(I:C) cytotoxic effect in breast carcinoma cells was enhanced by loading nanoparticles' mesopores with the anthracyclinic antibiotic doxorubicin, a commonly used chemotherapeutic agent.

  6. A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells.

    PubMed

    Papadakis, Emmanouil; Robson, Natalia; Yeomans, Alison; Bailey, Sarah; Laversin, Stephanie; Beers, Stephen; Sayan, A Emre; Ashton-Key, Margaret; Schwaiger, Stefan; Stuppner, Hermann; Troppmair, Jakob; Packham, Graham; Cutress, Ramsey

    2016-04-05

    Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial.

  7. A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells

    PubMed Central

    Papadakis, Emmanouil; Robson, Natalia; Yeomans, Alison; Bailey, Sarah; Laversin, Stephanie; Beers, Stephen; Sayan, A. Emre; Ashton-Key, Margaret; Schwaiger, Stefan; Stuppner, Hermann; Troppmair, Jakob; Packham, Graham; Cutress, Ramsey

    2016-01-01

    Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial. PMID:26958811

  8. Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24

    PubMed Central

    Bhutia, Sujit K.; Das, Swadesh K.; Azab, Belal; Menezes, Mitchell E.; Dent, Paul; Wang, Xiang-Yang; Sarkar, Devanand; Fisher, Paul B.

    2015-01-01

    Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis and modulation of antitumor immune responses. In our study, we elucidated the role of MDA-7/IL-24 in inhibiting growth of breast cancer-initiating/stem cells. Ad.mda-7 infection decreased proliferation of breast cancer-initiating/stem cells without affecting normal breast stem cells. Ad.mda-7 induced apoptosis and endoplasmic reticulum stress in breast cancer-initiating/stem cells similar to unsorted breast cancer cells and inhibited the self-renewal property of breast cancer-initiating/stem cells by suppressing Wnt/β-catenin signaling. Prevention of inhibition of Wnt signaling by LiCl increased cell survival upon Ad.mda-7 treatment, suggesting that Wnt signaling inhibition might play a key role in MDA-7/IL-24-mediated death of breast cancer-initiating/stem cells. In a nude mouse subcutaneous xenograft model, Ad.mda-7 injection profoundly inhibited growth of tumors generated from breast cancer-initiating/stem cells and also exerted a potent “bystander” activity inhibiting growth of distant uninjected tumors. Further studies revealed that tumor growth inhibition by Ad.mda-7 was associated with a decrease in proliferation and angiogenesis, two intrinsic features of MDA-7/IL-24, and a reduction in vivo in the percentage of breast cancer-initiating/stem cells. Our findings demonstrate that MDA-7/IL-24 is not only nontoxic to normal cells and normal stem cells but also can kill both unsorted cancer cells and enriched populations of cancer-initiating/stem cells, providing further documentation that MDA-7/IL-24 might be a safe and effective way to eradicate cancers and also potentially establish disease-free survival. PMID:23720015

  9. Role of HER2 mutations in refractory metastatic breast cancers: targeted sequencing results in patients with refractory breast cancer.

    PubMed

    Park, Yeon Hee; Shin, Hyun-Tae; Jung, Hae Hyun; Choi, Yoon-La; Ahn, TaeJin; Park, Kyunghee; Lee, Aeri; Do, In-Gu; Kim, Ji-Yeon; Ahn, Jin Seok; Park, Woong-Yang; Im, Young-Hyuck

    2015-10-13

    In women with metastatic breast cancer (MBC), introduction of the anti-HER2 (human epidermal growth factor receptor-2) directed therapies including trastuzumab, pertuzumab, lapatinib, and/or trastuzumab-DM1 has markedly improved overall survival. However, not all cases of HER2-positive breast tumours derive similar benefit from HER2-directed therapy, and a significant number of patients experience disease progression because of primary or acquired resistance to anti-HER2-directed therapies. We integrated genomic and clinicopathological analyses in a cohort of patients with refractory breast cancer to anti-HER2 therapies to identify the molecular basis for clinical heterogeneity. To study the molecular basis underlying refractory MBC, we obtained 36 MBC tumours tissues and used next-generation sequencing to investigate the mutational and transcriptional profiles of 83 genes. We focused on HER2 mutational sites and HER2 pathways to identify the roles of HER2 mutations and the HER2 pathway in the refractoriness to anti-HER2 therapies. Analysis using massively parallel sequencing platform, CancerSCAN™, revealed that HER2 mutations were found in six of 36 patients (16.7%). One patient was ER (estrogen receptor)-positive and HER2-negative and the other five HER2 mutated patients were HER2-positive and HR (hormone receptor)-negative. Most importantly, four of these five patients did not show any durable clinical response to HER2-directed therapies. The HER2 pathway score obtained through transcriptional analyses identified that Growth Receptor Biding protein 2 (GRB2) was the most significantly down regulated gene in the HER2 mutated samples. Detection of HER2 mutations using higher deep DNA sequencing may identify a predictive biomarker of resistance to HER2-directed therapy. Functional validation is warranted.

  10. Anti-HER2/neu peptide-conjugated iron oxide nanoparticles for targeted delivery of paclitaxel to breast cancer cells

    NASA Astrophysics Data System (ADS)

    Mu, Qingxin; Kievit, Forrest M.; Kant, Rajeev J.; Lin, Guanyou; Jeon, Mike; Zhang, Miqin

    2015-10-01

    Nanoparticles (NPs) for targeted therapy are required to have appropriate size, stability, drug loading and release profiles, and efficient targeting ligands. However, many of the existing NPs such as albumin, liposomes, polymers, gold NPs, etc. encounter size limit, toxicity and stability issues when loaded with drugs, fluorophores, and targeting ligands. Furthermore, antibodies are bulky and this can greatly affect the physicochemical properties of the NPs, whereas many small molecule-based targeting ligands lack specificity. Here, we report the utilization of biocompatible, biodegradable, small (~30 nm) and stable iron oxide NPs (IONPs) for targeted delivery of paclitaxel (PTX) to HER2/neu positive breast cancer cells using an anti-HER2/neu peptide (AHNP) targeting ligand. We demonstrate the uniform size and high stability of these NPs in biological medium, their effective tumour targeting in live mice, as well as their efficient cellular targeting and selective killing in human HER2/neu-positive breast cancer cells.Nanoparticles (NPs) for targeted therapy are required to have appropriate size, stability, drug loading and release profiles, and efficient targeting ligands. However, many of the existing NPs such as albumin, liposomes, polymers, gold NPs, etc. encounter size limit, toxicity and stability issues when loaded with drugs, fluorophores, and targeting ligands. Furthermore, antibodies are bulky and this can greatly affect the physicochemical properties of the NPs, whereas many small molecule-based targeting ligands lack specificity. Here, we report the utilization of biocompatible, biodegradable, small (~30 nm) and stable iron oxide NPs (IONPs) for targeted delivery of paclitaxel (PTX) to HER2/neu positive breast cancer cells using an anti-HER2/neu peptide (AHNP) targeting ligand. We demonstrate the uniform size and high stability of these NPs in biological medium, their effective tumour targeting in live mice, as well as their efficient cellular

  11. Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress

    PubMed Central

    Du, Zhanwen; Gao, Jinnan; Yang, Shuming; Gorityala, Shashank; Xiong, Xiahui; Deng, Ou; Ma, Zhefu; Yan, Chunhong; Susana, Gonzalo; Xu, Yan; Zhang, Junran

    2016-01-01

    Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells. PMID:27167194

  12. CD44-Tropic Polymeric Nanocarrier for Breast Cancer Targeted Rapamycin Chemotherapy

    PubMed Central

    Zhao, Yunqi; Zhang, Ti; Duan, Shaofeng; Davies, Neal M.; Forrest, M. Laird

    2014-01-01

    In contrast with the conventional targeting of nanoparticles to cancer cells with antibody or peptide conjugates, a hyaluronic acid (HA) matrix nanoparticle with intrinsic-CD44-tropism was developed to deliver rapamycin for localized CD44-positive breast cancer treatment. Rapamycin was chemically conjugated to the particle surface via a novel sustained-release linker, 3-amino-4-methoxy-benzoic acid. The release of the drug from the HA nanoparticle was improved by 42-fold compared to HA-temsirolimus in buffered saline. In CD44 positive MDA-MB-468 cells, using HA as drug delivery carrier, the cell-viability was significantly decreased compared to free rapamycin and CD44-blocked controls. Rat pharmacokinetics showed that the area-under-the-curve of HA nanoparticle formulation was 2.96-fold greater than that of the free drug, and the concomitant total body clearance was 8.82-fold slower. Moreover, in immunocompetent BALB/c mice bearing CD44-positive 4T1.2neu breast cancer, the rapamycin1loaded HA particles significantly improved animal survival, suppressed tumor growth and reduced the prevalence of lung metastasis. PMID:24637218

  13. A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II

    PubMed Central

    Cui, Guozhen; Chan, Judy Yuet-Wa; Wang, Li; Li, Chuwen; Shan, Luchen; Xu, Changjiang; Zhang, Qingwen; Wang, Yuqiang; Di, Lijun; Lee, Simon Ming-Yuen

    2016-01-01

    The mitochondrial respiratory chain, including mitochondrial complex II, has emerged as a potential target for cancer therapy. In the present study, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), DT-010, was synthesized. Our results showed that DT-010 is more potent than its parental compounds separately or in combination, in inhibiting the proliferation of MCF-7 and MDA-MB-231 cells by inducing cytotoxicity and promoting cell cycle arrest. It also inhibited the growth of 4T1 breast cancer cells in vivo. DT-010 suppressed the fundamental parameters of mitochondrial function in MCF-7 cells, including basal respiration, ATP turnover, maximal respiration. Treatment with DT-010 in MCF-7 and MDA-MB-231 cells resulted in the loss of mitochondrial membrane potential and decreased ATP production. DT-010 also promoted ROS generation, while treatment with ROS scavenger, NAC (N-acetyl-L-cysteine), reversed DT-010-induced cytotoxicity. Further study showed that DT-010 suppressed succinate-induced mitochondrial respiration and impaired mitochondrial complex II enzyme activity indicating that DT-010 may inhibit mitochondrial complex II. Overall, our results suggested that the antitumor activity of DT-010 is associated with inhibition of mitochondrial complex II, which triggers ROS generation and mitochondrial dysfunction in breast cancer cells. PMID:27081033

  14. Overexpression of miR-206 suppresses glycolysis, proliferation and migration in breast cancer cells via PFKFB3 targeting

    SciTech Connect

    Ge, Xin; Lyu, Pengwei; Cao, Zhang; Li, Jingruo; Guo, Guangcheng; Xia, Wanjun; Gu, Yuanting

    2015-08-07

    miRNAs, sorting as non-coding RNAs, are differentially expressed in breast tumor and act as tumor promoters or suppressors. miR-206 could suppress the progression of breast cancer, the mechanism of which remains unclear. The study here was aimed to investigate the effect of miR-206 on human breast cancers. We found that miR-206 was down-regulated while one of its predicted targets, 6-Phosphofructo-2-kinase (PFKFB3) was up-regulated in human breast carcinomas. 17β-estradiol dose-dependently decreased miR-206 expression as well as enhanced PFKFB3 mRNA and protein expression in estrogen receptor α (ERα) positive breast cancer cells. Furthermore, we identified that miR-206 directly interacted with 3′-untranslated region (UTR) of PFKFB3 mRNA. miR-206 modulated PFKFB3 expression in MCF-7, T47D and SUM159 cells, which was influenced by 17β-estradiol depending on ERα expression. In addition, miR-206 overexpression impeded fructose-2,6-bisphosphate (F2,6BP) production, diminished lactate generation and reduced cell proliferation and migration in breast cancer cells. In conclusion, our study demonstrated that miR-206 regulated PFKFB3 expression in breast cancer cells, thereby stunting glycolysis, cell proliferation and migration. - Highlights: • miR-206 was down-regulated and PFKFB3 was up-regulated in human breast carcinomas. • 17β-estradiol regulated miR-206 and PFKFB3 expression in ERα+ cancer cells. • miR-206directly interacted with 3′-UTR of PFKFB3 mRNA. • miR-206 fructose-2,6-bisphosphate (F2,6BP) impeded production and lactate generation. • miR-206 reduced cell proliferation and migration in breast cancer cells.

  15. Biodegradable nanoparticles for targeted ultrasound imaging of breast cancer cells in vitro

    NASA Astrophysics Data System (ADS)

    Liu, Jun; Li, Jie; Rosol, Thomas J.; Pan, Xueliang; Voorhees, Jeffrey L.

    2007-08-01

    Disease-specific enhanced imaging through a targeted agent promises to improve the specificity of medical ultrasound. Nanoparticles may provide unique advantages for targeted ultrasound imaging due to their novel physical and surface properties. In this study, we examined a nanoparticle agent developed from a biodegradable polymer, polylactic acid (PLA). The nanoparticles (mean diameter = 250 nm) were surface conjugated to an anti-Her2 antibody (i.e., Herceptin) for specific binding to breast cancer cells that overexpress Her2 receptors. We examined the targeting specificity and the resultant ultrasound enhancement in Her2-positive and negative cells. Flow cytometry and confocal imaging were used to assess the nanoparticle-cell binding. Her2-positive cells demonstrated substantial staining after incubation with nanoparticle/antibody conjugates, while minimal staining was found in Her2-negative cells, indicating receptor-specific binding of the conjugated PLA nanoparticles. In high-resolution ultrasound B-mode images, the average gray scale of the Her2-positive cells was consistently and significantly higher after nanoparticle treatment (133 ± 4 in treated cells versus 109 ± 4 in control, p < 0.001, n = 5), while no difference was detected in the cells that did not overexpress the receptors (117 ± 3 in treated cells versus 118 ± 5 in control). In conclusion, the feasibility of using targeted nanoparticles to enhance ultrasonic images was demonstrated in vitro. This may be a promising approach to target cancer biomarkers for site-specific ultrasound imaging.

  16. Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C.

    PubMed

    Dryden, Nicola H; Broome, Laura R; Dudbridge, Frank; Johnson, Nichola; Orr, Nick; Schoenfelder, Stefan; Nagano, Takashi; Andrews, Simon; Wingett, Steven; Kozarewa, Iwanka; Assiotis, Ioannis; Fenwick, Kerry; Maguire, Sarah L; Campbell, James; Natrajan, Rachael; Lambros, Maryou; Perrakis, Eleni; Ashworth, Alan; Fraser, Peter; Fletcher, Olivia

    2014-11-01

    Genome-wide association studies have identified more than 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions and several map to gene deserts, regions of several hundred kilobases lacking protein-coding genes. We hypothesized that gene deserts harbor long-range regulatory elements that can physically interact with target genes to influence their expression. To test this, we developed Capture Hi-C (CHi-C), which, by incorporating a sequence capture step into a Hi-C protocol, allows high-resolution analysis of targeted regions of the genome. We used CHi-C to investigate long-range interactions at three breast cancer gene deserts mapping to 2q35, 8q24.21, and 9q31.2. We identified interaction peaks between putative regulatory elements ("bait fragments") within the captured regions and "targets" that included both protein-coding genes and long noncoding (lnc) RNAs over distances of 6.6 kb to 2.6 Mb. Target protein-coding genes were IGFBP5, KLF4, NSMCE2, and MYC; and target lncRNAs included DIRC3, PVT1, and CCDC26. For one gene desert, we were able to define two SNPs (rs12613955 and rs4442975) that were highly correlated with the published risk variant and that mapped within the bait end of an interaction peak. In vivo ChIP-qPCR data show that one of these, rs4442975, affects the binding of FOXA1 and implicate this SNP as a putative functional variant.

  17. MiR-132 prohibits proliferation, invasion, migration, and metastasis in breast cancer by targeting HN1

    SciTech Connect

    Zhang, Zhan-Guo Chen, Wei-Xun Wu, Yan-Hui Liang, Hui-Fang Zhang, Bi-Xiang

    2014-11-07

    Highlights: • MiR-132 is down-regulated in breast cancer tissues and cell lines. • MiR-132 directly regulates HN1 by binding its 3′ UTR. • MiR-132 shows regulatory role in proliferation, invasion, migration and metastasis. • HN1 is involved in miR-132-mediated cell behavior. • Aberrant HN1 is associated with worse overall survival of breast cancer patients. - Abstract: Accumulating evidence indicates that miRNAs play critical roles in tumorigenesis and cancer progression. This study aims to investigate the role and the underlying mechanism of miR-132 in breast cancer. Here, we report that miR-132 is significantly down-regulated in breast cancer tissues and cancer cell lines. Additional study identifies HN1 as a novel direct target of miR-132. MiR-132 down-regulates HN1 expression by binding to the 3′ UTR of HN1 transcript, thereby, suppressing multiple oncogenic traits such as cancer cell proliferation, invasion, migration and metastasis in vivo and in vitro. Overexpression of HN1 restores miR-132-suppressed malignancy. Importantly, higher HN1 expression is significantly associated with worse overall survival of breast cancer patients. Taken together, our data demonstrate a critical role of miR-132 in prohibiting cell proliferation, invasion, migration and metastasis in breast cancer through direct suppression of HN1, supporting the potential utility of miR-132 as a novel therapeutic strategy against breast cancer.

  18. VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers

    PubMed Central

    Bartolomé, Rubén A.; Torres, Sofía; de Val, Soledad Isern; Escudero-Paniagua, Beatriz; Calviño, Eva; Teixidó, Joaquín; Casal, J. Ignacio

    2017-01-01

    We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VE-cadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE-cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and α2β1 integrin, with the RGD motifs found to directly affect β1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VE-cadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE-cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers. PMID:27966446

  19. Targeting of the Nuclear Receptor Coactivator Isoform Delta3Air in Breast Cancer

    DTIC Science & Technology

    2005-03-01

    Annabell Oh on a study in which siRNA directed at nucleotides 564-582 of AIBI to selectively reduce AIBI gene expression in the MCF-7 breast cancer...I mediates Insulin-like Growth Factor 1-Induced Phenotypic Changes in Human Breast Cancer Cells." Annabell Oh, Heinz Joachim List, Ronald Reiter...Receptor Coactivator AIB1 Mediates Insulin-like Growth Factor I-induced Phenotypic Changes in Human Breast Cancer Cells Annabell Oh,1 Heinz-Joachim List,1

  20. Sulphoraphane, a naturally occurring isothiocyanate induces apoptosis in breast cancer cells by targeting heat shock proteins

    SciTech Connect

    Sarkar, Ruma; Mukherjee, Sutapa; Biswas, Jaydip; Roy, Madhumita

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer HSPs (27, 70 and 90) and HSF1 are overexpressed in MCF-7 and MDA-MB-231 cells. Black-Right-Pointing-Pointer Sulphoraphane, a natural isothiocyanate inhibited HSPs and HSF1 expressions. Black-Right-Pointing-Pointer Inhibition of HSPs and HSF1 lead to regulation of apoptotic proteins. Black-Right-Pointing-Pointer Alteration of apoptotic proteins activate of caspases particularly caspase 3 and 9 leading to induction of apoptosis. Black-Right-Pointing-Pointer Alteration of apoptotic proteins induce caspases leading to induction of apoptosis. -- Abstract: Heat shock proteins (HSPs) are involved in protein folding, aggregation, transport and/or stabilization by acting as a molecular chaperone, leading to inhibition of apoptosis by both caspase dependent and/or independent pathways. HSPs are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion and metastasis. HSPs particularly 27, 70, 90 and the transcription factor heat shock factor1 (HSF1) play key roles in the etiology of breast cancer and can be considered as potential therapeutic target. The present study was designed to investigate the role of sulphoraphane, a natural isothiocyanate on HSPs (27, 70, 90) and HSF1 in two different breast cancer cell lines MCF-7 and MDA-MB-231 cells expressing wild type and mutated p53 respectively, vis-a-vis in normal breast epithelial cell line MCF-12F. It was furthermore investigated whether modulation of HSPs and HSF1 could induce apoptosis in these cells by altering the expressions of p53, p21 and some apoptotic proteins like Bcl-2, Bax, Bid, Bad, Apaf-1 and AIF. Sulphoraphane was found to down-regulate the expressions of HSP70, 90 and HSF1, though the effect on HSP27 was not pronounced. Consequences of HSP inhibition was upregulation of p21 irrespective of p53 status. Bax, Bad, Apaf-1, AIF were upregulated followed by down-regulation of Bcl-2 and this effect was prominent

  1. Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer

    PubMed Central

    Murase, Ryuichi; Kawamura, Rumi; Singer, Eric; Pakdel, Arash; Sarma, Pranamee; Judkins, Jonathon; Elwakeel, Eiman; Dayal, Sonali; Martinez-Martinez, Esther; Amere, Mukkanti; Gujjar, Ramesh; Mahadevan, Anu; Desprez, Pierre-Yves; McAllister, Sean D

    2014-01-01

    Background and Purpose The psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabinoid cannabidiol (CBD) can both reduce cancer progression, each through distinct anti-tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti-tumour pathways. Experimental Approach To measure breast cancer cell proliferation/viability and invasion, MTT and Boyden chamber assays were used. Modulation of reactive oxygen species (ROS) and apoptosis was measured using dichlorodihydrofluorescein and annexin/propidium iodide, respectively, in combination with cell flow cytometry. Changes in protein levels were evaluated using Western analysis. Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of cannabinoids in vivo. Key Results CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1. However, this was associated with moderate increases in survival. We therefore screened for analogues that could co-target cannabinoid anti-tumour pathways (CBD- and THC-associated) and discovered the compound O-1663. This analogue inhibited Id1, produced a marked stimulation of ROS, up-regulated autophagy and induced apoptosis. Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo. Conclusions and Implications O-1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti-tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer. PMID:24910342

  2. Targeting single-walled carbon nanotubes for the treatment of breast cancer using photothermal therapy

    NASA Astrophysics Data System (ADS)

    Neves, Luís F. F.; Krais, John J.; Van Rite, Brent D.; Ramesh, Rajagopal; Resasco, Daniel E.; Harrison, Roger G.

    2013-09-01

    This paper focuses on the targeting of single-walled carbon nanotubes (SWNTs) for the treatment of breast cancer with minimal side effects using photothermal therapy. The human protein annexin V (AV) binds specifically to anionic phospholipids expressed externally on the surface of tumour cells and endothelial cells that line the tumour vasculature. A 2 h incubation of the SWNT-AV conjugate with proliferating endothelial cells followed by washing and near-infrared (NIR) irradiation at a wavelength of 980 nm was enough to induce significant cell death; there was no significant cell death with irradiation or the conjugate alone. Administration of the same conjugate i.v. in BALB/c female mice with implanted 4T1 murine mammary at a dose of 0.8 mg SWNT kg-1 and followed one day later by NIR irradiation of the tumour at a wavelength of 980 nm led to complete disappearance of implanted 4T1 mouse mammary tumours for the majority of the animals by 11 days since the irradiation. The combination of the photothermal therapy with the immunoadjuvant cyclophosphamide resulted in increased survival. The in vivo results suggest the SWNT-AV/NIR treatment is a promising approach to treat breast cancer.

  3. Targeted delivery of doxorubicin to breast cancer cells by aptamer functionalized DOTAP/DOPE liposomes.

    PubMed

    Song, Xingli; Ren, Yi; Zhang, Jing; Wang, Gang; Han, Xuedong; Zheng, Wei; Zhen, Linlin

    2015-10-01

    Doxorubicin is used to treat numerous types of tumors including breast cancer, yet dose-associated toxicities limit its clinical application. Here, we demonstrated a novel strategy by which to deliver doxorubicin to breast cancer cells by conjugating cancer cell-specific single-strand DNA aptamers with doxorubicin-encapsulated DOTAP:DOPE nanoparticles (NPs). We utilizing a whole-cell-SELEX strategy, and 4T1 cells with high invasive and metastatic potential were used as target cells, while non-invasive and non-metastatic 67NR cells were used as subtractive cells. Ten potential aptamers were generated after multi-pool selection. Studies on the selected aptamers revealed that SRZ1 had the highest and specific binding affinity to 4T1 cells. Then we developed SRZ1 aptamer-carried DOTAP:DOPE-DOX NPs. In vitro uptake results which were conducted by FACS indicated that the aptamer significantly promoted the uptake efficiency of DOTAP:DOPE-DOX NPs by 4T1 cells. ATPlite assay was performed to test 4T1, 67NR and NMuMG cell viability after treatment with free doxorubicin, DOTAP:DOPE-DOX particles and aptamer‑loaded DOTAP:DOPE-DOX particles. As expected, the aptamers effectively enhanced accumulation of doxorubicin in the 4T1 tumor tissues as determined by in vivo mouse body images and biodistribution analysis. Consistent with the in vitro findings, aptamer-conjugated doxorubicin-loaded DOTAP:DOPE particles markedly suppressed tumor growth and significantly increased the survival rate of 4T1 tumor-bearing mice. These studies demonstrated that aptamer SRZ1 could be a promising molecule for chemotherapeutic drug targeting deliver.

  4. Exploring and Exploiting the Protein S100A7 as a New Target for Breast Cancer Therapy

    DTIC Science & Technology

    2011-01-01

    express key ER- target genes such as progesterone receptor in response to estrogen. In addition to ER suppression and S100A7 induction, OSM induces...receptor (PR), a key target gene of estrogen receptor (Fig. 2a). In contrast, OSM strongly prevented induction of PR at both 24 and 48h of E2...Award Number: W81XWH-08-1-0781 TITLE Exploring and Exploiting the Protein S100A7 as a New Target for Breast Cancer

  5. Reproduction and Breast Cancer Risk

    PubMed Central

    Hanf, Volker; Hanf, Dorothea

    2014-01-01

    Summary Reproduction is doubtlessly one of the main biological meanings of life. It is therefore not surprising that various aspects of reproduction impact on breast cancer risk. Various developmental levels may become targets of breast tumorigenesis. This review follows the chronologic sequence of events in the life of a female at risk, starting with the intrauterine development. Furthermore, the influence of both contraceptive measures and fertility treatment on breast cancer development is dealt with, as well as various pregnancy-associated factors, events, and perinatal outcomes. Finally, the contribution of breast feeding to a reduced breast cancer risk is discussed. PMID:25759622

  6. G-protein coupled receptors of the renin-angiotensin system: new targets against breast cancer?

    PubMed Central

    Rodrigues-Ferreira, Sylvie; Nahmias, Clara

    2015-01-01

    G-protein coupled receptors (GPCRs) constitute the largest family of membrane receptors, with high potential for drug discovery. These receptors can be activated by a panel of different ligands including ions, hormones, small molecules, and vasoactive peptides. Among those, angiotensins [angiotensin II (AngII) and angiotensin 1–7] are the major biologically active products of the classical and alternative renin-angiotensin system (RAS). These peptides bind and activate three different subtypes of GPCRs, namely AT1, AT2, and Mas receptors, to regulate cardiovascular functions. Over the past decade, the contribution of several RAS components in tumorigenesis has emerged as a novel important concept, AngII being considered as harmful and Ang1–7 as protective against cancer. Development of selective ligands targeting each RAS receptor may provide novel and efficient targeted therapeutic strategies against cancer. In this review, we focus on breast cancer to summarize current knowledge on angiotensin receptors (AT1, AT2, and Mas), and discuss the potential use of angiotensin receptor agonists and antagonists in clinics. PMID:25741281

  7. G-protein coupled receptors of the renin-angiotensin system: new targets against breast cancer?

    PubMed

    Rodrigues-Ferreira, Sylvie; Nahmias, Clara

    2015-01-01

    G-protein coupled receptors (GPCRs) constitute the largest family of membrane receptors, with high potential for drug discovery. These receptors can be activated by a panel of different ligands including ions, hormones, small molecules, and vasoactive peptides. Among those, angiotensins [angiotensin II (AngII) and angiotensin 1-7] are the major biologically active products of the classical and alternative renin-angiotensin system (RAS). These peptides bind and activate three different subtypes of GPCRs, namely AT1, AT2, and Mas receptors, to regulate cardiovascular functions. Over the past decade, the contribution of several RAS components in tumorigenesis has emerged as a novel important concept, AngII being considered as harmful and Ang1-7 as protective against cancer. Development of selective ligands targeting each RAS receptor may provide novel and efficient targeted therapeutic strategies against cancer. In this review, we focus on breast cancer to summarize current knowledge on angiotensin receptors (AT1, AT2, and Mas), and discuss the potential use of angiotensin receptor agonists and antagonists in clinics.

  8. Mapping Novel Metabolic Nodes Targeted by Anti-Cancer Drugs that Impair Triple-Negative Breast Cancer Pathogenicity.

    PubMed

    Roberts, Lindsay S; Yan, Peter; Bateman, Leslie A; Nomura, Daniel K

    2017-03-08

    Triple-negative breast cancers (TNBCs) are estrogen receptor, progesterone receptor, and HER2 receptor-negative subtypes of breast cancers that show the worst prognoses and lack targeted therapies. Here, we have coupled the screening of ∼400 anticancer agents that are under development or in the clinic with chemoproteomic and metabolomic profiling to identify novel metabolic mechanisms for agents that impair TNBC pathogenicity. We identify 20 anticancer compounds that significantly impaired cell survival across multiple types of TNBC cells. Among these 20 leads, the phytoestrogenic natural product licochalcone A was of interest, since TNBCs are unresponsive to estrogenic therapies, indicating that licochalcone A was likely acting through another target. Using chemoproteomic profiling approaches, we reveal that licochalcone A impairs TNBC pathogenicity, not through modulating estrogen receptor activity but rather through inhibiting prostaglandin reductase 1, a metabolic enzyme involved in leukotriene B4 inactivation. We also more broadly performed metabolomic profiling to map additional metabolic mechanisms of compounds that impair TNBC pathogenicity. Overlaying lipidomic profiling with drug responses, we find that deubiquitinase inhibitors cause dramatic elevations in acyl carnitine levels, which impair mitochondrial respiration and contribute to TNBC pathogenic impairments. We thus put forth two unique metabolic nodes that are targeted by drugs or drug candidates that impair TNBC pathogenicity. Our results also showcase the utility of coupling drug screens with chemoproteomic and metabolomic profiling to uncover unique metabolic drivers of TNBC pathogenicity.

  9. Male Breast Cancer

    MedlinePlus

    ... hasn't spread beyond your breast tissue. Radiation therapy Radiation therapy uses high-energy beams to kill ... option for men with advanced breast cancer. Hormone therapy Most men with male breast cancer have tumors ...

  10. FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation.

    PubMed

    Zhou, H; Liu, Y; Zhu, R; Ding, F; Wan, Y; Li, Y; Liu, Z

    2017-01-09

    Krüppel-like factor 4 (KLF4, GKLF) is a zinc-finger transcription factor involved in a large variety of cellular processes, including apoptosis, cell cycle progression, as well as stem cell renewal. KLF4 is critical for cell fate decision and has an ambivalent role in tumorigenesis. Emerging data keep reminding us that KLF4 dysregulation either facilitates or impedes tumor progression, making it important to clarify the regulating network of KLF4. Like most transcription factors, KLF4 has a rather short half-life within the cell and its turnover must be carefully orchestrated by ubiquitination and ubiquitin-proteasome system. To better understand the mechanism of KLF4 ubiquitination, we performed a genome-wide screen of E3 ligase small interfering RNA library based on western blot and identified SCF-FBXO32 to be a new E3 ligase, which is responsible for KLF4 ubiquitination and degradation. The F-box domain is critical for FBXO32-dependent KLF4 ubiquitination and degradation. Furthermore, we demonstrated that FBXO32 physically interacts with the N-terminus (1-60 aa) of KLF4 via its C-terminus (228-355 aa) and directly targets KLF4 for ubiquitination and degradation. We also found out that p38 mitogen-activated protein kinase pathway may be implicated in FBXO32-mediated ubiquitination of KLF4, as p38 kinase inhibitor coincidently abrogates endogenous KLF4 ubiquitination and degradation, as well as FBXO32-dependent exogenous KLF4 ubiquitination and degradation. Finally, FBXO32 inhibits colony formation in vitro and primary tumor initiation and growth in vivo through targeting KLF4 into degradation. Our findings thus further elucidate the tumor-suppressive function of FBXO32 in breast cancer. These results expand our understanding of the posttranslational modification of KLF4 and of its role in breast cancer development and provide a potential target for diagnosis and therapeutic treatment of breast cancer.Oncogene advance online publication, 9 January 2017; doi:10

  11. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance

    PubMed Central

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia

    2017-01-01

    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance. PMID:28262781

  12. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance.

    PubMed

    Zheng, Hongping; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu-Xia

    2017-03-06

    Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance.

  13. Grape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancer.

    PubMed

    Castillo-Pichardo, Linette; Dharmawardhane, Suranganie F

    2012-01-01

    We recently reported that a combination of dietary grape polyphenols resveratrol, quercetin, and catechin (RQC), at low concentrations, was effective at inhibiting metastatic cancer progression. Herein, we investigate the molecular mechanisms of RQC in breast cancer and explore the potential of RQC as a potentiation agent for the epidermal growth factor receptor (EGFR) therapeutic gefitinib. Our in vitro experiments showed RQC induced apoptosis in gefitinib-resistant breast cancer cells via regulation of a myriad of proapoptotic proteins. Because the Akt/mammalian target of rapamycin (mTOR) signaling pathway is often elevated during development of anti-EGFR therapy resistance, the effect of RQC on the mTOR upstream effector Akt and the negative regulator AMP kinase (AMPK) was investigated. RQC was found to reduce Akt activity, induce the activation of AMPK, and inhibit mTOR signaling in breast cancer cells. Combined RQC and gefitinib decreased gefitinib resistant breast cancer cell viability to a greater extent than RQC or gefitinib alone. Moreover, RQC inhibited Akt and mTOR and activated AMPK even in the presence of gefitinib. Our in vivo experiments showed combined RQC and gefitinib was more effective than the individual treatments at inhibiting mammary tumor growth and metastasis in nude mice. Therefore, RQC treatment inhibits breast cancer progression and may potentiate anti-EGFR therapy by inhibition of Akt/mTOR signaling.

  14. Breast cancer in men

    MedlinePlus

    ... in situ - male; Intraductal carcinoma - male; Inflammatory breast cancer - male; Paget disease of the nipple - male; Breast cancer - male ... The cause of breast cancer in men is not clear. But there are risk factors that make breast cancer more likely in men: Exposure to ...

  15. Tumor Genomic Profiling in Breast Cancer Patients Using Targeted Massively Parallel Sequencing

    DTIC Science & Technology

    2015-04-30

    exome sequencing to identify genomic mechanisms of therapeutic resistance The goal of this aim is perfotm whole exome sequencing in breast cancer...identify novel resistance mechanisms . Of the 72 patients described above, we have been able to obtain matched pre-treatment primary tissues from 28...advanced breast cancer, and novel strategies to overcome resistance mechanisms . If widely deployed, implementation of this approach may open new

  16. Estrogen-Induced Depurination of DNA: A Novel Target for Breast Cancer Prevention

    DTIC Science & Technology

    2008-05-01

    serum samples [4]. This new finding has led to studies of prevention with specific antioxidants that decrease the level of depurinating estrogen...Yang, L., Gaikwad, N., Ingle, J.N., Sandhu, N., Suman, V., Cavalieri, E.L., Rogan, E.G. Novel serum biomarkers for assessing breast cancer risk...breast cancer by using ultraperformance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) and began analyzing serum samples. B-ii

  17. Neuropeptide Y Y1 receptor-mediated biodegradable photoluminescent nanobubbles as ultrasound contrast agents for targeted breast cancer imaging.

    PubMed

    Li, Juan; Tian, Yuchen; Shan, Dingying; Gong, An; Zeng, Leyong; Ren, Wenzhi; Xiang, Lingchao; Gerhard, Ethan; Zhao, Jinshun; Yang, Jian; Wu, Aiguo

    2017-02-01

    Targeted molecular imaging has attracted great attention in cancer diagnosis and treatment. However, most clinically used ultrasound contrast agents (UCAs) are non-targeted microbubbles seldom used for cancer imaging. Here, we fabricated fluorescent nanobubbles (NBs) by encapsulation of liquid tetradecafluorohexane (C6F14) within biodegradable photoluminescent polymers (BPLPs) through an emulsion-evaporation process and conjugation of PNBL-NPY ligand for specific targeting of Y1 receptors overexpressed in breast tumors. The developed PNBL-NPY modified NBs were uniform in size with good dispersibility and photostability, presenting good ultrasound enhancement. Further, in vitro and in vivo results indicated that the fabricated NBs exhibit high affinity and specificity to Y1 receptor-overexpressing breast cancer cells and tumors with minimal toxicity and damage to organs. Our developed PNBL-NPY-modified NBs are novel targeted UCAs for safe, efficient and specific targeted breast cancer imaging, and may provide a new nanoplatform for early cancer diagnosis and treatment in the future.

  18. A dual mode targeting probe for distinguishing HER2-positive breast cancer cells using silica-coated fluorescent magnetic nanoparticles

    NASA Astrophysics Data System (ADS)

    Li, Jia; An, Yan-Li; Zang, Feng-Chao; Zong, Shen-Fei; Cui, Yi-Ping; Teng, Gao-Jun

    2013-10-01

    We report a composite nanoprobe based on silica-coated magnetic nanoparticles (NPs) for distinguishing breast cancers at different HER2 statuses. The nanoprobe has a core-shell structure, with Fe3O4 NPs as the magnetic core and dye-embedded silica as the fluorescent shell, whose average size is about 150 nm. Besides, the outmost surfaces of the probes were modified with specific antibodies to endow the probe with a targeting ability. With such a structure, the nanoprobe can accomplish dual mode targeting of human breast cancer cells based on fluorescence and magnetic resonance imaging (MRI). In the experiments, three human breast cancer cell lines were used to test the targeting ability of the nanoprobe. Specifically, SKBR3 cells with a high HER2 expression level were used as the model target cells, while MCF7 cells with a lower HER2 expression levels and HER2-negative MDA-MB-231 cells were used as the controls. Both the fluorescence and MRI imaging results confirmed that the nanoprobe can distinguish three cancer cell lines with different HER2 expression levels. With the dual mode imaging and specific targeting properties, we anticipate that the presented nanoprobe may have a great potential in the diagnosis and treatment of cancerous diseases.

  19. The latest progress in research on triple negative breast cancer (TNBC): risk factors, possible therapeutic targets and prognostic markers.

    PubMed

    Jiao, Qingli; Wu, Aiguo; Shao, Guoli; Peng, Haoyu; Wang, Mengchuan; Ji, Shufeng; Liu, Peng; Zhang, Jian

    2014-09-01

    Triple negative breast cancer (TNBC) is one type of breast cancer (BC), which is defined as negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (Her2). Its origins and development seem to be elusive. And for now, drugs like tamoxifen or trastuzumab which specifically apply to ER, PR or Her2 positive BC seem unforeseeable in TNBC clinical treatment. Due to its extreme malignancy, high recurrence rate and poor prognosis, a lot of work on the research of TNBC is needed. This review aims to summarize the latest findings in TNBC in risk factors, possible therapeutic targets and possible prognostic makers.

  20. Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle

    PubMed Central

    Zhang, Li; Varma, Nadimpalli RS; Gang, Zhang Z.; Ewing, James R.; Arbab, Ali S; Ali, Meser M

    2016-01-01

    There is no available targeted therapy or imaging agent for triple negative breast cancer (TNBC). We developed a small-sized dendrimer-based nanoparticle containing a clinical relevant MRI contrast agent, GdDOTA and a NIR fluorescent dye, DL680. Systemic delivery of dual-modal nanoparticles led to accumulation of the agents in a flank mouse model of TNBC that were detected by both optical and MR imaging. In-vivo fluorescence images, as well as ex-vivo fluorescence images of individual organs, demonstrated that nanoparticles accumulated into tumor selectively. A dual modal strategy resulted in a selective delivery of a small-sized (GdDOTA)42-G4-DL680 dendrimeric agent to TNBC tumors, avoiding other major organs. PMID:28018751

  1. Targeted chemotherapy of endometrial, ovarian and breast cancers with cytotoxic analogs of luteinizing hormone-releasing hormone (LHRH).

    PubMed

    Engel, J B; Schally, A V; Buchholz, S; Seitz, S; Emons, G; Ortmann, O

    2012-08-01

    Receptors luteinizing hormone-releasing hormone (LHRH) are expressed in about 80 % of human endometrial and ovarian cancers and account for more than 50 % of breast cancers including triple negative breast cancers. Apart from the pituitary and reproductive organs, no other organs or hematopoietic stem cells express LHRH (GnRH) receptors. Thus, these receptors can be regarded as an ideal target for a personalized medicine approach in cancer therapy. AEZS-108 (formerly known as AN-152) in which doxorubin is linked to the LHRH agonist [D: -Lys(6)]LHRH, appears to be the most advanced compound in late stage clinical development. Results of phase I and phase II clinical trials in patients with gynecological cancers demonstrated anticancer activity without any cardiotoxicity even in highly pretreated patients. AEZS-108 is therefore being considered for phase II trials in triple negative breast cancers and phase III studies in advanced endometrial cancers positive for LHRH-receptor. EP-100 is a membrane-disrupting peptide targeted to LHRH receptors, which is undergoing early clinical studies in ovarian cancer patients.

  2. tRNAs as Biomarkers and Regulators for Breast Cancer

    DTIC Science & Technology

    2008-08-01

    transduction pathways. These results demonstrate that studies of tRNA and breast cancer biology will be useful in understanding breast cancer type and progression and may lead to new drug targets for breast cancer treatment.

  3. Targeting Metabolic Remodeling in Triple Negative Breast Cancer in a Murine Model

    PubMed Central

    García-Castillo, Verónica; López-Urrutia, Eduardo; Villanueva-Sánchez, Octavio; Ávila-Rodríguez, Miguel Á.; Zentella-Dehesa, Alejandro; Cortés-González, Carlo; López-Camarillo, César; Jacobo-Herrera, Nadia J; Pérez-Plasencia, Carlos

    2017-01-01

    Background: Chemotherapy is the backbone of systemic treatment for triple negative breast cancer (TNBC), which is one of the most relevant breast cancers molecular types due to the ability of tumor cells to develop drug resistance, highlighting the urgent need to design newer and safer drug combinations for treatment. In this context, to overcome tumor cell drug resistance, we employed a novel combinatorial treatment including Doxorubicin, Metformin, and Sodium Oxamate (DoxMetOx). Such pharmacological combination targets indispensable hallmarks of cancer-related to aerobic glycolysis and DNA synthesis. Materials and Methods: Thirty-five female nude mice were transplanted subcutaneously with MDA-MB-231 triple negative human cancer cell line. Once tumors were visible, mice were treated with doxorubicin, metformin, oxamate or all possible pharmacologic combinations. Treatments were administered daily for 15 days and tumors were measured by calipers every day. MicroPET images were taken in three different occasions, basal state, in the middle of the treatment, and at the end of treatment. Western blot analyses, qRT-PCR, flow cytometry, and cytotoxicity assays were performed to elucidate the mechanism of cell death promoted by the drugs in vitro. Results: In this work we assessed the proof of concept of metabolic correction in solid tumors as an effective drug treatment; hence, mice bearing tumors treated with the DoxMetOx therapy showed a complete inhibition of the tumor mass growing in 15 days of treatment depicted by the micro PET images. In vitro studies displayed that the three drugs together act by inhibiting both, mTOR-phosphorylation and expression of LDH-A gene, promoting apoptosis via dependent on the caspase-3 pathway, accompanied by cleavage of PARP. Moreover, induction of autophagy process was observed by the accumulation of LC3-II, a primordial protein implicated in the conformation and elongation of the autophagolysosome. Conclusions: The lack of

  4. Current advances in biomarkers for targeted therapy in triple-negative breast cancer

    PubMed Central

    Fleisher, Brett; Clarke, Charlotte; Ait-Oudhia, Sihem

    2016-01-01

    Triple-negative breast cancer (TNBC) is a complex heterogeneous disease characterized by the absence of three hallmark receptors: human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor. Compared to other breast cancer subtypes, TNBC is more aggressive, has a higher prevalence in African-Americans, and more frequently affects younger patients. Currently, TNBC lacks clinically accepted targets for tailored therapy, warranting the need for candidate biomarkers. BiomarkerBase, an online platform used to find biomarkers reported in clinical trials, was utilized to screen all potential biomarkers for TNBC and select only the ones registered in completed TNBC trials through clinicaltrials.gov. The selected candidate biomarkers were classified as surrogate, prognostic, predictive, or pharmacodynamic (PD) and organized by location in the blood, on the cell surface, in the cytoplasm, or in the nucleus. Blood biomarkers include vascular endothelial growth factor/vascular endothelial growth factor receptor and interleukin-8 (IL-8); cell surface biomarkers include EGFR, insulin-like growth factor binding protein, c-Kit, c-Met, and PD-L1; cytoplasm biomarkers include PIK3CA, pAKT/S6/p4E-BP1, PTEN, ALDH1, and the PIK3CA/AKT/mTOR-related metabolites; and nucleus biomarkers include BRCA1, the gluco-corticoid receptor, TP53, and Ki67. Candidate biomarkers were further organized into a “cellular protein network” that demonstrates potential connectivity. This review provides an inventory and reference point for promising biomarkers for breakthrough targeted therapies in TNBC. PMID:27785100

  5. Targeting Mdmx to treat breast cancers with wild-type p53.

    PubMed

    Haupt, S; Buckley, D; Pang, J-M B; Panimaya, J; Paul, P J; Gamell, C; Takano, E A; Lee, Y Ying; Hiddingh, S; Rogers, T-M; Teunisse, A F A S; Herold, M J; Marine, J-C; Fox, S B; Jochemsen, A; Haupt, Y

    2015-07-16

    The function of the tumor suppressor p53 is universally compromised in cancers. It is the most frequently mutated gene in human cancers (reviewed). In cases where p53 is not mutated, alternative regulatory pathways inactivate its tumor suppressive functions. This is primarily achieved through elevation in the expression of the key inhibitors of p53: Mdm2 or Mdmx (also called Mdm4) (reviewed). In breast cancer (BrCa), the frequency of p53 mutations varies markedly between the different subtypes, with basal-like BrCas bearing a high frequency of p53 mutations, whereas luminal BrCas generally express wild-type (wt) p53. Here we show that Mdmx is unexpectedly highly expressed in normal breast epithelial cells and its expression is further elevated in most luminal BrCas, whereas p53 expression is generally low, consistent with wt p53 status. Inducible knockdown (KD) of Mdmx in luminal BrCa MCF-7 cells impedes the growth of these cells in culture, in a p53-dependent manner. Importantly, KD of Mdmx in orthotopic xenograft transplants resulted in growth inhibition associated with prolonged survival, both in a preventative model and also in a treatment model. Growth impediment in response to Mdmx KD was associated with cellular senescence. The growth inhibitory capacity of Mdmx KD was recapitulated in an additional luminal BrCa cell line MPE600, which expresses wt p53. Further, the growth inhibitory capacity of Mdmx KD was also demonstrated in the wt p53 basal-like cell line SKBR7 line. These results identify Mdmx growth dependency in wt p53 expressing BrCas, across a range of subtypes. Based on our findings, we propose that Mdmx targeting is an attractive strategy for treating BrCas harboring wt p53.

  6. miR-151-3p Targets TWIST1 to Repress Migration of Human Breast Cancer Cells

    PubMed Central

    Yeh, Ting-Chih; Huang, Tzu-Ting; Yeh, Tien-Shun; Chen, Yu-Ren; Hsu, Kai-Wen; Yin, Pen-Hui; Lee, Hsin-Chen; Tseng, Ling-Ming

    2016-01-01

    TWIST1 is a highly conserved basic helix-loop-helix transcription factor that contributes to cancer metastasis by promoting an epithelial-mesenchymal transition and repressing E-cadherin gene expression in breast cancer. In this study, we explored the potential role of miR-151 in TWIST1 expression and cancer properties in human breast cancer cells. We found that the human TWIST1 3’UTR contains a potential binging site for miR-151-3p at the putative target sequence 5’-CAGUCUAG-3’. Using a TWIST1-3’UTR luciferase reporter assay, we demonstrated that the target sequence within the TWIST1 3’UTR is required for miR-151-3p regulation of TWIST1 expression. Moreover, we found that ectopic expression of miR-151-3p by infection with adenoviruses expressing miR-151 significantly decreased TWIST1 expression, migration and invasion, but did not affect cell growth and tumorsphere formation of human breast cancer cells. In addition, overexpression of the protein coding region without the 3’UTR of TWIST1 reversed the repression of cell migration by miR-151-3p. Furthermore, knockdown of miR-151-3p increased TWIST1 expression, reduced E-cadherin expression, and enhanced cell migration. In conclusion, these results suggest that miR-151-3p directly regulates TWIST1 expression by targeting the TWIST1 3’UTR and thus repressing the migration and invasion of human breast cancer cells by enhancing E-cadherin expression. Our findings add to accumulating evidence that microRNAs are involved in breast cancer progression by modulating TWIST1 expression. PMID:27930738

  7. Targeted delivery of albumin bound paclitaxel in the treatment of advanced breast cancer.

    PubMed

    Di Costanzo, Francesco; Gasperoni, Silvia; Rotella, Virginia; Di Costanzo, Federica

    2009-02-18

    Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL(R) (CrEL) and Tween 80(R) respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane(R)), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer.

  8. L-Ferritin targets breast cancer stem cells and delivers therapeutic and imaging agents

    PubMed Central

    Ruiu, Roberto; Cadenazzi, Marta; Cavallo, Federica; Aime, Silvio; Crich, Simonetta Geninatti

    2016-01-01

    A growing body of evidence suggests that cancer stem cells (CSC) have the unique biological properties necessary for tumor maintenance and spreading, and function as a reservoir for the relapse and metastatic evolution of the disease by virtue of their resistance to radio- and chemo-therapies. Thus, the efficacy of a therapeutic approach relies on its ability to effectively target and deplete CSC. In this study, we show that CSC-enriched tumorspheres from breast cancer cell lines display an increased L-Ferritin uptake capability compared to their monolayer counterparts as a consequence of the upregulation of the L-Ferritin receptor SCARA5. L-Ferritin internalization was exploited for the simultaneous delivery of Curcumin, a natural therapeutic molecule endowed with antineoplastic action, and the MRI contrast agent Gd-HPDO3A, both entrapped in the L-Ferritin cavity. This theranostic system was able to impair viability and self-renewal of tumorspheres in vitro and to induce the regression of established tumors in mice. In conclusion, here we show that Curcumin-loaded L-Ferritin has a strong therapeutic potential due to the specific targeting of CSC and the improved Curcumin bioavailability, opening up the possibility of its use in a clinical setting. PMID:27579532

  9. Targeted Nanodiamonds as Phenotype Specific Photoacoustic Contrast Agents for Breast Cancer

    PubMed Central

    Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Cheng, Kun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M. Laird

    2015-01-01

    Aim The aim is to develop irradiated nanodiamonds (INDs) as a molecularly-targeted contrast agent for high resolution and phenotype-specific detection of breast cancer with photoacoustic (PA) imaging. Materials & Methods The surface of acid treated radiation-damaged nanodiamonds was grafted with polyethylene glycol (PEG) to improve its stability and circulation time in blood, followed by conjugation to an anti-Human epidermal growth factor receptor-2 (HER2) peptide (KCCYSL) with a final nanoparticle size of ca. 92 nm. Immunocompetent mice bearing orthotopic HER2 positive or negative tumors were administered INDs and PA imaged using an 820-nm near infrared laser. Results PA images demonstrated that INDs accumulate in tumors and completely delineated the entire tumor within 10 hours. HER2 targeting significantly enhanced imaging of HER2-positive tumors. Pathological examination demonstrated INDs are non-toxic. Conclusions PA technology is adaptable to low-cost bedside medicine, and with new contrast agents described herein, PA can achieve high resolution (sub-mm) and phenotype specific monitoring of cancer growth. PMID:25723091

  10. Targeting the Immune System’s Natural Response to Cell Death to Improve Therapeutic Response in Breast Cancers

    DTIC Science & Technology

    2015-07-01

    Award Number: W81XWH-13-1-0158 TITLE: Targeting the Immune System’s Natural Response to Cell Death to Improve Therapeutic Response in Breast...Targeting the Immune System’s Natural Response to Cell Death to 5a. CONTRACT NUMBER W81XWH-13-1-0158 Improve Therapeutic Response in Breast Cancers 5b...Appendix 1, Supplemental Figure S5E) E. Widespread cell death during post-partum involution induces M2 macrophage polarization, but this is blocked by

  11. Quantitative in situ Assessment of the Somatostatin Receptor in Breast Cancer to Assess Response to Targeted Therapy with 111-in-Pentetreotide

    DTIC Science & Technology

    2007-05-01

    Somatostatin Receptor in Breast Cancer to Assess Response to Targeted Therapy with 111-in-Pentetreotide PRINCIPAL INVESTIGATOR: Gina G...Quantitative in situ Assessment of the Somatostatin Receptor in Breast Cancer to Assess Response to Targeted Therapy with 111-in-Pentetreotide 5b. GRANT NUMBER...Somatostatin (SST) is a peptide hormone implicated in the growth and progression of cancers and SSTR2 is the predominant receptor subtype expressed in

  12. Tobacco mosaic virus-based protein nanoparticles and nanorods for chemotherapy delivery targeting breast cancer

    PubMed Central

    Bruckman, Michael A.; Czapar, Anna E.; VanMeter, Allen; Randolph, Lauren N.; Steinmetz, Nicole F.

    2016-01-01

    Drug delivery systems are required for drug targeting to avoid adverse effects associated with chemotherapy treatment regimes. Our approach is focused on the study and development of plant virus-based materials as drug delivery systems; specifically, this work focuses on the tobacco mosaic virus (TMV). Native TMV forms a hollow, high aspect-ratio nanotube measuring 300 × 18 nm with a 4 nm-wide central channel. Heat-transformation can be applied to TMV yielding spherical nanoparticles (SNPs) measuring ~50 nm in size. While bioconjugate chemistries have been established to modify the TMV rod, such methods have not yet been described for the SNP platform. In this work, we probed the reactivity of SNPs toward bioconjugate reactions targeting lysine, glutamine/aspartic acid, and cysteine residues. We demonstrate functionalization of SNPs using these chemistries yielding efficient payload conjugation. In addition to covalent labeling techniques, we developed encapsulation techniques, where the cargo is loaded into the SNP during heat-transition from rod-to-sphere. Finally, we developed TMV and SNP formulations loaded with the chemotherapeutic doxorubicin, and we demonstrate the application of TMV rods and spheres for chemotherapy delivery targeting breast cancer. PMID:26941034

  13. In silico study of breast cancer associated gene 3 using LION Target Engine and other tools.

    PubMed

    León, Darryl A; Cànaves, Jaume M

    2003-12-01

    Sequence analysis of individual targets is an important step in annotation and validation. As a test case, we investigated human breast cancer associated gene 3 (BCA3) with LION Target Engine and with other bioinformatics tools. LION Target Engine confirmed that the BCA3 gene is located on 11p15.4 and that the two most likely splice variants (lacking exon 3 and exons 3 and 5, respectively) exist. Based on our manual curation of sequence data, it is proposed that an additional variant (missing only exon 5) published in a public sequence repository, is a prediction artifact. A significant number of new orthologs were also identified, and these were the basis for a high-quality protein secondary structure prediction. Moreover, our research confirmed several distinct functional domains as described in earlier reports. Sequence conservation from multiple sequence alignments, splice variant identification, secondary structure predictions, and predicted phosphorylation sites suggest that the removal of interaction sites through alternative splicing might play a modulatory role in BCA3. This in silico approach shows the depth and relevance of an analysis that can be accomplished by including a variety of publicly available tools with an integrated and customizable life science informatics platform.

  14. Tobacco mosaic virus-based protein nanoparticles and nanorods for chemotherapy delivery targeting breast cancer.

    PubMed

    Bruckman, Michael A; Czapar, Anna E; VanMeter, Allen; Randolph, Lauren N; Steinmetz, Nicole F

    2016-06-10

    Drug delivery systems are required for drug targeting to avoid adverse effects associated with chemotherapy treatment regimes. Our approach is focused on the study and development of plant virus-based materials as drug delivery systems; specifically, this work focuses on the tobacco mosaic virus (TMV). Native TMV forms a hollow, high aspect-ratio nanotube measuring 300×18nm with a 4nm-wide central channel. Heat-transformation can be applied to TMV yielding spherical nanoparticles (SNPs) measuring ~50nm in size. While bioconjugate chemistries have been established to modify the TMV rod, such methods have not yet been described for the SNP platform. In this work, we probed the reactivity of SNPs toward bioconjugate reactions targeting lysine, glutamine/aspartic acid, and cysteine residues. We demonstrate functionalization of SNPs using these chemistries yielding efficient payload conjugation. In addition to covalent labeling techniques, we developed encapsulation techniques, where the cargo is loaded into the SNP during heat-transition from rod-to-sphere. Finally, we developed TMV and SNP formulations loaded with the chemotherapeutic doxorubicin, and we demonstrate the application of TMV rods and spheres for chemotherapy delivery targeting breast cancer.

  15. Targeted delivery of doxorubicin to breast cancer cells by magnetic LHRH chitosan bioconjugated nanoparticles.

    PubMed

    Varshosaz, Jaleh; Hassanzadeh, Farshid; Aliabadi, Hojat Sadeghi; Khoraskani, Fatemeh Rabbani; Mirian, Mina; Behdadfar, Behshid

    2016-12-01

    The novel dual targeted nanoparticles loaded with doxorubicin (DOX) and magnetic nanoparticles (MNPs) were prepared for treatment of breast cancer. Nanoparticles were produced by a layer-by-layer technique and functionalized with a bioconjugate of chitosan-poly(methyl vinyl ether maleic acid)(PMVMA)-LHRH to target LHRH receptors. The successful production of chitosan-PMVMA copolymer and its conjugation to LHRH was confirmed by FTIR and (1)HNMR spectroscopy. Capillary electrophoresis analysis showed 72.51% LHRH conjugation efficiency. Transmission electron microscopy and thermogravimetric analysis showed the entrapment of the MNPs in the core of the nanoparticles and vibrating sample magnetometery confirmed their paramagnetic properties. The iron content of nanoparticles determined by inductively coupled plasma optical emission spectrometry showed to be between 3.5-84%. Particle size, zeta potential, drug entrapment and release efficiency of the nanoparticles were 88.1-182.6nm, 10-30mV, 62.3-87.6% and 79.8-83.4%, respectively. No significant protein binding was seen by nanoparticles. The MTT assay showed in LHRH positive cells of MCF-7 the IC50 of the drug reduced to about 2 fold compared to the free drug. By saturation of LHRH receptors the viable MCF7 cells increased significantly after exposure with the targeted nanoparticles. Therefore, the cellular uptake of the nanoparticles might be done by active endocytosis through the LHRH receptors.

  16. Stages of Male Breast Cancer

    MedlinePlus

    ... Breast & Gynecologic Cancers Breast Cancer Screening Research Male Breast Cancer Treatment (PDQ®)–Patient Version General Information about Male Breast Cancer Go to Health Professional Version Key Points Male ...

  17. The locus of microRNA-10b: a critical target for breast cancer insurgence and dissemination.

    PubMed

    Biagioni, Francesca; Bossel Ben-Moshe, Noa; Fontemaggi, Giulia; Yarden, Yosef; Domany, Eytan; Blandino, Giovanni

    2013-08-01

    Contemporary microRNA research has led to significant advances in our understanding of the process of tumorigenesis. MicroRNAs participate in different events of a cancer cell's life, through their ability to target hundreds of putative transcripts involved in almost every cellular function, including cell cycle, apoptosis, and differentiation. The relevance of these small molecules is even more evident in light of the emerging linkage between their expression and both prognosis and clinical outcome of many types of human cancers. This identifies microRNAs as potential therapeutic modifiers of cancer phenotypes. From this perspective, we overview here the miR-10b locus and its involvement in cancer, focusing on its role in the establishment (miR-10b*) and spreading (miR-10b) of breast cancer. We conclude that targeting the locus of microRNA 10b holds great potential for cancer treatment.

  18. Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence

    PubMed Central

    Yano, Shuya; Takehara, Kiyoto; Miwa, Shinji; Kishimoto, Hiroyuki; Tazawa, Hiroshi; Urata, Yasuo; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M.

    2016-01-01

    We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative high-invasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)-light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model. PMID:27689331

  19. Targeting MED1 LxxLL Motifs for Tissue-Selective Treatment of Human Breast Cancer

    DTIC Science & Technology

    2012-09-01

    pRNA nanoparticle delivery system has been used to conjugate CD4 aptamers and anti-GP120 aptamers, and was tested in anti- cancer and viral infection... nanoparticles for specific delivery of multiple therapeutic molecules to cancer cells using RNA nanotechnology . Nano Lett 5, 1797-1808. Khvorova, A...estrogen receptor interacting NR boxes/LxxLL motifs of the MED1 protein and test their efficacy on breast cancer cell growth both in vitro and in

  20. miR-30a suppresses breast cancer cell proliferation and migration by targeting Eya2

    SciTech Connect

    Fu, Jing; Xu, Xiaojie; Kang, Lei; Zhou, Liying; Wang, Shibin; Lu, Juming; Cheng, Long; Fan, Zhongyi; Yuan, Bin; Tian, Peirong; Zheng, Xiaofei; Yu, Chengze; Ye, Qinong; Lv, Zhaohui

    2014-03-07

    Highlights: • miR-30a represses Eya2 expression by binding to the 3′-untranslated region of Eya2. • The miR-30a/EYA2 axis regulates breast cancer cell proliferation and migration. • The miR-30a/EYA2 axis modulates G1/S cell cycle progression. • The miR-30a/EYA2 axis is dysregulated in breast cancer patients. - Abstract: Eye absent (Eya) proteins are involved in cell fate determination in a broad spectrum of cells and tissues. Aberrant expression of Eya2 has been documented in a variety of cancers and correlates with clinical outcome. However, whether microRNAs (miRNAs) can regulate Eya2 expression remains unknown. Here, we show that miR-30a represses Eya2 expression by binding to the 3′-untranslated region of Eya2. Overexpression of Eya2 in miR-30a-transfected breast cancer cells effectively rescued the inhibition of cell proliferation and migration caused by miR-30a. Knockdown of Eya2 by small-interfering RNA (siRNA) in breast cancer cells mimicked the effect induced by miR-30a and abolished the ability of miR-30a to regulate breast cancer cell proliferation and migration. The miR-30a/Eya2 axis could regulate G1/S cell cycle progression, accompanied by the modulation of expression of cell cycle-related proteins, including cyclin A, cyclin D1, cyclin E, and c-Myc. Moreover, miR-30a expression was downregulated in breast cancer patients, and negatively correlated with Eya2, which was upregulated in breast cancer patients. These data suggest that the miR-30a/Eya2 axis may play an important role in breast cancer development and progression and that miR-30a activation or Eya2 inhibition may be a useful strategy for cancer treatment.

  1. Norstictic Acid Inhibits Breast Cancer Cell Proliferation, Migration, Invasion, and In Vivo Invasive Growth Through Targeting C-Met

    PubMed Central

    Ebrahim, Hassan Y.; Elsayed, Heba E.; Mohyeldin, Mohamed M.; Akl, Mohamed R.; Bhattacharjee, Joydeep; Egbert, Susan; El Sayed, Khalid A.

    2016-01-01

    Breast cancer is a major health problem affecting the female population worldwide. The triple-negative breast cancers (TNBCs) are characterized by malignant phenotypes, worse patient outcomes, poorest prognosis, and highest mortality rates. The proto-oncogenic receptor tyrosine kinase c-Met is usually dysregulated in TNBCs, contributing to their oncogenesis, tumor progression, and aggressive cellular invasiveness that is strongly linked to tumor metastasis. Therefore, c-Met is proposed as a promising candidate target for the control of TNBCs. Lichens-derived metabolites are characterized by their structural diversity, complexity, and novelty. The chemical space of lichen-derived metabolites has been extensively investigated, albeit their biological space is still not fully explored. The anticancer-guided fractionation of Usnea strigosa (Ach.) lichen extract led to the identification of the depsidone-derived norstictic acid as a novel bioactive hit against breast cancer cell lines. Norstictic acid significantly suppressed the TNBC MDA-MB-231 cell proliferation, migration, and invasion, with minimal toxicity to non-tumorigenic MCF-10A mammary epithelial cells. Molecular modeling, Z′-LYTE biochemical kinase assay and Western blot analysis identified c-Met as a potential macromolecular target. Norstictic acid treatment significantly suppressed MDA-MB-231/GFP tumor growth of a breast cancer xenograft model in athymic nude mice. Lichen-derived natural products are promising resources to discover novel c-Met inhibitors useful to control TNBCs. PMID:26744260

  2. Targeting inhibitors of apoptosis proteins (IAPs) for new breast cancer therapeutics.

    PubMed

    Wang, Shaomeng; Bai, Longchuan; Lu, Jianfeng; Liu, Liu; Yang, Chao-Yie; Sun, Haiying

    2012-12-01

    Apoptosis resistance is a hallmark of human cancer. Research in the last two decades has identified key regulators of apoptosis, including inhibitor of apoptosis proteins (IAPs). These critical apoptosis regulators have been targeted for the development of new cancer therapeutics. In this article, we will discuss three members of IAP proteins, namely XIAP, cIAP1 and cIAP2, as cancer therapeutic targets and the progress made in developing new cancer therapeutic agents to target these IAP proteins.

  3. The Endocannabinoid System as a Target for Treatment of Breast Cancer

    DTIC Science & Technology

    2009-08-01

    antiproliferative, or anti-invasion effects on breast cancer, as well as determine the mechanism of action. 15. SUBJECT TERMS Cannabinoid receptors; cell ...responsible for catabolism of the endogenous cannabinoid anandamide. We have excised these tumor cells and have been growing them in culture. Once the cells ...examining the effects of cannabinoids on the proliferation and invasion of the following human breast cell lines: Mcf-7, Mcf-10a, and MDA-MB-231

  4. Identification of Breast Cancer - Specific Proteolytic Activities for Targeted Prodrug Activation

    DTIC Science & Technology

    2005-05-01

    hK2 to generate models that can be used for in vivo testing. Studies with Human Breast Cancer extracts Our original intention was to incubate this...detection by fluorescence based cell sorting. Once we have optimized the system we will begin to analyze extracts from breast tissues and conditioned...fluorogenic substrates for assaying retroviral proteases by resonance energy transfer. Science 247:954-958, 1990. 27. Chagas JR, Juliano L, Prado ES

  5. MicroRNA-130b targets PTEN to mediate drug resistance and proliferation of breast cancer cells via the PI3K/Akt signaling pathway

    PubMed Central

    Miao, Yuan; Zheng, Wei; Li, Nana; Su, Zhen; Zhao, Lifen; Zhou, Huimin; Jia, Li

    2017-01-01

    Multidrug resistance (MDR) correlates with treatment failure and poor prognosis among breast cancer patients. This study was aimed to investigate the possible mechanism by which microRNA-130b-3p (miR-130b) mediates the chemoresistance and proliferation of breast cancer. MiR-130b was found to be up-regulated in tumor tissues versus adjacent tissues of breast cancer, as well as in adriamycin (ADR) resistant breast cancer cell line (MCF-7/ADR) versus its parental line (MCF-7) and the non-malignant breast epithelial cell line (MCF-10A), demonstrating its crucial relevance for breast cancer biology. We identified that PTEN was a direct target of miR-130b and inversely correlated with miR-130b expression in breast cancer. Moreover, over-expression of miR-130b promoted drug resistance, proliferation and decreased apoptosis of MCF-7 cells, while suppression of miR-130b enhanced drug cytotoxicity and apoptosis, as well as reduced proliferation of MCF-7/ADR cells in vitro and in vivo. Particularly, miR-130b mediated the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway as well as the chemoresistance and proliferation of breast cancer cell lines, which was partially blocked following knockdown of PTEN. Altogether, miR-130b targets PTEN to induce MDR, proliferation, and apoptosis via PI3K/Akt signaling pathway. This provides a novel promising candidate for breast cancer therapy. PMID:28165066

  6. Nanobiopolymer for Direct Targeting and Inhibition of EGFR Expression in Triple Negative Breast Cancer

    PubMed Central

    Inoue, Satoshi; Patil, Rameshwar; Portilla-Arias, Jose; Ding, Hui; Konda, Bindu; Espinoza, Andres; Mongayt, Dmitriy; Markman, Janet L.; Elramsisy, Adam; Phillips, H. Westley; Black, Keith L.; Holler, Eggehard; Ljubimova, Julia Y.

    2012-01-01

    Treatment options for triple negative breast cancer (TNBC) are generally limited to cytotoxic chemotherapy. Recently, anti-epidermal growth factor receptor (EGFR) therapy has been introduced for TNBC patients. We engineered a novel nanobioconjugate based on a poly(β-L-malic acid) (PMLA) nanoplatform for TNBC treatment. The nanobioconjugate carries anti-tumor nucleosome-specific monoclonal antibody (mAb) 2C5 to target breast cancer cells, anti-mouse transferrin receptor (TfR) antibody for drug delivery through the host endothelial system, and Morpholino antisense oligonucleotide (AON) to inhibit EGFR synthesis. The nanobioconjugates variants were: (1) P (BioPolymer) with AON, 2C5 and anti-TfR for tumor endothelial and cancer cell targeting, and EGFR suppression (P/AON/2C5/TfR), and (2) P with AON and 2C5 (P/AON/2C5). Controls included (3) P with 2C5 but without AON (P/2C5), (4) PBS, and (5) P with PEG and leucine ester (LOEt) for endosomal escape (P/mPEG/LOEt). Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissue accumulation of injected nanobioconjugates labeled with Alexa Fluor 680 was examined by Xenogen IVIS 200 (live imaging) and confocal microscopy of tissue sections. Levels of EGFR, phosphorylated and total Akt in tumor samples were detected by western blotting. In vitro western blot showed that the leading nanobioconjugate P/AON/2C5/TfR inhibited EGFR synthesis significantly better than naked AON. In vivo imaging revealed that 2C5 increased drug-tumor accumulation. Significant tumor growth inhibition was observed in mice treated with the lead nanobioconjugate (1) [P = 0.03 vs. controls; P<0.05 vs. nanobioconjugate variant (2)]. Lead nanobioconjugate (1) also showed stronger inhibition of EGFR expression and Akt phosphorylation than other treatments. Treatment of TNBC with the new nanobioconjugate results in tumor growth arrest by inhibiting EGFR and its downstream signaling intermediate, phosphorylated Akt. The nanobioconjugate

  7. Synthesis, characterization and in vitro evaluation of exquisite targeting SPIONs-PEG-HER in HER2+ human breast cancer cells

    NASA Astrophysics Data System (ADS)

    Hamzehalipour Almaki, Javad; Nasiri, Rozita; Idris, Ani; Majid, Fadzilah Adibah Abdul; Salouti, Mojtaba; Wong, Tet Soon; Dabagh, Shadab; Marvibaigi, Mohsen; Amini, Neda

    2016-03-01

    A stable, biocompatible and exquisite SPIONs-PEG-HER targeting complex was developed. Initially synthesized superparamagnetic iron oxide nanoparticles (SPIONs) were silanized using 3-aminopropyltrimethoxysilane (APS) as the coupling agent in order to allow the covalent bonding of polyethylene glycol (PEG) to the SPIONs to improve the biocompatibility of the SPIONs. SPIONs-PEG were then conjugated with herceptin (HER) to permit the SPIONs-PEG-HER to target the specific receptors expressed over the surface of the HER2+ metastatic breast cancer cells. Each preparation step was physico-chemically analyzed and characterized by a number of analytical methods including AAS, FTIR spectroscopy, XRD, FESEM, TEM, DLS and VSM. The biocompatibility of SPIONs-PEG-HER was evaluated in vitro on HSF-1184 (human skin fibroblast cells), SK-BR-3 (human breast cancer cells, HER+), MDA-MB-231 (human breast cancer cells, HER-) and MDA-MB-468 (human breast cancer cells, HER-) cell lines by performing MTT and trypan blue assays. The hemolysis analysis results of the SPIONs-PEG-HER and SPIONs-PEG did not indicate any sign of lysis while in contact with erythrocytes. Additionally, there were no morphological changes seen in RBCs after incubation with SPIONs-PEG-HER and SPIONs-PEG under a light microscope. The qualitative and quantitative in vitro targeting studies confirmed the high level of SPION-PEG-HER binding to SK-BR-3 (HER2+ metastatic breast cancer cells). Thus, the results reflected that the SPIONs-PEG-HER can be chosen as a favorable biomaterial for biomedical applications, chiefly magnetic hyperthermia, in the future.

  8. Genomic Analyses as a Guide to Target Identification and Preclinical Testing of Mouse Models of Breast Cancer

    PubMed Central

    Bennett, Christina N; Green, Jeffrey E.

    2012-01-01

    Cross-species genomic analyses have proven useful for identifying common genomic alterations that occur in human cancers and mouse models designed to recapitulate human tumor development. High-throughput molecular analyses provide a valuable tool for identifying particular animal models that may represent aspects of specific subtypes of human cancers. Corresponding alterations in gene copy number and expression in tumors from mouse and human suggest that these conserved changes may be mechanistically essential for cancer development and progression, and therefore, they may be critical targets for therapeutic intervention. Using a cross-species analysis approach, mouse models in which the functions of p53, Rb, and BRCA1 have been disrupted demonstrate molecular features of human, triple-negative (ER-, PR-, and ERBB2-), basal-type breast cancer. Using mouse tumor models based on the targeted abrogation of p53 and Rb function, we identified a large, integrated genetic network that correlates to poor outcome in several human epithelial cancers. This gene signature is highly enriched for genes involved in DNA replication and repair, chromosome maintenance, cell cycle regulation, and apoptosis. Current studies are determining whether inactivation of specific members within this signature, using drugs or siRNA, will identify potentially important new targets to inhibit triple-negative, basal-type breast cancer for which no targeted therapies currently exist. PMID:20080934

  9. Role of inhibitors of mammalian target of rapamycin in the treatment of luminal breast cancer.

    PubMed

    Ciruelos, Eva; Cortes-Funes, Hernán; Ghanem, Ismael; Manso, Luis; Arteaga, Carlos

    2013-09-01

    Approximately 75% of patients with breast cancer present hormone receptor-positive tumors. This subtype of breast cancer initially shows a high overall response rate to hormonal treatments. However, resistance eventually develops, resulting in tumor progression. The PI3K/Akt/mTOR pathway regulates several cellular functions in cancer such as cell growth, survival, and proliferation. In addition, a high activation level of the PI3K/Akt/mTOR pathway is related to resistance to conventional chemotherapy and hormone therapy. The mTOR inhibitor everolimus, in combination with hormonal treatments, has led to excellent results in progression-free survival in patients with metastatic breast cancer resistant to hormone therapies. Therefore, everolimus has entered the National Comprehensive Cancer Network (NCCN) guidelines 2012 and its combination with exemestane was approved recently by the US Food and Drug Administration and the European Medicines Agency. This is the first time that a drug will have been approved for the restoration of hormone sensitivity in breast cancer.

  10. Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility

    PubMed Central

    Mantere, Tuomo; Winqvist, Robert; Kauppila, Saila; Grip, Mervi; Jukkola-Vuorinen, Arja; Tervasmäki, Anna; Rapakko, Katrin; Pylkäs, Katri

    2016-01-01

    Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remain unknown. Here, we performed a targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication of hereditary disease susceptibility and focused the analysis on protein truncating mutations. A recurrent heterozygous mutation (c.904_916del, p.Arg304ValfsTer3) was identified in early DNA damage response gene, MCPH1, significantly associating with breast cancer susceptibility both in familial (5/145, 3.4%, P = 0.003, OR 8.3) and unselected cases (16/1150, 1.4%, P = 0.016, OR 3.3). A total of 21 mutation positive families were identified, of which one-third exhibited also brain tumors and/or sarcomas (P = 0.0007). Mutation carriers exhibited significant increase in genomic instability assessed by cytogenetic analysis for spontaneous chromosomal rearrangements in peripheral blood lymphocytes (P = 0.0007), suggesting an effect for MCPH1 haploinsufficiency on cancer susceptibility. Furthermore, 40% of the mutation carrier tumors exhibited loss of the wild-type allele. These findings collectively provide strong evidence for MCHP1 being a novel breast cancer susceptibility gene, which warrants further investigations in other populations. PMID:26820313

  11. Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer.

    PubMed

    Phelps-Polirer, Kendall; Abt, Melissa A; Smith, Danzell; Yeh, Elizabeth S

    2016-01-01

    Strategies for successful primary treatment of HER2-positive breast cancer include use of the HER2 inhibitors trastuzumab or lapatinib in combination with standard chemotherapy. While successful, many patients develop resistance to these HER2 inhibitors indicating an unmet need. Consequently, current research efforts are geared toward understanding mechanisms of resistance and the signaling modalities that regulate these mechanisms. We have undertaken a study to examine whether signaling molecules downstream of epidermal growth factor receptor, which often act as compensatory signaling outlets to circumvent HER2 inhibition, can be co-targeted to overcome resistance. We identified JNK signaling as a potential area of intervention and now show that inhibiting JNK using the pan-JNK inhibitor, SP600125, is effective in the HER2-positive, resistant JIMT-1 xenograft mammary tumor model. We also investigate potential combination strategies to bolster the effects of JNK inhibition and find that co-targeting of JNK and the protein kinase HUNK can prohibit tumor growth of resistant HER2-positive mammary tumors in vivo.

  12. Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer

    PubMed Central

    Phelps-Polirer, Kendall; Abt, Melissa A.; Smith, Danzell; Yeh, Elizabeth S.

    2016-01-01

    Strategies for successful primary treatment of HER2-positive breast cancer include use of the HER2 inhibitors trastuzumab or lapatinib in combination with standard chemotherapy. While successful, many patients develop resistance to these HER2 inhibitors indicating an unmet need. Consequently, current research efforts are geared toward understanding mechanisms of resistance and the signaling modalities that regulate these mechanisms. We have undertaken a study to examine whether signaling molecules downstream of epidermal growth factor receptor, which often act as compensatory signaling outlets to circumvent HER2 inhibition, can be co-targeted to overcome resistance. We identified JNK signaling as a potential area of intervention and now show that inhibiting JNK using the pan-JNK inhibitor, SP600125, is effective in the HER2-positive, resistant JIMT-1 xenograft mammary tumor model. We also investigate potential combination strategies to bolster the effects of JNK inhibition and find that co-targeting of JNK and the protein kinase HUNK can prohibit tumor growth of resistant HER2-positive mammary tumors in vivo. PMID:27045589

  13. 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

  14. Targeting Alpha5 Beta1 Integrin to Prevent Metastatic Breast Cancer Cell Invasion: PhScN Target Site Definition and Plasma Stability

    DTIC Science & Technology

    2015-11-01

    Definition and Plasma Stability” PRINCIPAL INVESTIGATOR: Philip Andrews CONTRACTING ORGANIZATION: The Regents of the University of Michigan...Integrin to Prevent Metastatic Breast Cancer Cell Invasion: PhScN Target Site Definition and Plasma Stability 5a. CONTRACT NUMBER 5b. GRANT NUMBER...termini, and/or cysteine side chain to determine the initial spatial constraints of the binding pocket of the ligand to its target site. This will

  15. Endoplasmic Reticulum-Associated Degradation Factor ERLIN2: Oncogenic Roles and Molecular Targeting of Breast Cancer

    DTIC Science & Technology

    2013-06-01

    that fatty acid synthesis and expression of lipogenic genes in breast c © The Authors Journal compilation c © 2012 Biochemical Society 22 ERLIN2 regulates... gene amplification at 8p12 specifies luminal B breast cancer. EMBO Mol. Med. 3, 153–166 12 Yang, Z. Q., Liu, G., Bollig-Fischer, A., Giroux, C . N. and...with differentiated functions in chemically defined medium. Cancer Res. 42 , 3858–3863 20 Laing, S., Wang, G., Briazova, T., Zhang, C ., Wang, A., Zheng

  16. Targeting Nuclear FGF Receptor to Improve Chemotherapy Response in Triple-Negative Breast Cancer

    DTIC Science & Technology

    2015-10-01

    for this grant proposal, MDA- MB-231 and SUM159PT cells were already obtained from the Duke Cell Culture facility. SUM159PT cells were provided by this...bFGF) for preventing TN breast cancer recurrence. Methods Cell culture SUM159 TN breast cancer cells were obtained from the Duke Cell Culture ...were obtained from the Duke Cell Culture Facility and maintained in RPMI 1640 medium containing 10 % heat-inactivated FBS, 1 μg/ml insulin, 10 mM HEPES

  17. The PD1/PDL1 axis, a promising therapeutic target in aggressive breast cancers.

    PubMed

    Bertucci, François; Finetti, Pascal; Birnbaum, Daniel; Mamessier, Emilie

    2016-03-01

    Analysis of PDL1 mRNA expression in ∼5,500 breast cancers showed PDL1 upregulation in 38% of basal tumors and 38% of inflammatory breast cancers (IBC). Upregulation, associated with signs of strong cytotoxic local immune response, was associated with a better survival in the basal or triple-negative subtypes, and with a better pathological response to chemotherapy in these subtypes and IBC. Reactivation of dormant tumor-infiltrating lymphocytes (TILs) by PD1/PDL1-inhibitors represents a promising strategy in these aggressive tumors.

  18. The PD1/PDL1 axis, a promising therapeutic target in aggressive breast cancers

    PubMed Central

    Bertucci, François; Finetti, Pascal; Birnbaum, Daniel; Mamessier, Emilie

    2016-01-01

    ABSTRACT Analysis of PDL1 mRNA expression in ∼5,500 breast cancers showed PDL1 upregulation in 38% of basal tumors and 38% of inflammatory breast cancers (IBC). Upregulation, associated with signs of strong cytotoxic local immune response, was associated with a better survival in the basal or triple-negative subtypes, and with a better pathological response to chemotherapy in these subtypes and IBC. Reactivation of dormant tumor-infiltrating lymphocytes (TILs) by PD1/PDL1-inhibitors represents a promising strategy in these aggressive tumors. PMID:27141340

  19. Oncolytic virotherapy of breast cancer.

    PubMed

    Hartkopf, Andreas D; Fehm, Tanja; Wallwiener, Diethelm; Lauer, Ulrich M

    2011-10-01

    The use of replication competent viruses that selectively target and destroy cancer cells has rapidly evolved over the past decade and numerous innovative oncolytic viruses have been created. Many of these promising anti-cancer agents have recently entered into clinical trials (including those on breast cancer) and demonstrated encouraging safety and efficacy. Virotherapeutic strategies are thus of considerable interest to combat breast cancer in both (i) the primary disease situation in which relapse should be avoided as good as possible and (ii) in the metastatic situation which remains incurable to date. Here, we summarize data from preclinical and clinical trials using oncolytic virotherapy to treat breast cancer. This includes strategies to specifically target breast cancer cells, to arm oncolytic viruses with additional therapeutic transgenes and an outlining of future challenges when translating these promising therapeutics "from bench to bedside".

  20. Targeted Proteomics Enables Simultaneous Quantification of Folate Receptor Isoforms and Potential Isoform-based Diagnosis in Breast Cancer

    PubMed Central

    Yang, Ting; Xu, Feifei; Fang, Danjun; Chen, Yun

    2015-01-01

    The distinct roles of protein isoforms in cancer are becoming increasingly evident. FRα and FRβ, two major isoforms of the folate receptor family, generally have different cellular distribution and tissue specificity. However, the presence of FRβ in breast tumors, where FRα is normally expressed, complicates this situation. Prior to applying any FR isoform-based diagnosis and therapeutics, it is essential to monitor the expression profile of FR isoforms in a more accurate manner. An LC-MS/MS-based targeted proteomics assay was developed and validated in this study because of the lack of suitable methodology for the simultaneous and specific measurement of highly homologous isoforms occurring at low concentrations. FRα and FRβ monitoring was achieved by measuring their surrogate isoform-specific peptides. Five human breast cell lines, isolated macrophages and 60 matched pairs of breast tissue samples were subjected to the analysis. The results indicated that FRβ was overexpressed in tumor-associated macrophages (TAMs) but not epithelial cells, in addition to an enhanced level of FRα in breast cancer cells and tissue samples. Moreover, the levels of the FR isoforms were evaluated according to the histology, histopathological features and molecular subtypes of breast cancer. Several positive associations with PR/ER and HER2 status and metastasis were revealed. PMID:26573433

  1. Public education and targeted outreach to underserved women through the National Breast and Cervical Cancer Early Detection Program.

    PubMed

    Levano, Whitney; Miller, Jacqueline W; Leonard, Banning; Bellick, Linda; Crane, Barbara E; Kennedy, Stephenie K; Haslage, Natalie M; Hammond, Whitney; Tharpe, Felicia S

    2014-08-15

    The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) was established to provide low-income, uninsured, and underinsured women access to cancer screening and diagnostic services with the goal of increasing the early detection and prevention of breast and cervical cancer. Although this is a valuable resource for women who might not have the means to get screened otherwise, providing services at no cost, by itself, does not guarantee uptake of screening services. Public education and targeted outreach facilitate the critical link between public service programs and the communities they serve. The purpose of public education and outreach in the NBCCEDP is to increase the number of women who use breast and cervical cancer screening services by raising awareness, providing education, addressing barriers, and motivating women to complete screening exams and follow-up. Effective strategies focus on helping to remove structural, physical, interpersonal, financial, and cultural barriers; educate women about the importance of screening and inform women about the services available to them. This article provides an overview of the importance of public education and targeted outreach activities for cancer screening through community-based programs including examples from NBCCEDP grantees that highlight successes, challenges, and solutions, encountered when conducting these types of interventions.

  2. Public Education and Targeted Outreach to Underserved Women Through the National Breast and Cervical Cancer Early Detection Program

    PubMed Central

    Levano, Whitney; Miller, Jacqueline W.; Leonard, Banning; Bellick, Linda; Crane, Barbara E.; Kennedy, Stephenie K.; Haslage, Natalie M.; Hammond, Whitney; Tharpe, Felicia S.

    2015-01-01

    The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) was established to provide low-income, uninsured, and underinsured women access to cancer screening and diagnostic services with the goal of increasing the early detection and prevention of breast and cervical cancer. Although this is a valuable resource for women who might not have the means to get screened otherwise, providing services at no cost, by itself, does not guarantee uptake of screening services. Public education and targeted outreach facilitate the critical link between public service programs and the communities they serve. The purpose of public education and outreach in the NBCCEDP is to increase the number of women who use breast and cervical cancer screening services by raising awareness, providing education, addressing barriers, and motivating women to complete screening exams and follow-up. Effective strategies focus on helping to remove structural, physical, interpersonal, financial, and cultural barriers; educate women about the importance of screening and inform women about the services available to them. This article provides an overview of the importance of public education and targeted outreach activities for cancer screening through community-based programs including examples from NBCCEDP grantees that highlight successes, challenges, and solutions, encountered when conducting these types of interventions. PMID:25099902

  3. MDM4 is a rational target for treating breast cancers with mutant p53.

    PubMed

    Miranda, Panimaya Jeffreena; Buckley, Daniel; Raghu, Dinesh; Pang, Jia-Min B; Takano, Elena A; Vijayakumaran, Reshma; Teunisse, Amina Fas; Posner, Atara; Procter, Tahlia; Herold, Marco J; Gamell, Cristina; Marine, Jean-Christophe; Fox, Stephen B; Jochemsen, Aart; Haupt, Sue; Haupt, Ygal

    2017-04-01

    Mutation of the key tumour suppressor p53 defines a transition in the progression towards aggressive and metastatic breast cancer (BC) with the poorest outcome. Specifically, the p53 mutation frequency exceeds 50% in triple-negative BC. Key regulators of mutant p53 that facilitate its oncogenic functions are potential therapeutic targets. We report here that the MDM4 protein is frequently abundant in the context of mutant p53 in basal-like BC samples. Importantly, we show that MDM4 plays a critical role in the proliferation of these BC cells. We demonstrate that conditional knockdown (KD) of MDM4 provokes growth inhibition across a range of BC subtypes with mutant p53, including luminal, Her2(+) and triple-negative BCs. In vivo, MDM4 was shown to be crucial for the establishment and progression of tumours. This growth inhibition was mediated, at least in part, by the cell cycle inhibitor p27. Depletion of p27 together with MDM4 KD led to recovery of the proliferative capacity of cells that were growth-inhibited by MDM4 KD alone. Consistently, we identified low levels of p27 expression in basal-like tumours corresponding to high levels of MDM4 and p53. This predicts a signature for a subset of tumours that may be amenable to therapies targeted towards MDM4 and mutant p53. The therapeutic potential of MDM4 as a target in BC with mutant p53 was shown in vitro by use of a small-molecule inhibitor. Overall, our study supports MDM4 as a novel therapeutic target for BC expressing mutant p53. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  4. Current Management Strategies in Breast Cancer by Targeting Key Altered Molecular Players

    PubMed Central

    Ali, Shazia; Mondal, Neelima; Choudhry, Hani; Rasool, Mahmood; Pushparaj, Peter N.; Khan, Mohammad A.; Mahfooz, Maryam; Sami, Ghufrana A.; Jarullah, Jummanah; Ali, Ashraf; Jamal, Mohammad S.

    2016-01-01

    Breast cancer is the second largest disease affecting women worldwide. It remains the most frequently reported and leading cause of death among women in both developed and developing countries. Tamoxifen and raloxifene are commonly used selective estrogen receptor modulators for treatment of breast cancer in women with high risk, although resistance occurs by tamoxifen after 5 years of therapy and both drugs cause uterine cancer and thromboembolic events. Aromatase inhibitors (AIs) are one of the optional modes used for breast cancer treatment. The combination of AIs along with tamoxifen can also be beneficial. Various therapeutic agents from different sources are being studied, which further need to be improved for potential outcome. For this, clinical trials based on large number of patients with optimal dose and lesser side effects have to be more in practice. Despite the clinical trials going on, there is need of better molecular models, which can identify high risk population, new agents with better benefit having less side effects, and improved biomarkers for treating breast cancer. PMID:26973813

  5. New Immunotherapy Strategies in Breast Cancer

    PubMed Central

    Yu, Lin-Yu; Tang, Jie; Zhang, Cong-Min; Zeng, Wen-Jing; Yan, Han; Li, Mu-Peng; Chen, Xiao-Ping

    2017-01-01

    Breast cancer is the most commonly diagnosed cancer among women. Therapeutic treatments for breast cancer generally include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, immunotherapy becomes a promising new field in breast cancer therapies. In this review, we discussed recent progress in breast cancer immunotherapy, including cancer vaccines, bispecific antibodies, and immune checkpoint inhibitors. Several additional immunotherapy modalities in early stages of development are also highlighted. It is believed that these new immunotherapeutic strategies will ultimately change the current status of breast cancer therapies. PMID:28085094

  6. New Immunotherapy Strategies in Breast Cancer.

    PubMed

    Yu, Lin-Yu; Tang, Jie; Zhang, Cong-Min; Zeng, Wen-Jing; Yan, Han; Li, Mu-Peng; Chen, Xiao-Ping

    2017-01-12

    Breast cancer is the most commonly diagnosed cancer among women. Therapeutic treatments for breast cancer generally include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, immunotherapy becomes a promising new field in breast cancer therapies. In this review, we discussed recent progress in breast cancer immunotherapy, including cancer vaccines, bispecific antibodies, and immune checkpoint inhibitors. Several additional immunotherapy modalities in early stages of development are also highlighted. It is believed that these new immunotherapeutic strategies will ultimately change the current status of breast cancer therapies.

  7. Transcriptome-wide analysis of compression-induced microRNA expression alteration in breast cancer for mining therapeutic targets.

    PubMed

    Kim, Baek Gil; Kang, Suki; Han, Hyun Ho; Lee, Joo Hyun; Kim, Ji Eun; Lee, Sung Hwan; Cho, Nam Hoon

    2016-05-10

    Tumor growth-generated mechanical compression may increase or decrease expression of microRNAs, leading to tumor progression. However, little is known about whether mechanical compression induces aberrant expression of microRNAs in cancer and stromal cells. To investigate the relationship between compression and microRNA expression, microRNA array analysis was performed with breast cancer cell lines and cancer-associated fibroblasts (CAFs) exposed to different compressive conditions. In our study, mechanical compression induced alteration of microRNA expression level in breast cancer cells and CAFs. The alteration was greater in the breast cancer cells than CAFs. Mechanical compression mainly induced upregulation of microRNAs rather than downregulation. In a parallel mRNA array analysis, more than 25% of downregulated target genes were functionally involved in tumor suppression (apoptosis, cell adhesion, and cell cycle arrest), whereas generally less than 15% were associated with tumor progression (epithelial-mesenchymal transition, migration, invasion, and angiogenesis). Of all cells examined, MDA-MB-231 cells showed the largest number of compression-upregulated microRNAs. miR-4769-5p and miR-4446-3p were upregulated by compression in both MDA-MB-231 cells and CAFs. Our results suggest that mechanical compression induces changes in microRNA expression level, which contribute to tumor progression. In addition, miR-4769-5p and miR-4446-3p may be potential therapeutic targets for incurable cancers, such as triple negative breast cancer, in that this would reduce or prevent downregulation of tumor-suppressing genes in both the tumor and its microenvironment simultaneously.

  8. Transcriptome-wide analysis of compression-induced microRNA expression alteration in breast cancer for mining therapeutic targets

    PubMed Central

    Kim, Baek Gil; Kang, Suki; Han, Hyun Ho; Lee, Joo Hyun; Kim, Ji Eun; Lee, Sung Hwan; Cho, Nam Hoon

    2016-01-01

    Tumor growth–generated mechanical compression may increase or decrease expression of microRNAs, leading to tumor progression. However, little is known about whether mechanical compression induces aberrant expression of microRNAs in cancer and stromal cells. To investigate the relationship between compression and microRNA expression, microRNA array analysis was performed with breast cancer cell lines and cancer-associated fibroblasts (CAFs) exposed to different compressive conditions. In our study, mechanical compression induced alteration of microRNA expression level in breast cancer cells and CAFs. The alteration was greater in the breast cancer cells than CAFs. Mechanical compression mainly induced upregulation of microRNAs rather than downregulation. In a parallel mRNA array analysis, more than 25% of downregulated target genes were functionally involved in tumor suppression (apoptosis, cell adhesion, and cell cycle arrest), whereas generally less than 15% were associated with tumor progression (epithelial-mesenchymal transition, migration, invasion, and angiogenesis). Of all cells examined, MDA-MB-231 cells showed the largest number of compression-upregulated microRNAs. miR-4769-5p and miR-4446-3p were upregulated by compression in both MDA-MB-231 cells and CAFs. Our results suggest that mechanical compression induces changes in microRNA expression level, which contribute to tumor progression. In addition, miR-4769-5p and miR-4446-3p may be potential therapeutic targets for incurable cancers, such as triple negative breast cancer, in that this would reduce or prevent downregulation of tumor-suppressing genes in both the tumor and its microenvironment simultaneously. PMID:27027350

  9. Selection of Novel Peptides Homing the 4T1 CELL Line: Exploring Alternative Targets for Triple Negative Breast Cancer.

    PubMed

    Silva, Vera L; Ferreira, Debora; Nobrega, Franklin L; Martins, Ivone M; Kluskens, Leon D; Rodrigues, Ligia R

    2016-01-01

    The use of bacteriophages to select novel ligands has been widely explored for cancer therapy. Their application is most warranted in cancer subtypes lacking knowledge on how to target the cancer cells in question, such as the triple negative breast cancer, eventually leading to the development of alternative nanomedicines for cancer therapeutics. Therefore, the following study aimed to select and characterize novel peptides for a triple negative breast cancer murine mammary carcinoma cell line- 4T1. Using phage display, 7 and 12 amino acid random peptide libraries were screened against the 4T1 cell line. A total of four rounds, plus a counter-selection round using the 3T3 murine fibroblast cell line, was performed. The enriched selective peptides were characterized and their binding capacity towards 4T1 tissue samples was confirmed by immunofluorescence and flow cytometry analysis. The selected peptides (4T1pep1 -CPTASNTSC and 4T1pep2-EVQSSKFPAHVS) were enriched over few rounds of selection and exhibited specific binding to the 4T1 cell line. Interestingly, affinity to the human MDA-MB-231 cell line was also observed for both peptides, promoting the translational application of these novel ligands between species. Additionally, bioinformatics analysis suggested that both peptides target human Mucin-16. This protein has been implicated in different types of cancer, as it is involved in many important cellular functions. This study strongly supports the need of finding alternative targeting systems for TNBC and the peptides herein selected exhibit promising future application as novel homing peptides for breast cancer therapy.

  10. Selection of Novel Peptides Homing the 4T1 CELL Line: Exploring Alternative Targets for Triple Negative Breast Cancer

    PubMed Central

    Nobrega, Franklin L.; Martins, Ivone M.

    2016-01-01

    The use of bacteriophages to select novel ligands has been widely explored for cancer therapy. Their application is most warranted in cancer subtypes lacking knowledge on how to target the cancer cells in question, such as the triple negative breast cancer, eventually leading to the development of alternative nanomedicines for cancer therapeutics. Therefore, the following study aimed to select and characterize novel peptides for a triple negative breast cancer murine mammary carcinoma cell line– 4T1. Using phage display, 7 and 12 amino acid random peptide libraries were screened against the 4T1 cell line. A total of four rounds, plus a counter-selection round using the 3T3 murine fibroblast cell line, was performed. The enriched selective peptides were characterized and their binding capacity towards 4T1 tissue samples was confirmed by immunofluorescence and flow cytometry analysis. The selected peptides (4T1pep1 –CPTASNTSC and 4T1pep2—EVQSSKFPAHVS) were enriched over few rounds of selection and exhibited specific binding to the 4T1 cell line. Interestingly, affinity to the human MDA-MB-231 cell line was also observed for both peptides, promoting the translational application of these novel ligands between species. Additionally, bioinformatics analysis suggested that both peptides target human Mucin-16. This protein has been implicated in different types of cancer, as it is involved in many important cellular functions. This study strongly supports the need of finding alternative targeting systems for TNBC and the peptides herein selected exhibit promising future application as novel homing peptides for breast cancer therapy. PMID:27548261

  11. Targeted Intraoperative Radiotherapy for Breast Cancer in Patients in Whom External Beam Radiation Is Not Possible

    SciTech Connect

    Keshtgar, Mohammed R.S.; Joseph, David; Stacey, Chris; Metaxas, Marinos G.; Corica, Tammy; Williams, Norman R.; Baum, Michael

    2011-05-01

    Purpose: External beam radiation therapy (EBRT) following wide local excision of the primary tumor is the standard treatment in early breast cancer. In some circumstances this procedure is not possible or is contraindicated or difficult. The purpose of this study was to determine the safety and efficacy of targeted intraoperative radiotherapy (TARGIT) when EBRT is not feasible. Methods and Materials: We report our experience with TARGIT in three centers (Australia, Germany, and the United Kingdom) between 1999 and 2008. Patients at these centers received a single radiation dose of 20 Gy to the breast tissue in contact with the applicator (or 6 Gy at 1-cm distance), as they could not be given EBRT and were keen to avoid mastectomy. Results: Eighty patients were treated with TARGIT. Reasons for using TARGIT were 21 patients had previously received EBRT, and 31 patients had clinical reasons such as systemic lupus erythematosus, motor neuron disease, Parkinson's disease, ankylosing spondylitis, morbid obesity, and cardiovascular or severe respiratory disease. Three of these patients received percutaneous radiotherapy without surgery; 28 patients were included for compelling personal reasons, usually on compassionate grounds. After a median follow-up of 38 months, only two local recurrences were observed, an annual local recurrence rate of 0.75% (95% confidence interval, 0.09%-2.70%). Conclusions: While we await the results of the randomized trial (over 2,000 patients have already been recruited), TARGIT is an acceptable option but only in highly selected cases that cannot be recruited in the trial and in whom EBRT is not feasible/possible.

  12. Breast cancer staging

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000911.htm Breast cancer staging To use the sharing features on this ... Once your health care team knows you have breast cancer , they will do more tests to stage it. ...

  13. Stages of Breast Cancer

    MedlinePlus

    ... to treat breast cancer. Internal radiation therapy with strontium-89 (a radionuclide ) is used to relieve bone ... breast cancer that has spread to the bones. Strontium-89 is injected into a vein and travels ...

  14. Breast Cancer Treatment

    MedlinePlus

    ... to treat breast cancer. Internal radiation therapy with strontium-89 (a radionuclide ) is used to relieve bone ... breast cancer that has spread to the bones. Strontium-89 is injected into a vein and travels ...

  15. Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer.

    PubMed

    Wu, Xinyan; Zahari, Muhammad Saddiq; Renuse, Santosh; Nirujogi, Raja Sekhar; Kim, Min-Sik; Manda, Srikanth S; Stearns, Vered; Gabrielson, Edward; Sukumar, Saraswati; Pandey, Akhilesh

    2015-11-01

    Tamoxifen, an estrogen receptor-α (ER) antagonist, is an important agent for the treatment of breast cancer. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying this resistance, we treated the MCF7 breast cancer cell line with tamoxifen for over six months and showed that this cell line acquired resistance to tamoxifen in vitro and in vivo. We performed SILAC-based quantitative phosphoproteomic profiling on the tamoxifen resistant and vehicle-treated sensitive cell lines to quantify the phosphorylation alterations associated with tamoxifen resistance. From >5600 unique phosphopeptides identified, 1529 peptides exhibited hyperphosphorylation and 409 peptides showed hypophosphorylation in the tamoxifen resistant cells. Gene set enrichment analysis revealed that focal adhesion pathway was one of the most enriched signaling pathways activated in tamoxifen resistant cells. Significantly, we showed that the focal adhesion kinase FAK2 was not only hyperphosphorylated but also transcriptionally up-regulated in tamoxifen resistant cells. FAK2 suppression by specific siRNA knockdown or a small molecule inhibitor repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 is significantly associated with shorter metastasis-free survival in estrogen receptor-positive breast cancer patients treated with tamoxifen. Our studies suggest that FAK2 is a potential therapeutic target for the management of hormone-refractory breast cancers.

  16. FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target

    PubMed Central

    Horton, Janet K.; Siamakpour-Reihani, Sharareh; Lee, Chen-Ting; Zhou, Ying; Chen, Wei; Geradts, Joseph; Fels, Diane R.; Hoang, Peter; Ashcraft, Kathleen A.; Groth, Jeff; Kung, Hsiu-Ni; Dewhirst, Mark W.; Chi, Jen-Tsan A.

    2015-01-01

    Although a standardized approach to radiotherapy has been used to treat breast cancer, regardless of subtype (e.g., luminal, basal), recent clinical data suggest that radiation response may vary significantly among subtypes. We hypothesized that this clinical variability may be due, in part, to differences in cellular radiation response. In this study, we utilized RNA samples for microarray analysis from two sources: 1. Paired pre- and postirradiation breast tumor tissue from 32 early-stage breast cancer patients treated in our unique preoperative radiation Phase I trial; and 2. Sixteen biologically diverse breast tumor cell lines exposed to 0 and 5 Gy irradiation. The transcriptome response to radiation exposure was derived by comparing gene expression in samples before and after irradiation. Genes with the highest coefficient of variation were selected for further evaluation and validated at the RNA and protein level. Gene editing and agonistic antibody treatment were performed to assess the impact of gene modulation on radiation response. Gene expression in our cohort of luminal breast cancer patients was distinctly different before and after irradiation. Further, two distinct patterns of gene expression were observed in our biologically diverse group of breast cancer cell lines pre- versus postirradiation. Cell lines that showed significant change after irradiation were largely luminal subtype, while gene expression in the basal and HER2+ cell lines was minimally impacted. The 100 genes with the most significant response to radiation in patients were identified and analyzed for differential patterns of expression in the radiation-responsive versus nonresponsive cell lines. Fourteen genes were identified as significant, including FAS, a member of the tumor necrosis factor receptor family known to play a critical role in programed cell death. Modulation of FAS in breast cancer cell lines altered radiation response phenotype and enhanced radiation sensitivity in

  17. Breast Cancer Early Detection and Diagnosis

    MedlinePlus

    ... En Español Category Cancer A-Z Breast Cancer Breast Cancer Early Detection and Diagnosis Breast cancer is sometimes ... cancer screening is so important. Learn more. Can Breast Cancer Be Found Early? Breast cancer is sometimes found ...

  18. Src Kinase: A Novel Target of Early-Stage ER-Negative Breast Cancer

    DTIC Science & Technology

    2012-03-01

    and examine the sensitivity of these ER- breast cancer to Tamoxifen/ Herceptin using in vitro and MMTV-Neu mouse model. Task 1. To determine the...months: Test the sensitivity of AZD0530 and/Lapatinib treated ER- tumors with Tamoxifen/ Herceptin using immunodeficient and MMTV-Neu mouce model

  19. A Partnership Training Program: Studying Targeted Drug Delivery Using Nanoparticles In Breast Cancer Diagnosis and Therapy

    DTIC Science & Technology

    2011-10-01

    paramagnetic gadolinium chelates, organic dyes, metallic gold nanoparticles , semiconducting quantum dots and magnetic nanoparticles into single probes 14...particles [11, 16, 21, 31–36]. The magnetization directions of small super paramagnetic crystals were constrained by mag- netic interactions with...Delivery Nanoparticles in Breast Cancer Diagnosis and Therapy I. INTRODUCTION In this proposed training program a partnership between Howard

  20. Onboard SPECT for Localizing Functional and Molecular Targets in Metastatic Breast Cancer

    DTIC Science & Technology

    2009-07-01

    A. Clemenson, S. Charrier, V. Feil- lel, G. Le Bouedec, P. Kaufmann, J. Dauplat, and A. Veyre, “ Technetium - 99m-sestamibi uptake in breast tumor and...Savelli, and E. Bombardieri, “Assessment of mediastinal involvement in lung cancer with technetium -99m-sestamibi SPECT,” J. Nucl. Med. 37, 938–942 1996

  1. Local microRNA delivery targets Palladin and prevents metastatic breast cancer

    PubMed Central

    Gilam, Avital; Conde, João; Weissglas-Volkov, Daphna; Oliva, Nuria; Friedman, Eitan; Artzi, Natalie; Shomron, Noam

    2016-01-01

    Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3′-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug. PMID:27641360

  2. Targeting Thromboxane A2 Receptor for Antimetastasis Therapy of Breast Cancer

    DTIC Science & Technology

    2010-09-01

    expression in breast cancers, we used multi pronged approaches. First, we have generated rabbit polyclonal antibody against TPbeta specific peptide...sequences. Currently we are validating the specificity of the polyclonal antibody . The antibody developed was not working well as expected. Second, we...initiated collaboration with Dr. Kinsella in Ireland, who has TPalpha and TPbeta specific antibodies . Using these isoform specific antibodies , we

  3. Epigenetic events associated with breast cancer and their prevention by dietary components targeting the epigenome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aberrant epigenetic alterations in the genome such as DNA methylation and chromatin remodeling play a significant role in breast cancer development. Since epigenetic alterations are considered to be more easily reversible compared to genetic changes, epigenetic therapy is potentially very useful in ...

  4. Universal Breast Cancer Antigens as Targets Linking Early Detection and Therapeutic Vaccination

    DTIC Science & Technology

    2005-09-01

    the presence of carcinoma. We further hypothesize that immunologic responses can be elicited in advanced breast cancer patients using vaccines...trial. Immunologic responses were assessed and the optimal dose level was chosen and an additional four patients were treated at that dose...which to assess presence of tumor- associated antigens and therefore the potential for preventative vaccination. Evidence of immunologic response to

  5. Aurora kinase A and B as new treatment targets in aromatase inhibitor-resistant breast cancer cells.

    PubMed

    Hole, Stine; Pedersen, Astrid M; Lykkesfeldt, Anne E; Yde, Christina W

    2015-02-01

    Aromatase inhibitors (AIs) are used for treatment of estrogen receptor α (ER)-positive breast cancer; however, resistance is a major obstacle for optimal outcome. This preclinical study aimed at identifying potential new treatment targets in AI-resistant breast cancer cells. Parental MCF-7 breast cancer cells and four newly established cell lines, resistant to the AIs exemestane or letrozole, were used for a functional kinase inhibitor screen. A library comprising 195 different compounds was tested for preferential growth inhibition of AI-resistant cell lines. Selected targets were validated by analysis of cell growth, cell cycle phase distribution, protein expression, and subcellular localization. We identified 24 compounds, including several inhibitors of Aurora kinases e.g., JNJ-7706621 and barasertib. Protein expression of Aurora kinase A and B was found upregulated in AI-resistant cells compared with MCF-7, and knockdown studies showed that Aurora kinase A was essential for AI-resistant cell growth. In AI-resistant cell lines, the clinically relevant Aurora kinase inhibitors alisertib and danusertib blocked cell cycle progression at the G2/M phase, interfered with chromosome alignment and spindle pole formation, and resulted in preferential growth inhibition compared with parental MCF-7 cells. Even further growth inhibition was obtained when combining the Aurora kinase inhibitors with the antiestrogen fulvestrant. Our study is the first to demonstrate that Aurora kinase A and B may be treatment targets in AI-resistant cells, and our data suggest that therapy targeting both ER and Aurora kinases may be a potent treatment strategy for overcoming AI resistance in breast cancer.

  6. Quantitative in Situ Assessment of the Somatostatin Receptor in Breast Cancer to Assess Response to Targeted Therapy With 111-in-Penetreotide

    DTIC Science & Technology

    2006-05-01

    Somatostatin Receptor in Breast Cancer to Assess Response to Targeted Therapy with 111-in-Pentetreotide PRINCIPAL INVESTIGATOR: Gina G...31 Mar 2006 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Quantitative in situ Assessment of the Somatostatin Receptor in Breast Cancer to Assess...Somatostatin (SST) is a peptide hormone implicated in the growth and progression of cancers and SSTR2 is the predominant receptor subtype expressed

  7. Incorporating gold nanoclusters and target-directed liposomes as a synergistic amplified colorimetric sensor for HER2-positive breast cancer cell detection

    PubMed Central

    Tao, Yu; Li, Mingqiang; Kim, Bumjun; Auguste, Debra T.

    2017-01-01

    Breast cancer is the second leading cause of cancer-related mortality in women. Successful development of sensitive nanoprobes for breast cancer cell detection is of great importance for breast cancer diagnosis and symptomatic treatment. Herein, inspired by the intrinsic peroxidase property of gold nanoclusters, high loading, and targeting ability of ErbB2/Her2 antibody functionalized liposomes, we report that gold nanoclusters-loaded, target-directed, functionalized liposomes can serve as a robust sensing platform for amplified colorimetric detection of HER2-positive breast cancer cells. This approach allows HER2-positive breast cancer cell identification at high sensitivity with high selectivity. In addition, the colorimetric “readout” offers extra advantages in terms of low-cost, portability, and easy-to-use applications. The practicality of this platform was further proved by successful detection of HER2-positive breast cancer cells in human serum samples and in breast cancer tissue, which indicated our proposed method has potential for application in cancer theranostics. PMID:28382162

  8. Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin

    PubMed Central

    Wong, Ada Hang-Heng; Vazquez-Ortiz, Guelaguetza; Chen, Weiping; Xu, Xiaoling; Deng, Chu-Xia

    2016-01-01

    Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatin-resistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors' unique molecular adaptations. PMID:27806319

  9. Breast Cancer (For Kids)

    MedlinePlus

    ... With Breast Cancer Breast Cancer Prevention en español Cáncer de mama You may have heard about special events, like walks or races, to raise money for breast cancer research. Or maybe you've seen people wear ...

  10. A novel class of mitochondria-targeted soft electrophiles modifies mitochondrial proteins and inhibits mitochondrial metabolism in breast cancer cells through redox mechanisms.

    PubMed

    Vayalil, Praveen K; Oh, Joo-Yeun; Zhou, Fen; Diers, Anne R; Smith, M Ryan; Golzarian, Hafez; Oliver, Patsy G; Smith, Robin A J; Murphy, Michael P; Velu, Sadanandan E; Landar, Aimee

    2015-01-01

    Despite advances in screening and treatment over the past several years, breast cancer remains a leading cause of cancer-related death among women in the United States. A major goal in breast cancer treatment is to develop safe and clinically useful therapeutic agents that will prevent the recurrence of breast cancers after front-line therapeutics have failed. Ideally, these agents would have relatively low toxicity against normal cells, and will specifically inhibit the growth and proliferation of cancer cells. Our group and others have previously demonstrated that breast cancer cells exhibit increased mitochondrial oxygen consumption compared with non-tumorigenic breast epithelial cells. This suggests that it may be possible to deliver redox active compounds to the mitochondria to selectively inhibit cancer cell metabolism. To demonstrate proof-of-principle, a series of mitochondria-targeted soft electrophiles (MTSEs) has been designed which selectively accumulate within the mitochondria of highly energetic breast cancer cells and modify mitochondrial proteins. A prototype MTSE, IBTP, significantly inhibits mitochondrial oxidative phosphorylation, resulting in decreased breast cancer cell proliferation, cell attachment, and migration in vitro. These results suggest MTSEs may represent a novel class of anti-cancer agents that prevent cancer cell growth by modification of specific mitochondrial proteins.

  11. A Novel Class of Mitochondria-Targeted Soft Electrophiles Modifies Mitochondrial Proteins and Inhibits Mitochondrial Metabolism in Breast Cancer Cells through Redox Mechanisms

    PubMed Central

    Vayalil, Praveen K.; Oh, Joo-Yeun; Zhou, Fen; Diers, Anne R.; Smith, M. Ryan; Golzarian, Hafez; Oliver, Patsy G.; Smith, Robin A. J.; Murphy, Michael P.; Velu, Sadanandan E.; Landar, Aimee

    2015-01-01

    Despite advances in screening and treatment over the past several years, breast cancer remains a leading cause of cancer-related death among women in the United States. A major goal in breast cancer treatment is to develop safe and clinically useful therapeutic agents that will prevent the recurrence of breast cancers after front-line therapeutics have failed. Ideally, these agents would have relatively low toxicity against normal cells, and will specifically inhibit the growth and proliferation of cancer cells. Our group and others have previously demonstrated that breast cancer cells exhibit increased mitochondrial oxygen consumption compared with non-tumorigenic breast epithelial cells. This suggests that it may be possible to deliver redox active compounds to the mitochondria to selectively inhibit cancer cell metabolism. To demonstrate proof-of-principle, a series of mitochondria-targeted soft electrophiles (MTSEs) has been designed which selectively accumulate within the mitochondria of highly energetic breast cancer cells and modify mitochondrial proteins. A prototype MTSE, IBTP, significantly inhibits mitochondrial oxidative phosphorylation, resulting in decreased breast cancer cell proliferation, cell attachment, and migration in vitro. These results suggest MTSEs may represent a novel class of anti-cancer agents that prevent cancer cell growth by modification of specific mitochondrial proteins. PMID:25785718

  12. Artemisinin loaded chitosan magnetic nanoparticles for theefficient targeting to the breast cancer.

    PubMed

    Natesan, Subramanian; Ponnusamy, Chandrasekar; Sugumaran, Abimanyu; Chelladurai, Senthilkumar; Palaniappan, Sharavanan Shanmugam; Palanichamy, Rajaguru

    2017-03-27

    Artemisinin, a natural anti-malarial agent, also possesses anti-proliferative and anti-angiogenic activity in cancer cells with very low toxicity to normal healthy cells. Drug loaded magnetic nanoparticlesby using external magnetic field could selectively accumulate the drug at the target site and thereby reduce the doses required to achieve therapeutic concentration which may otherwise produce serious side effects on healthy cells. In the present study the artemisinin magnetic nanoparticles were successfully formulated using chitosan by ionic-gelation method. The developed magnetic nanoparticles of artemisinin were smooth and spherical in natureand their size was in the range of 349 to 445nm. The polydispersity index (PDI) and zeta potential of the formulated nanoparticles were in the range of 0.373 to 0.908 and -9.34 to -33.3 respectively. They showed 55% to 62.5% of drug encapsulation efficiency and 20% to 25% drug loading capacity. Around 62% to 78% of artemisinin was released from the artemisinin magnetic nanoparticles over the period of 48h. On application of physiologically acceptable external magnetic field, FITC conjugated artemisinin magnetic nanoparticles showed an enhanced accumulation of nanoparticles in the 4T1 breast tumour tissues of BALB/c mice model.

  13. Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice

    PubMed Central

    Overman, Jeroen; Fontaine, Frank; Moustaqil, Mehdi; Mittal, Deepak; Sierecki, Emma; Sacilotto, Natalia; Zuegg, Johannes; Robertson, Avril AB; Holmes, Kelly; Salim, Angela A; Mamidyala, Sreeman; Butler, Mark S; Robinson, Ashley S; Lesieur, Emmanuelle; Johnston, Wayne; Alexandrov, Kirill; Black, Brian L; Hogan, Benjamin M; De Val, Sarah; Capon, Robert J; Carroll, Jason S; Bailey, Timothy L; Koopman, Peter; Jauch, Ralf; Smyth, Mark J; Cooper, Matthew A; Gambin, Yann; Francois, Mathias

    2017-01-01

    Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics. DOI: http://dx.doi.org/10.7554/eLife.21221.001 PMID:28137359

  14. Synthesis of Bisethylnorspermine Lipid Prodrug as Gene Delivery Vector Targeting Polyamine Metabolism in Breast Cancer

    PubMed Central

    Dong, Yanmei; Zhu, Yu; Li, Jing; Zhou, Qing-Hui; Wu, Chao; Oupický, David

    2013-01-01

    Progress in the development of nonviral gene delivery vectors continues to be hampered by low transfection activity and toxicity. Here we proposed to develop a lipid prodrug based on a polyamine analogue bisethylnorspermine (BSP) that can function dually as gene delivery vector and, after intracellular degradation, as active anticancer agent targeting dysregulated polyamine metabolism. We synthesized a prodrug of BSP (LS-BSP) capable of intracellular release of BSP using thiolytically sensitive dithiobenzyl carbamate linker. Biodegradability of LS-BSP contributed to decreased toxicity compared with nondegradable control L-BSP. BSP showed a strong synergistic enhancement of cytotoxic activity of TNF-related apoptosis-inducing ligand (TRAIL) in human breast cancer cells. Decreased enhancement of TRAIL activity was observed for LS-BSP when compared with BSP. LS-BSP formed complexes with plasmid DNA and mediated transfection activity comparable to DOTAP and L-BSP. Our results show that BSP-based vectors are promising candidates for combination drug/gene delivery. PMID:22545813

  15. ICAM-1-Targeted, Lcn2 siRNA-Encapsulating Liposomes are Potent Anti-angiogenic Agents for Triple Negative Breast Cancer

    PubMed Central

    Guo, Peng; Yang, Jiang; Jia, Di; Moses, Marsha A.; Auguste, Debra T.

    2016-01-01

    Lipocalin 2 (Lcn2) is a promising therapeutic target as well as a potential diagnostic biomarker for breast cancer. It has been previously shown to promote breast cancer progression by inducing the epithelial to mesenchymal transition in breast cancer cells as well as by enhancing angiogenesis. Lcn2 levels in urine and tissue samples of breast cancer patients has also been correlated with breast cancer status and poor patient prognosis. In this study, we have engineered a novel liposomal small interfering RNA (siRNA) delivery system to target triple negative breast cancer (TNBC) via a recently identified molecular target, intercellular adhesion molecule-1 (ICAM-1). This ICAM-1-targeted, Lcn2 siRNA- encapsulating liposome (ICAM-Lcn2-LP) binds human TNBC MDA-MB-231cells significantly stronger than non-neoplastic MCF-10A cells. Efficient Lcn2 knockdown by ICAM-Lcn2-LPs led to a significant reduction in the production of vascular endothelial growth factor (VEGF) from MDA-MB-231 cells, which, in turn, led to reduced angiogenesis both in vitro and in vivo. Angiogenesis (neovascularization) is a requirement for solid tumor growth and progression, and its inhibition is an important therapeutic strategy for human cancers. Our results indicate that a tumor-specific strategy such as the TNBC-targeted, anti-angiogenic therapeutic approach developed here, may be clinically useful in inhibiting TNBC progression. PMID:26722369

  16. Consumer Health Education. Breast Cancer.

    ERIC Educational Resources Information Center

    Arkansas Univ., Fayetteville, Cooperative Extension Service.

    This short booklet is designed to be used by health educators when teaching women about breast cancer and its early detection and the procedure for breast self-examination. It includes the following: (1) A one-page teaching plan consisting of objectives, subject matter, methods (including titles of films and printed materials), target audience,…

  17. Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer.

    PubMed

    Garattini, Enrico; Bolis, Marco; Gianni', Maurizio; Paroni, Gabriela; Fratelli, Maddalena; Terao, Mineko

    2016-07-05

    Breast-cancer is heterogeneous and consists of various groups with different biological characteristics. Innovative pharmacological approaches accounting for this heterogeneity are needed. The forty eight human Nuclear-Hormone-Receptors are ligand-dependent transcription-factors and are classified into Endocrine-Receptors, Adopted-Orphan-Receptors (Lipid-sensors and Enigmatic-Orphans) and Orphan-receptors. Nuclear-Receptors represent ideal targets for the design/synthesis of pharmacological ligands. We provide an overview of the literature available on the expression and potential role played by Lipid-sensors, Enigmatic-Orphans and Orphan-Receptors in breast-cancer. The data are complemented by an analysis of the expression levels of each selected Nuclear-Receptor in the PAM50 breast-cancer groups, following re-elaboration of the data publicly available. The major aim is to support the idea that some of the Nuclear-Receptors represent largely unexploited therapeutic-targets in breast-cancer treatment/chemo-prevention. On the basis of our analysis, we conclude that the Lipid-Sensors, NR1C3, NR1H2 and NR1H3 are likely to be onco-suppressors in breast-cancer. The Enigmatic-Orphans, NR1F1 NR2A1 and NR3B3 as well as the Orphan-Receptors, NR0B1, NR0B2, NR1D1, NR2F1, NR2F2 and NR4A3 exert a similar action. These Nuclear-Receptors represent candidates for the development of therapeutic strategies aimed at increasing their expression or activating them in tumor cells. The group of Nuclear-Receptors endowed with potential oncogenic properties consists of the Lipid-Sensors, NR1C2 and NR1I2, the Enigmatic-Orphans, NR1F3, NR3B1 and NR5A2, as well as the Orphan-Receptors, NR2E1, NR2E3 and NR6A1. These oncogenic Nuclear-Receptors should be targeted with selective antagonists, reverse-agonists or agents/strategies capable of reducing their expression in breast-cancer cells.

  18. Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer

    PubMed Central

    Garattini, Enrico; Bolis, Marco; Gianni', Maurizio; Paroni, Gabriela; Fratelli, Maddalena; Terao, Mineko

    2016-01-01

    Breast-cancer is heterogeneous and consists of various groups with different biological characteristics. Innovative pharmacological approaches accounting for this heterogeneity are needed. The forty eight human Nuclear-Hormone-Receptors are ligand-dependent transcription-factors and are classified into Endocrine-Receptors, Adopted-Orphan-Receptors (Lipid-sensors and Enigmatic-Orphans) and Orphan-receptors. Nuclear-Receptors represent ideal targets for the design/synthesis of pharmacological ligands. We provide an overview of the literature available on the expression and potential role played by Lipid-sensors, Enigmatic-Orphans and Orphan-Receptors in breast-cancer. The data are complemented by an analysis of the expression levels of each selected Nuclear-Receptor in the PAM50 breast-cancer groups, following re-elaboration of the data publicly available. The major aim is to support the idea that some of the Nuclear-Receptors represent largely unexploited therapeutic-targets in breast-cancer treatment/chemo-prevention. On the basis of our analysis, we conclude that the Lipid-Sensors, NR1C3, NR1H2 and NR1H3 are likely to be onco-suppressors in breast-cancer. The Enigmatic-Orphans, NR1F1 NR2A1 and NR3B3 as well as the Orphan-Receptors, NR0B1, NR0B2, NR1D1, NR2F1, NR2F2 and NR4A3 exert a similar action. These Nuclear-Receptors represent candidates for the development of therapeutic strategies aimed at increasing their expression or activating them in tumor cells. The group of Nuclear-Receptors endowed with potential oncogenic properties consists of the Lipid-Sensors, NR1C2 and NR1I2, the Enigmatic-Orphans, NR1F3, NR3B1 and NR5A2, as well as the Orphan-Receptors, NR2E1, NR2E3 and NR6A1. These oncogenic Nuclear-Receptors should be targeted with selective antagonists, reverse-agonists or agents/strategies capable of reducing their expression in breast-cancer cells. PMID:26894976

  19. 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).

  20. Targeting Notch1 inhibits invasion and angiogenesis of human breast cancer cells via inhibition Nuclear Factor-κB signaling

    PubMed Central

    Liu, Yuan; Su, Chuanfu; Shan, Yuqing; Yang, Shouxiang; Ma, Guifeng

    2016-01-01

    Notch-1, a type-1 transmembrane protein, plays critical roles in the pathogenesis and progression of human malignancies, including breast cancer; however, the precise mechanism by which Notch-1 causes tumor cell invasion and angiogenesis remain unclear. Nuclear factor-κB (NF-κB), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether targeting Notch-1 could be mechanistically associated with the down-regulation of NF-κB, IL-8, VEGF, and MMP-9, resulting in the inhibition of invasion and angiogenesis of breast cancer cells. Our data showed that down-regulation of Notch-1 leads to the inactivation of NF-κB activity and inhibits the expression of its target genes, such as IL-8, VEGF and MMP-9. We also found that down-regulation of Notch-1 decreased cell invasion, and vice versa Consistent with these results, we also found that the down-regulation of Notch-1 not only decreased MMP-9 mRNA and its protein expression but also inhibited MMP-9 active form. Moreover, conditioned medium from Notch-1 siRNA-transfected breast cancer cells showed reduced levels of IL-8 and VEGF and, in turn, inhibited the tube formation of HUVECs, suggesting that down-regulation of Notch-1 leads to the inhibition of angiogenesis. Furthermore, conditioned medium from Notch-1 cDNA-transfected breast cancer cells showed increased levels of IL-8 and VEGF and, in turn, promoted the tube formation of HUVECs, suggesting that Notch-1 overexpression leads to the promotion of angiogenesis.We therefore concluded that down-regulation of Notch-1 leads to the inactivation NF-κB and its target genes (IL-8, MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis. PMID:27398151

  1. Osteoclastic miR-214 targets TRAF3 to contribute to osteolytic bone metastasis of breast cancer

    PubMed Central

    Liu, Jin; Li, Defang; Dang, Lei; Liang, Chao; Guo, Baosheng; Lu, Cheng; He, Xiaojuan; Cheung, Hilda Y. S.; He, Bing; Liu, Biao; Li, Fangfei; Lu, Jun; Wang, Luyao; Shaikh, Atik Badshah; Jiang, Feng; Lu, Changwei; Peng, Songlin; Zhang, Zongkang; Zhang, Bao-Ting; Pan, Xiaohua; Xiao, Lianbo; Lu, Aiping; Zhang, Ge

    2017-01-01

    The role of osteoclastic miRNAs in regulating osteolytic bone metastasis (OBM) of breast cancer is still underexplored. Here, we examined the expression profiles of osteoclastogenic miRNAs in human bone specimens and identified that miR-214-3p was significantly upregulated in breast cancer patients with OBM. Consistently, we found increased miR-214-3p within osteoclasts, which was associated with the elevated bone resorption, during the development of OBM in human breast cancer xenografted nude mice (BCX). Furthermore, genetic ablation of osteoclastic miR-214-3p in nude mice prevent the development of OBM. Conditioned medium from MDA-MB-231 cells dramatically stimulated miR-214-3p expression to promote osteoclast differentiation. Mechanistically, a series of in vitro study showed that miR-214-3p directly targeted Traf3 to promote osteoclast activity and bone-resorbing activity. In addition, osteoclast-specific miR-214-3p knock-in mice showed remarkably increased bone resorption when compared to the littermate controls, which was attenuated after osteoclast-targeted treatment with Traf3 3′UTR-containing plasmid. In BCX nude mice, osteoclast-targeted antagomir-214-3p delivery could recover the TRAF3 protein expression and attenuate the development of OBM, respectively. Collectively, inhibition of osteoclastic miR-214-3p may be a potential therapeutic strategy for breast cancer patients with OBM. Meanwhile, the intraosseous TRAF3 could be a promising biomarker for evaluation of the treatment response of antagomir-214-3p. PMID:28071724

  2. Inhibition of Cancer Cell Proliferation and Breast Tumor Targeting of pHLIP-Monomethyl Auristatin E Conjugates

    PubMed Central

    Burns, Kelly E.; Robinson, Matthew K.; Théveninr, Damien

    2015-01-01

    Localized delivery is vital for the successful development of novel and effective therapeutics for the treatment of cancer. The targeting and delivery described herein is based on the pH(Low) Insertion Peptide (pHLIP), a unique delivery peptide that can selectively target tumors in mice and translocate and release cargo molecules intra-cellularly based solely on the low extracellular pH intrinsic to cancer cells. In this study, we investigate the efficacy of pHLIP to target and deliver the highly potent and clinically validated microtubule inhibitor monomethyl auristatin E (MMAE) to cancer cells and breast tumors. We show that pHLIP-MMAE conjugates induce a potent cytotoxic effect (> 90% inhibition of cell growth) in a concentration- and pH-dependent manner after only 2-hour incubation without any apparent disruption of the plasma membrane. pHLIP-MMAE conjugates exhibit between an 11 and 144-fold higher anti-proliferative effect at low pH than at physiological pH, and a pronounced pH-dependent cytotoxicity as compared to free drug. Furthermore, we demonstrate that a pHLIP-MMAE drug conjugate effectively targets triple negative breast tumor xenografts in mice. These results indicate pHLIP-based auristatin conjugates may have an enhanced therapeutic window as compared to free drug, providing a targeting mechanism to attenuate systemic toxicity. PMID:25741818

  3. In silico Analysis of Combinatorial microRNA Activity Reveals Target Genes and Pathways Associated with Breast Cancer Metastasis

    PubMed Central

    Dombkowski, Alan A.; Sultana, Zakia; Craig, Douglas B.; Jamil, Hasan

    2011-01-01

    This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited. Aberrant microRNA activity has been reported in many diseases, and studies often find numerous microRNAs concurrently dysregulated. Most target genes have binding sites for multiple microRNAs, and mounting evidence indicates that it is important to consider their combinatorial effect on target gene repression. A recent study associated the coincident loss of expression of six microRNAs with metastatic potential in breast cancer. Here, we used a new computational method, miR-AT!, to investigate combinatorial activity among this group of microRNAs. We found that the set of transcripts having multiple target sites for these microRNAs was significantly enriched with genes involved in cellular processes commonly perturbed in metastatic tumors: cell cycle regulation, cytoskeleton organization, and cell adhesion. Network analysis revealed numerous target genes upstream of cyclin D1 and c-Myc, indicating that the collective loss of the six microRNAs may have a focal effect on these two key regulatory nodes. A number of genes previously implicated in cancer metastasis are among the predicted combinatorial targets, including TGFB1, ARPC3, and RANKL. In summary, our analysis reveals extensive combinatorial interactions that have notable implications for their potential role in breast cancer metastasis and in therapeutic development. PMID:21552493

  4. 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

  5. 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

  6. Breast Cancer Rates by State

    MedlinePlus

    ... Associated Lung Ovarian Prostate Skin Uterine Cancer Home Breast Cancer Rates by State Language: English Español (Spanish) Recommend ... from breast cancer each year. Rates of Getting Breast Cancer by State The number of people who get ...

  7. Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer.

    PubMed

    Liu, Shuying; Meng, Xiaolong; Chen, Huiqin; Liu, Wenbin; Miller, Todd; Murph, Mandi; Lu, Yiling; Zhang, Fan; Gagea, Mihai; Arteaga, Carlos L; Mills, Gordon B; Meric-Bernstam, Funda; González-Angulo, Ana M

    2014-10-15

    Despite numerous therapies that effectively inhibit estrogen signaling in breast cancer, a significant proportion of patients with estrogen receptor (ER)-positive malignancy will succumb to their disease. Herein we demonstrate that long-term estrogen deprivation (LTED) therapy among ER-positive breast cancer cells results in the adaptive increase in ER expression and subsequent activation of multiple tyrosine kinases. Combination therapy with the ER down-regulator fulvestrant and dasatinib, a broad kinase inhibitor, exhibits synergistic activity against LTED cells, by reduction of cell proliferation, cell survival, cell invasion and mammary acinar formation. Screening kinase phosphorylation using protein arrays and functional proteomic analysis demonstrates that the combination of fulvestrant and dasatinib inhibits multiple tyrosine kinases and cancer-related pathways that are constitutively activated in LTED cells. Because LTED cells display increased insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF-1R) signaling, we added an ant-IGF-1 antibody to the combination with fulvestrant and dasatinib in an effort to further increase the inhibition. However, adding MK0646 only modestly increased the inhibition of cell growth in monolayer culture, but neither suppressed acinar formation nor inhibited cell migration in vitro and invasion in vivo. Therefore, combinations of fulvestrant and dasatinib, but not MK0646, may benefit patients with tyrosine-kinase-activated, endocrine therapy-resistant breast cancer.

  8. Tamoxifen as the First Targeted Long Term Adjuvant Therapy for Breast Cancer

    PubMed Central

    Jordan, V. Craig

    2014-01-01

    Tamoxifen is an unlikely pioneering medicine in medical oncology. Nevertheless, the medicine has continued to surprise us, perform and save lives for the past 40 years. Unlike any other medicine in oncology, it is used to treat all stages of breast cancer, ductal carcinoma in situ, male breast cancer, pioneered the use of chemoprevention by reducing the incidence of breast cancer in women at high risk and induces ovulation in subfertile women! The impact of tamoxifen is ubiquitous. However, the power to save lives from this unlikely success story came from the first laboratory studies which defined that “longer was going to be better” when tamoxifen was being considered as an adjuvant therapy (Jordan 1978 Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy Reviews in Endocrine Related Cancer. October Supplement: 49–55.). This is that success story, with a focus on the interdependent components of: excellence in drug discovery, investment in self-selecting young investigators, a conversation with Nature, a conversation between the laboratory and the clinic, and the creation of the Oxford Overview Analysis. Each of these factors was essential to propel the progress of tamoxifen to evolve as an essential part of the fabric of society. “Science is adventure, discovery, new horizons, insight into our world, a means of predicting the future and enormous power to help others”(Hoagland 1990).- Mahlon Hoagland, MD. Director, Worcester Foundation for Experimental Biology (1970–85) PMID:24659478

  9. Physical Activity and Sedentary Behavior in Breast Cancer Survivors: New Insight into Activity Patterns and Potential Intervention Targets

    PubMed Central

    Phillips, Siobhan M.; Dodd, Kevin W.; Steeves, Jeremy; McClain, James; Alfano, Catherine M.; McAuley, Edward

    2016-01-01

    Background Inactivity and sedentary behavior are related to poorer health outcomes in breast cancer survivors. However, few studies examining these behaviors in survivors have used objective measures, considered activities other than moderate-to-vigorous intensity activity (MVPA) and/or sedentary behavior (i.e. low intensity activities) or compared survivors to healthy controls. The purpose of the present study is to compare accelerometer-measured activity of various intensities (total, light, lifestyle, MVPA) and sedentary behavior between breast cancer survivors and non-cancer controls. Methods An imputation-based approach of independent sample t-tests adjusting for multiple comparisons was used to compare estimates of participation in each activity and sedentary behavior between survivors [n=398; M(SD)age=56.95 (9.11)] and block-matched non-cancer controls [n=1120; M(SD)age=54.88 (16.11)]. Potential moderating effects of body mass index (BMI), age, and education were also examined. Results Breast cancer survivors registered less daily total (282.8 v. 346.9) light (199.1 v. 259.3) and lifestyle (62.0 v. 71.7) activity minutes and more MVPA (21.6 v. 15.9) and sedentary behavior (555.7 v. 500.6) minutes than controls (p<0.001 for all). These relationships were largely consistent across BMI, age and education. On average, survivors spent an estimated 66.4% of their waking time sedentary and 31.1% in light/lifestyle activity and 2.6% in MVPA. Conclusions Breast cancer survivors are more sedentary and participate in less low intensity activity than controls. Although survivors registered more MVPA, these levels were insufficient. Future research should explore these differences and potential benefits of targeting low intensity activities and reducing sedentary time in this population. PMID:26026737

  10. Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer

    PubMed Central

    Heinonen, Henna; Nieminen, Anni; Saarela, Matti; Kallioniemi, Anne; Klefström, Juha; Hautaniemi, Sampsa; Monni, Outi

    2008-01-01

    Background The 70 kDa ribosomal protein S6 kinase (RPS6KB1), located at 17q23, is amplified and overexpressed in 10–30% of primary breast cancers and breast cancer cell lines. p70S6K is a serine/threonine kinase regulated by PI3K/mTOR pathway, which plays a crucial role in control of cell cycle, growth and survival. Our aim was to determine p70S6K and PI3K/mTOR/p70S6K pathway dependent gene expression profiles by microarrays using five breast cancer cell lines with predefined gene copy number and gene expression alterations. The p70S6K dependent profiles were determined by siRNA silencing of RPS6KB1 in two breast cancer cell lines overexpressing p70S6K. These profiles were further correlated with gene expression alterations caused by inhibition of PI3K/mTOR pathway with PI3K inhibitor Ly294002 or mTOR inhibitor rapamycin. Results Altogether, the silencing of p70S6K altered the expression of 109 and 173 genes in two breast cancer cell lines and 67 genes were altered in both cell lines in addition to RPS6KB1. Furthermore, 17 genes including VTCN1 and CDKN2B showed overlap with genes differentially expressed after PI3K or mTOR inhibition. The gene expression signatures responsive to both PI3K/mTOR pathway and p70S6K inhibitions revealed previously unidentified genes suggesting novel downstream targets for PI3K/mTOR/p70S6K pathway. Conclusion Since p70S6K overexpression is associated with aggressive disease and poor prognosis of breast cancer patients, the potential downstream targets of p70S6K and the whole PI3K/mTOR/p70S6K pathway identified in our study may have diagnostic value. PMID:18652687

  11. Pembrolizumab in Treating Patients With Triple-Negative Breast Cancer

    ClinicalTrials.gov

    2017-04-11

    Estrogen Receptor Negative; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Stage 0 Breast Cancer; Stage I Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-Negative Breast Carcinoma

  12. Functional roles of sialylation in breast cancer progression through miR-26a/26b targeting ST8SIA4

    PubMed Central

    Ma, Xiaolu; Dong, Weijie; Su, Zhen; Zhao, Lifen; Miao, Yuan; Li, Nana; Zhou, Huimin; Jia, Li

    2016-01-01

    Sialylation is one of the altered glycosylation patterns associated with cancer progression. In this study, we investigated the N-glycan profiles of breast cancer patients and cell lines to reveal sialylation associated with breast cancer progression, and provided new evidences of miRNA-mediated sialylation. MALDI-TOF MS analysis revealed that N-glycans found in breast cancer tissues and breast cancer cell MDA-MB-231 featured increased levels of sialylation compared with adjacent tissues and normal breast epithelial cell MCF-10A. The expressional profiles of 20 sialyltransferase genes were then analyzed and found significantly different comparing breast cancer samples with adjacent tissues, and two breast cancer cell lines MDA-MB-231 and MCF-7 with different metastatic potential and MCF-10A cells. Tumor tissues and highly metastatic breast cancer cell line MDA-MB-231 exhibited higher levels of ST8SIA4. Knocking down ST8SIA4 in breast cancer cell lines significantly inhibited their malignant behaviors including cell proliferation and invasion in a sialyltransferase-dependent manner. By applying bioinformatic approaches for the prediction of miRNA targeting 3′-UTR of ST8SIA4, we identified ST8SIA4 as one of the miR-26a/26b-targeted genes. Further data analysis revealed the inversely related expression of ST8SIA4 and miR-26a/26b in breast cancer cells, tumor tissues and corresponding adjacent tissues. The ability of miR-26a/26b to interact specifically with and regulate the 3′-UTR of ST8SIA4 was demonstrated via a luciferase reporter assay. The forced expression of miR-26a/26b was able to induce a decrease of ST8SIA4 level and also to affect breast cancer cells progression, while altered expression of ST8SIA4 in breast cancer cells modulated progression upon transfection with miR-26a/26b mimics or inhibiter. Taken together, these results indicate that changes in the glycosylation patterns and sialylation levels may be useful markers of the progression of breast

  13. Targeting CXCR1/2 Significantly Reduces Breast Cancer Stem Cell Activity and Increases the Efficacy of Inhibiting HER2 via HER2-dependent and -independent Mechanisms

    PubMed Central

    Singh, Jagdeep K.; Farnie, Gillian; Bundred, Nigel J.; Simões, Bruno M; Shergill, Amrita; Landberg, Göran; Howell, Sacha; Clarke, Robert B.

    2012-01-01

    Purpose Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are predicted to be responsible for tumour initiation, maintenance and metastases. Interleukin-8 (IL-8) is upregulated in breast cancer and associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy. Experimental design CSC activity of metastatic and invasive human breast cancers (n=19) was assessed ex vivo using the mammosphere colony forming assay. Results Metastatic fluid IL-8 level correlated directly with mammosphere formation (r=0.652; P<0.05; n=10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n=17). IL-8 induced activation of EGFR/HER2 and downstream signalling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, PI3K or MEK. Furthermore, lapatinib inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers. Conclusions These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and demonstrate that IL-8/CXCR1/2 signalling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients. PMID:23149820

  14. Identification and targeting of a TACE-dependent autocrine loopwhich predicts poor prognosis in breast cancer

    SciTech Connect

    Kenny, Paraic A.; Bissell, Mina J.

    2005-06-15

    The ability to proliferate independently of signals from other cell types is a fundamental characteristic of tumor cells. Using a 3D culture model of human breast cancer progression, we have delineated a protease-dependent autocrine loop which provides an oncogenic stimulus in the absence of proto-oncogene mutation. Inhibition of this protease, TACE/ADAM17, reverts the malignant phenotype by preventing mobilization of two crucial growth factors, Amphiregulin and TGF{alpha}. We show further that the efficacy of EGFR inhibitors is overcome by physiological levels of growth factors and that successful EGFR inhibition is dependent on reducing ligand bioavailability. Using existing patient outcome data, we demonstrate a strong correlation between TACE and TGF{alpha} expression in human breast cancers that is predictive of poor prognosis.

  15. Identification of Novel Therapeutic Targets for Triple-Negative Breast Cancer

    DTIC Science & Technology

    2012-12-01

    reduced in comparison to shCON. Metabolomic profiling – alternative metabolic pathways during serum starvation and the coordination of LRP8/ApoE4...hours / siCON at 48 hours). Serum- starvation resulted in the activation of Warburg metabolism , with increases in tryptophan and reduced NAD+ levels...receptor (VLDLR) signaling in triple-negative breast cancer which results in activation of glycolytic and lipid metabolism to drive TNBC tumor cell growth

  16. Targeting MUC1-Mediated Tumor-Stromal Metabolic Interactions in Triple-Negative Breast Cancer

    DTIC Science & Technology

    2015-09-01

    dFBS. MTT Cell Viability Assay The viability of cultured cells was determined by assaying the reduction of 3-(4,5-dimethyltiazol- 2-yl)-2,5...and stimulated with EGF at the indicated concentration and time. Next cells were starved for glucose for 2 h and then incubated for 20 min with 1µCi... cell growth of breast cancer cells was investigated (Figure 6). Cell viability assays revealed that CM had increased cell growth compared to control

  17. Endoplasmic Reticulum-Associated Degradation Factor ERLIN2: Oncogenic Roles and Molecular Targeting of Breast Cancer

    DTIC Science & Technology

    2013-06-01

    fatty acid synthesis and expression of lipogenic genes in breast c © The Authors Journal compilation c © 2012 Biochemical Society 22 ERLIN2 regulates lipid...differentiated functions in chemically defined medium. Cancer Res. 42 , 3858–3863 20 Laing, S., Wang, G., Briazova, T., Zhang, C ., Wang, A., Zheng, Z... C ) Expression of the ERLIN2 gene and the genes involved in lipid droplet formation and lipogenesis, including FSP27, ADRP and FIT1, in ERLIN2

  18. Seamless Integration of Detection and Therapy for Breast Cancer using Targeted Engineered Nanoparticles

    DTIC Science & Technology

    2007-06-01

    have spread to regional lymph nodes (stage III). Overall, 50% of surgically treated patients sufferCorresponding author: Fortina, P. (paolo.fortina...Detection of lymph node involvement in hematologic malignancies using micromagnetic resonance lymphan- giography with a gadolinum-labeled dendrimer...nanoparticle. Neoplasia 7, 984–991 42 Kobayashi, H. et al. (2004) Lymphatic drainage imaging of breast cancer in mice by micro-magnetic resonance

  19. Evaluation of Cyclooxygenase-2 as a Novel Target for Breast Cancer Prevention

    DTIC Science & Technology

    2001-07-01

    with carmine alum, and whole mounts examined microscopically. As previously described, mammary glands from Wnt-1 transgenic mice exhibited striking...we examined the ability of B-catenin to activate COX-2 promoter reporter constructs in transient transfection assays. In addition, since Ets...mammary oncogene to examine the relationship between Cox-2 and breast cancer. Our first set of experiments were designed to test whether Cox-2 is important

  20. Epidermal Growth Factor Receptor Overexpression as a Target for Auger Electron Radiotherapy of Breast Cancer

    DTIC Science & Technology

    1999-08-01

    proportion of estrogen receptor-negative and hormone-resistant breast cancers. Our objective is to construct a human epidermal growth factor (hEGF...61 5 INTRODUCTION Overexpression of the epidermal growth factor receptor (EGFR) occurs in a high proportion of estrogen receptor-negative and...Lac Iq promotor induced by isopropyl-b- D -thiogalactopyranoside (IPTG). The DNA sequence of the final hEGF-CH1 construct was confirmed (FUi. 2). BamHJ

  1. Estrogen-Induced Depurination of DNA: A Novel Target for Breast Cancer Prevention

    DTIC Science & Technology

    2006-05-01

    Milchgrub, S., Minna, J.D., and Gazdar, A.F. (1999) Multiple regions of chromosome 4 demonstrating allelic losses in breast carcinomas. Cancer Res. 59...treated. Mammary tissue, uterus, ovaries and liver were isolated and frozen. Groups of 6-8 rats were treated for 20 weeks. Polymerase-β- deficient ...potency was low and multiple exposures were necessary to observe statistically significant increases in the mutant fraction (MF). We have recently

  2. microRNA-133a regulates the cell cycle and proliferation of breast cancer cells by targeting epidermal growth factor receptor through the EGFR/Akt signaling pathway.

    PubMed

    Cui, Wenjing; Zhang, Shuai; Shan, Changliang; Zhou, Li; Zhou, Zhemin

    2013-08-01

    microRNAs are small, highly conserved, non-coding RNAs that regulate gene expression of target mRNAs through cleavage or translational inhibition, and are widely involved in carcinogenesis and cancer development. In this study, the expression profile of microRNA-133a (miR-133a) was examined in breast cancer cells and breast cancer tissues. The results showed that expression of miR-133a in both breast cancer cells and breast cancer tissues was significantly down-regulated. Over-expression of miR-133a in tumor cells arrested the cell cycle by drastically decreasing the G2 /S phase and retarded the newly synthesized DNA, suggesting a regulatory role for miR-133a in proliferation of breast cancer cells. Bioinformatics prediction showed that epidermal growth factor receptor (EGFR) is a potential target for miR-133a. A dual luciferase reporter gene assay showed that miR-133a bound to the 3' UTR of EGFR but not a mutated 3' UTR, thereby down-regulating the protein expression level. Accordingly, we found that expression of EGFR protein decreased with increased expression of miR-133a in MCF-7 and MDA-MB-231 cells. Over-expression of miR-133a in breast cancer cells resulted in suppression of the level of phosphorylated Akt protein (p-Akt) and inhibition of p-Akt nuclear translocation. These results demonstrate that miR-133a, which may act as a tumor suppressor in breast cancer, regulates the cell cycle and proliferation in tumorigenesis by targeting EGFR through the downstream signal molecule Akt. Overall, these results show that miR-133a may be used as biomarker and/or therapeutic target for diagnosis and therapy of breast cancer.

  3. Mammary gland involution as an immunotherapeutic target for postpartum breast cancer.

    PubMed

    Fornetti, Jaime; Martinson, Holly A; Betts, Courtney B; Lyons, Traci R; Jindal, Sonali; Guo, Qiuchen; Coussens, Lisa M; Borges, Virginia F; Schedin, Pepper

    2014-07-01

    Postpartum mammary gland involution has been identified as tumor-promotional and is proposed to contribute to the increased rates of metastasis and poor survival observed in postpartum breast cancer patients. In rodent models, the involuting mammary gland microenvironment is sufficient to induce enhanced tumor cell growth, local invasion, and metastasis. Postpartum involution shares many attributes with wound healing, including upregulation of genes involved in immune responsiveness and infiltration of tissue by immune cells. In rodent models, treatment with non-steroidal anti-inflammatory drugs (NSAIDs) ameliorates the tumor-promotional effects of involution, consistent with the immune milieu of the involuting gland contributing to tumor promotion. Currently, immunotherapy is being investigated as a means of breast cancer treatment with the purpose of identifying ways to enhance anti-tumor immune responses. Here we review evidence for postpartum mammary gland involution being a uniquely defined 'hot-spot' of pro-tumorigenic immune cell infiltration, and propose that immunotherapy should be explored for prevention and treatment of breast cancers that arise in this environment.

  4. Male Breast Cancer

    PubMed Central

    Yalaza, Metin; İnan, Aydın; Bozer, Mikdat

    2016-01-01

    Male breast cancer (MBC) is a rare disease, accounting for less than 1% of all breast cancer diagnoses worldwide. Although breast carcinomas share certain characteristics in both genders, there are notable differences. Most studies on men with breast cancer are very small. Thus, most data on male breast cancer are derived from studies on females. However, when a number of these small studies are grouped together, we can learn more from them. This review emphasizes the incidence, etiology, clinical features, diagnosis, treatment, pathology, survival, and prognostic factors related to MBC.

  5. Chemotherapy for Metastatic Breast Cancer – An Anachronism in the Era of Personalised and Targeted Oncological Therapy?

    PubMed Central

    Schneeweiss, A.; Ruckhäberle, E.; Huober, J.

    2015-01-01

    Based on the findings of modern molecular biology, breast cancer is nowadays considered to be a heterogeneous disease. This leads to the objective of an individualised, more patient-oriented therapy. A series of target molecules for this purpose has already been identified. The principle of targeted oncological therapy was realised decades ago with the introduction of endocrine therapy for patients with hormone receptor-positive tumours. The modern therapy for HER2-positive tumours is a further example for the translation of targeted therapy into clinical routine. For patients with HER2-negative metastatic breast cancer, to date two targeted drugs, bevacizumab and everolimus, are available for routine clinical use. Many other substances are still undergoing clinical development. However, validated predictive markers to aid in therapeutic decision-making and therapy control are still lacking. Chemotherapy constitutes an effective palliative therapy with proven efficacy for the patients. In this process strategies have also been realised for a targeted therapy against tumour cells with the help of chemotherapeutic agents such as, for example, the intracellular activation of the prodrug capecitabine or the active albumin-mediated transport of nab-paclitaxel which leads to higher peri- and intratumoural enrichments. The continuing unchanged relevance of chemotherapy is often underestimated in the current discussions and will be comprehensively evaluated in this review. PMID:26166838

  6. 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

  7. Enhancement of chemotherapeutic efficacy in hypermethylator breast cancer cells through targeted and pharmacologic inhibition of DNMT3b.

    PubMed

    Sandhu, Rupninder; Rivenbark, Ashley G; Coleman, William B

    2012-01-01

    A subset of primary breast cancers and breast cancer cell lines express a hypermethylation defect (characterized by DNMT hyperactivity and DNMT3b overexpression) which contributes to chemotherapy resistance and provides a target for development of new treatment strategies. The objective of the current study was to determine if targeting the epigenome enhances the sensitivity of breast cancer cells to cytotoxic chemotherapy. Hypermethylator breast cancer cell lines (MDA-MB-453, BT549, and Hs578T) were treated with 250 or 500 nM 5-aza-2'-deoxycytidine (5-aza) and/or were subjected to RNAi-mediated DNMT3b knockdown (KD), and then tested for sensitivity to doxorubicin hydrochloride (DOX), paclitaxel (PAX), and 5-fluorouracil (5-FU). In MDA-MB-453 cells, DNMT3b KD reduces the IC(50) for DOX from 0.086 to 0.048 μM (44% reduction), for PAX from 0.497 to 0.376 nM (24%), and for 5-FU from 0.817 to 0.145 mM (82%). Treatment with 250 nM 5-aza for 7 days did not increase the efficacy of DOX, PAX, or 5-FU, but 7-day treatment with 500 nM 5-aza sensitized cells, reducing the IC(50) for DOX to 0.035 μM (60%), PAX to 0.311 nM (37%), and 5-FU to 0.065 mM (92%). 5-aza treatment of DNMT3b KD cells reduced the IC(50) for DOX to 0.036 μM (59%), for PAX to 0.313 nM (37%) and for 5-FU to 0.067 (92%). Similar trends of enhancement of cell kill were seen in BT549 (13-60%) and Hs578T (29-70%) cells after RNAi-mediated DNMT3b KD and/or treatment with 5-aza. The effectiveness of DOX, PAX, and 5-FU is enhanced through targeted and/or pharmacological inhibition of DNMT3b, strongly suggesting that combined epigenetic and cytotoxic treatment will improve the efficacy of breast cancer chemotherapy.

  8. Profiling Global Kinome Signatures of the Radioresistant MCF-7/C6 Breast Cancer Cells Using MRM-based Targeted Proteomics

    PubMed Central

    2015-01-01

    Ionizing radiation is widely used in cancer therapy; however, cancer cells often develop radioresistance, which compromises the efficacy of cancer radiation therapy. Quantitative assessment of the alteration of the entire kinome in radioresistant cancer cells relative to their radiosensitive counterparts may provide important knowledge to define the mechanism(s) underlying tumor adaptive radioresistance and uncover novel target(s) for effective prevention and treatment of tumor radioresistance. By employing a scheduled multiple-reaction monitoring analysis in conjunction with isotope-coded ATP affinity probes, we assessed the global kinome of radioresistant MCF-7/C6 cells and their parental MCF-7 human breast cancer cells. We rigorously quantified 120 kinases, of which 1/3 exhibited significant differences in expression levels or ATP binding affinities. Several kinases involved in cell cycle progression and DNA damage response were found to be overexpressed or hyperactivated, including checkpoint kinase 1 (CHK1), cyclin-dependent kinases 1 and 2 (CDK1 and CDK2), and the catalytic subunit of DNA-dependent protein kinase. The elevated expression of CHK1, CDK1, and CDK2 in MCF-7/C6 cells was further validated by Western blot analysis. Thus, the altered kinome profile of radioresistant MCF-7/C6 cells suggests the involvement of kinases on cell cycle progression and DNA repair in tumor adaptive radioresistance. The unique kinome profiling results also afforded potential effective targets for resensitizing radioresistant cancer cells and counteracting deleterious effects of ionizing radiation exposure. PMID:25341124

  9. Targeting Signal Transducers and Activators of Transcription-3 (Stat3) As a Novel Strategy In Sensitizing Breast Cancer To Egfr-Targeted Therapy

    DTIC Science & Technology

    2008-06-01

    transition of the epithelial to the mesenchymal -like phenotype in cultured breast cancer cells . Cancer cells of epithelial origin undergo EMT as...induce epithelial mesenchymal transition by activating expression of TWIST, an E-cadherin repressor. In breast cancer cells with high levels of EGFR...expressing cancer cells to undergo a transition from the epithelial to the spindle-like

  10. Carnitine palmitoyl transferase-1A (CPT1A): a new tumor specific target in human breast cancer

    PubMed Central

    Zonetti, Maria Josè; Fisco, Tommaso; Polidoro, Chiara; Bocchinfuso, Gianfranco; Palleschi, Antonio; Novelli, Giuseppe; Spagnoli, Luigi G.

    2016-01-01

    Transcriptional mechanisms epigenetically-regulated in tumoral tissues point out new targets for anti-cancer therapies. Carnitine palmitoyl transferase I (CPT1) is the rate-limiting enzyme in the transport of long-chain fatty acids for β-oxidation. Here we identified the tumor specific nuclear CPT1A as a product of the transcript variant 2, that doesn't retain the classical transferase activity and is strongly involved in the epigenetic regulation of cancer pro-survival, cell death escaping and tumor invasion pathways. The knockdown of CPT1A variant 2 by small interfering RNAs (siRNAs), was sufficient to induce apoptosis in MCF-7, SK-BR3 and MDA-MB-231 breast cancer cells. The cell death triggered by CPT1A silencing correlated with reduction of HDAC activity and histone hyperacetylation. Docking experiments and molecular dynamics simulations confirmed an high binding affinity of the variant 2 for HDAC1. The CPT1A silenced cells showed an up-regulated transcription of pro-apoptotic genes (BAD, CASP9, COL18A1) and down-modulation of invasion and metastasis related-genes (TIMP-1, PDGF-A, SERPINB2). These findings provide evidence of the CPT1 variant 2 involvement in breast cancer survival, cell death escape and invasion. Thus, we propose nuclear CPT1A as a striking tumor specific target for anticancer therapeutics, more selective and effective as compared with the well-known HDAC inhibitors. PMID:26799588

  11. 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

  12. 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.

  13. Near infrared light-actuated gold nanorods with cisplatin-polypeptide wrapping for targeted therapy of triple negative breast cancer

    NASA Astrophysics Data System (ADS)

    Feng, Bing; Xu, Zhiai; Zhou, Fangyuan; Yu, Haijun; Sun, Qianqian; Wang, Dangge; Tang, Zhaohui; Yu, Haiyang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2015-09-01

    Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR) laser illumination, the resulting FA-GNR@Pt hybrid nanoparticles are able to significantly inhibit the growth of the TNBC tumor when administered systemically. In particular, they can extensively suppress the dissemination of TNBC cells from the primary tumor to the lung by eliminating the peripheral tumor blood vessels. Collectively, our studies demonstrate that the combined PT therapy and chemotherapy using cisplatin-loaded GNRs with FA conjugation might imply a promising strategy for targeted treatment of TNBC.Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR

  14. Breast Cancer in Men

    MedlinePlus

    ... Older age • B RCA2 gene mutation • F amily history of breast cancer • Gynecomastia (enlargement of the breast tissue) • Klinefelter’s syndrome (a genetic condition related to high levels ...

  15. Targeting FASN in Breast Cancer and the Discovery of Promising Inhibitors from Natural Products Derived from Traditional Chinese Medicine

    PubMed Central

    Cheng, Chien-shan; Wang, Zhiyu; Chen, Jianping

    2014-01-01

    Molecular targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells process a fundamental change in its bioenergetic metabolism from normal cells on an altered lipid metabolism, also known as the de novo fatty acid synthesis, for sustaining their high proliferation rates. Fatty acid synthesis is now associated with clinically aggressive tumor behavior and tumor cell growth and has become a novel target pathway for chemotherapy development. Although the underlying mechanisms of the altered de novo fatty acid synthesis still remains unclear, recent progress has shown that by targeting Fatty acid synthase (FASN), a key enzyme that catalyzes the synthesis of endogenous long chain fatty acid could be a critical target for drug discovery. However, relatively few FASN inhibitors have been discovered. With the long history of clinical practices and numerous histological case study reports, traditional Chinese medicine enjoys an important role in seeking bioactive anticancer natural compounds. Herein, we will give an overall picture of the current progress of molecular targeted therapy in cancer fatty acid synthesis, describe the advances in the research on natural products-derived FASN inhibitors and their potential for enhancing our understanding of fatty acids in tumor biology, and may provide new therapeutic moieties for breast cancer patient care. PMID:24778702

  16. MicroRNA-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/β-catenin signaling pathway.

    PubMed

    Jiang, Qian; He, Miao; Guan, Shu; Ma, Mengtao; Wu, Huizhe; Yu, Zhaojin; Jiang, Longyang; Wang, Yan; Zong, Xingyue; Jin, Feng; Wei, Minjie

    2016-04-01

    Wnt/β-catenin signaling pathway plays a major role in the cancer metastasis. Several microRNAs (miRNAs) are contributed to the inhibition of breast cancer metastasis. Here, we attempted to find novel targets and mechanisms of microRNA-100 (miR-100) in regulating the migration and invasion of breast cancer cells. In this study, we found that miR-100 expression was downregulated in human breast cancer tissues and cell lines. The overexpression of miR-100 inhibited the migration and invasion of MDA-MB-231 breast cancer cells. Inversely, the downregulation of miR-100 increased the migration and invasion of MCF-7 breast cancer cells. Furthermore, FZD-8, a receptor of Wnt/β-catenin signaling pathway, was demonstrated a direct target of miR-100. The overexpression of miR-100 decreased the expression levels not only FZD-8 but also the key components of Wnt/β-catenin pathway, including β-catenin, metalloproteniase-7 (MMP-7), T-cell factor-4 (TCF-4), and lymphoid enhancing factor-1 (LEF-1), and increased the protein expression levels of GSK-3β and p-GSK-3β in MDA-MB-231 cells, and the transfection of miR-100 inhibitor in MCF-7 cells showed the opposite effects. In addition, the expression of miR-100 was negatively correlated with the FZD-8 expression in human breast cancer tissues. Overall, these findings suggest that miR-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/β-catenin signaling pathway and manipulation of miR-100 may provide a promoting therapeutic strategy for cancer breast treatment.

  17. MicroRNA-320a sensitizes tamoxifen-resistant breast cancer cells to tamoxifen by targeting ARPP-19 and ERRγ.

    PubMed

    Lü, Mingrong; Ding, Keshuo; Zhang, Guofeng; Yin, Mianmian; Yao, Guidong; Tian, Hui; Lian, Jie; Liu, Lin; Liang, Meng; Zhu, Tao; Sun, Fei

    2015-03-04

    Tamoxifen represents a major adjuvant therapy to those patients with estrogen receptor-alpha positive breast cancer. However, tamoxifen resistance occurs quite often, either de novo or acquired during treatment. To investigate the role of miR-320a in the development of resistance to tamoxifen, we established tamoxifen-resistant (TamR) models by continually exposing MCF-7 or T47D breast cancer cells to tamoxifen, and identified microRNA(miRNA)-320a as a down-regulated miRNA in tamoxifen resistant cells. Re-expression of miR-320a was sufficient to sensitize TamR cells to tamoxifen by targeting cAMP-regulated phosphoprotein (ARPP-19) and estrogen-related receptor gamma (ERRγ) as well as their downstream effectors, c-Myc and Cyclin D1. Furthermore, progesterone (P4) promoted the expression of miR-320a by repressing c-Myc expression, while estrogen (E2) exerted the opposite effect. These results suggest the potential therapeutic approach for tamoxifen-resistant breast cancer by restorating miR-320a expression or depleting ARPP-19/ERRγ expression.

  18. Do We Know What Causes Breast Cancer?

    MedlinePlus

    ... Research? Breast Cancer About Breast Cancer How Does Breast Cancer Form? Changes or mutations in DNA can cause ... please see our Content Usage Policy . More In Breast Cancer About Breast Cancer Risk and Prevention Early Detection ...

  19. Treating Male Breast Cancer by Stage

    MedlinePlus

    ... Men Treating Breast Cancer in Men Treatment of Breast Cancer in Men, by Stage Because there have been ... Doctor About Breast Cancer in Men? More In Breast Cancer In Men About Breast Cancer in Men Causes, ...

  20. Living as a Breast Cancer Survivor

    MedlinePlus

    ... a Breast Cancer Survivor Follow up Care After Breast Cancer Treatment Many women are relieved or excited to ... Menopausal Hormone Therapy After Breast Cancer More In Breast Cancer About Breast Cancer Risk and Prevention Early Detection ...

  1. Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy.

    PubMed

    Mast, Natalia; Lin, Joseph B; Pikuleva, Irina A

    2015-09-01

    Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6- and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.

  2. Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

    PubMed Central

    Mast, Natalia; Lin, Joseph B.

    2015-01-01

    Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6- and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification. PMID:26082378

  3. TRPV2 is a novel biomarker and therapeutic target in triple negative breast cancer.

    PubMed

    Elbaz, Mohamad; Ahirwar, Dinesh; Xiaoli, Zhang; Zhou, Xinyu; Lustberg, Maryam; Nasser, Mohd W; Shilo, Konstantin; Ganju, Ramesh K

    2016-05-27

    Transient receptor potential vanilloid type-2 (TRPV2) is an ion channel that is triggered by agonists like cannabidiol (CBD). Triple negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Chemotherapy is still the first line for the treatment of TNBC patients; however, TNBC usually gains rapid resistance and unresponsiveness to chemotherapeutic drugs. In this study, we found that TRPV2 protein is highly up-regulated in TNBC tissues compared to normal breast tissues. We also observed that TNBC and estrogen receptor alpha negative (ERα-) patients with higher TRPV2 expression have significantly higher recurrence free survival compared to patients with lower TRPV2 expression especially those who were treated with chemotherapy. In addition, we showed that TRPV2 overexpression or activation by CBD significantly increased doxorubicin (DOX) uptake and apoptosis in TNBC cells. The induction of DOX uptake was abrogated by TRPV2 blocking or downregulation. In vivo mouse model studies showed that the TNBC tumors derived from CBD+DOX treated mice have significantly reduced weight and increased apoptosis compared to those treated with CBD or DOX alone. Overall, our studies for the first time revealed that TRPV2 might be a good prognostic marker for TNBC and ERα- breast cancer patient especially for those who are treated with chemotherapy. In addition, TRPV2 activation could be a novel therapeutic strategy to enhance the uptake and efficacy of chemotherapy in TNBC patients.

  4. Targeting Tumor Metabolism to Enhance the Effectiveness of Antitumor Immune Response in the Treatment of Breast Cancer

    DTIC Science & Technology

    2013-11-01

    the effectiveness of antitumor immune response in the treatment of breast cancer PRINCIPAL INVESTIGATOR: Shanmugasundaram Ganapathy-Kanniappan...the effectiveness of antitumor immune response in the treatment of breast cancer 5b. GRANT NUMBER W81XWH-11-1-0343 5c. PROGRAM ELEMENT NUMBER 6...response. Data from the current research investigation demonstrate that human breast cancer cells pre-treated with low, non-toxic dose of the

  5. Targeted and intracellular triggered delivery of therapeutics to cancer cells and the tumor microenvironment: impact on the treatment of breast cancer.

    PubMed

    Moura, Vera; Lacerda, Manuela; Figueiredo, Paulo; Corvo, Maria L; Cruz, Maria E M; Soares, Raquel; de Lima, Maria C Pedroso; Simões, Sérgio; Moreira, João N

    2012-05-01

    Limiting tumor invasion to the surrounding healthy tissues has proven to be clinically relevant for anticancer treatment options. We have demonstrated that, within a solid tumor, it is possible to achieve such a goal with the same nanoparticle by intracellular and triggered targeted drug delivery to more than one cell population. We have identified the nucleolin receptor in endothelial and cancer cells in tissue samples from breast cancer patients, which enabled the design of a F3-peptide-targeted sterically stabilized pH-sensitive liposome. The clinical potential of such strategy was demonstrated by the successful specific cellular association by breast cancer cells harvested from tumors of patients submitted to mastectomy. In vitro, the nanoparticle targeted the nucleolin receptor on a cell and ligand-specific manner and improved cytotoxicity of doxorubicin (used as a model drug) towards breast cancer and endothelial cells by 177- and 162-fold, respectively, relative to the commercially available non-targeted non-pH-sensitive liposomes. Moreover, active accumulation of F3-targeted pH-sensitive liposomes into human orthotopic tumors, implanted in the mammary fat pad of nude mice, was registered for a time point as short as 4 h, reaching 48% of the injected dose/g of tissue. Twenty-four hours post-injection the accumulation of the dual-targeted pH-sensitive nanoparticle in the tumor tissue was 33-fold higher than the non-targeted non-pH-sensitive counterpart. In mice treated with the developed targeted nanoparticle significant decrease of the tumor viable rim area and microvascular density, as well as limited invasion to surrounding healthy tissues were observed (as opposed to other tested controls), which may increase the probability of tumors falling in the category of "negative margins" with reduced risk of relapse.

  6. miR-221/222 control luminal breast cancer tumor progression by regulating different targets.

    PubMed

    Dentelli, Patrizia; Traversa, Matteo; Rosso, Arturo; Togliatto, Gabriele; Olgasi, Cristina; Marchiò, Caterina; Provero, Paolo; Lembo, Antonio; Bon, Giulia; Annaratone, Laura; Sapino, Anna; Falcioni, Rita; Brizzi, Maria Felice

    2014-01-01

    α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3'UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted "normal" breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy.

  7. Albumin-based micro-composite drug carriers with dual chemo-agents for targeted breast cancer treatment.

    PubMed

    Abedin, Farhana; Anwar, Md R; Asmatulu, Ramazan; Yang, Shang-You

    2015-07-01

    Albumin-based drug-carrying micro-composite spheres were fabricated and studied to evaluate their potentials for breast cancer treatment. Magnetic nanoparticles and albumin were incorporated within poly(D l-lactide-co-glycolide) microspheres to increase accumulation of the microspheres at the target site. Two chemotherapeutics, cyclophosphamide and 5-fluorouracil, were encapsulated into the microspheres. The drug-release study revealed an initial burst of drug and then sustained release by diffusion. A Fourier transform infrared spectroscopy study confirmed the presence of all components of the drug delivery system. An in vitro study using fibroblast cells (3T3) and breast cancer cells (MDA-486) exhibited an effective cytotoxicity behavior when exposed to the drug delivery system in a dose- and time-dependent manner. The therapeutic influence of the drug delivery system was evaluated in vivo using a nude mouse breast cancer model. A continuous decrease in tumor size was observed in groups treated with microspheres containing the chemotherapeutics, whereas mice treated with direct chemotherapy without drug delivery system showed less efficacy and suggested tumor relapse after cessation of treatment. The enhanced therapeutic influence of the drug delivery system may be attributed to the increased uptake of the microspheres by malignant cells due to the presence of albumin and magnetic force. The bioavailability of chemotherapeutics at the target site was further increased due to the sustained release of the drugs by diffusion following the burst release. Continuous investigations will optimize the size of the drug delivery system and portions of the target driving-force components (magnetic nanoparticles and albumin) in the drug delivery system to maximize its therapeutic efficacy and minimize potential long-term side effects.

  8. AR Signaling in Breast Cancer

    PubMed Central

    Rahim, Bilal; O’Regan, Ruth

    2017-01-01

    Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies. PMID:28245550

  9. AR Signaling in Breast Cancer.

    PubMed

    Rahim, Bilal; O'Regan, Ruth

    2017-02-24

    Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.

  10. Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer.

    PubMed

    Zhao, Xin; Wang, Qiuting; Yang, Shijun; Chen, Chen; Li, Xiaoya; Liu, Jinyu; Zou, Zhongmei; Cai, Dayong

    2016-06-15

    Vascular endothelial growth factor receptor 2 (VEGFR2) mediated calcineurin/nuclear factor of activated T-cells (NFAT) pathway is crucial in the angiogenesis of human breast cancer. Quercetin (Qu), a flavonoid known to possess anti-angiogenesis and antitumor properties, inhibited calcineurin activity in vitro. Herein, we performed a study in vivo to evaluate the effects of Qu on the angiogenesis in breast cancer. Female BALB/c nude mice were injected with MCF-7 cells into the mammary fat and were randomly divided into four groups. The animals were treated with vehicle solution, tamoxifen (TAM, 5.6mg/kg), tacrolimus (FK506, 3mg/kg), or Qu (34mg/kg) for 21 days, respectively. The results showed that, similar to TAM and FK506, Qu decreased tumor growth, limited oncocyte proliferation and promoted tumor necrosis. Anti-angiogenic actions of Qu were demonstrated as decreased serum VEGF (P<0.01), and sparse microvessel density (P<0.05). Qu significantly inhibited tumor calcineurin activities, and the inhibitory rate was 62.73% in Qu treated animals, compared to that was 72.90% in FK506 group (P>0.05). Effects of Qu on calcineurin/NFAT pathway were confirmed as decreased subcellular located levels of VEGF (P<0.05), VEGFR2 (P<0.05) and NFATc3 (P<0.01), downregulated gene expression of VEGF (P<0.05), VEGFR2 (P<0.05) and NFATc3 (P<0.01), reduced protein levels of VEGF (P<0.05), VEGFR2 (P<0.05), and NFATc3 (P<0.01) in tumor tissues. These findings indicate that Qu inhibit angiogenesis of human breast cancer xenograft in nude mice, which was associated with suppressing calcineurin activity and its regulated pathway activation.

  11. Targeting triple negative breast cancer cells by N3-substituted 9,10-Phenanthrenequinone thiosemicarbazones and their metal complexes

    NASA Astrophysics Data System (ADS)

    Afrasiabi, Zahra; Stovall, Preston; Finley, Kristen; Choudhury, Amitava; Barnes, Charles; Ahmad, Aamir; Sarkar, Fazlul; Vyas, Alok; Padhye, Subhash

    2013-10-01

    Novel N3-substituted 9,10-Phenanthrenequinone thiosemicarbazones and their copper, nickel and palladium complexes are structurally characterized and reported along with the single crystal X-ray structures of three ligands and one nickel complex. All compounds were evaluated for their antiproliferative potential against Triple Negative Breast Cancer (TNBC) cells which have poor prognosis and no effective drugs to treat with. All compounds exhibited antiproliferative activity against these cells. Among the metal complexes evaluated, redox active copper complexes were found to be more potent. The possible mechanism for such enhanced activity can be attributed to the generation of oxidative stress, which was amenable for targeting through metal complexation.

  12. Immunomodulation via Chemotherapy and Targeted Therapy: A New Paradigm in Breast Cancer Therapy?

    PubMed

    Stagg, John; Andre, Fabrice; Loi, Sherene

    2012-08-01

    Cytotoxic chemotherapy in the treatment of tumors has traditionally been thought to be immunosuppressive. Increasing evidence suggests the contrary and has introduced the concept of 'immunogenic' chemotherapy or, in other words, the concept that the innate and adaptive immune systems are critical in determining the long-term efficacy of some cytotoxic-based (and radiotherapy-based) regimens. The underlying mechanisms how these therapies can stimulate an antitumor immune response have been demonstrated recently. In this article, we review the background of this new paradigm and how combinations of traditional agents with the new immunotherapeutic therapies may significantly advance our treatment of breast cancer.

  13. Onboard SPECT for Localizing Functional and Molecular Targets in Metastatic Breast Cancer

    DTIC Science & Technology

    2010-08-01

    Feillel V, Le Bouedec G, Kaufmann P, Dauplat J, Veyre A. Technetium -99m-sestamibi uptake in breast tumor and associated lymph nodes. Journal of...deLatour, D. Mestas, A. Clemenson, S. Charrier, V. Feil- lel, G. Le Bouedec, P. Kaufmann, J. Dauplat, and A. Veyre, “ Technetium - 99m-sestamibi uptake in...Gasparini, G. Savelli, and E. Bombardieri, “Assessment of mediastinal involvement in lung cancer with technetium -99m-sestamibi SPECT,” J. Nucl. Med

  14. Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells

    NASA Astrophysics Data System (ADS)

    Geninatti Crich, S.; Cadenazzi, M.; Lanzardo, S.; Conti, L.; Ruiu, R.; Alberti, D.; Cavallo, F.; Cutrin, J. C.; Aime, S.

    2015-04-01

    In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation.In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation. Electronic supplementary information (ESI) available: Competition studies with free apoferritin, Fig. S1; APO-FITC intracellular distribution by

  15. [Organized breast cancer screening].

    PubMed

    Rouëssé, Jacques; Sancho-Garnier, Hélèn

    2014-02-01

    Breast screening programs are increasingly controversial, especially regarding two points: the number of breast cancer deaths they avoid, and the problem of over-diagnosis and over-treatment. The French national breast cancer screening program was extended to cover the whole country in 2004. Ten years later it is time to examine the risk/benefit ratio of this program and to discuss the need for change. Like all forms of cancer management, screening must be regularly updated, taking into account the state of the art, new evidence, and uncertainties. All screening providers should keep themselves informed of the latest findings. In the French program, women aged 50-74 with no major individual or familial risk factors for breast cancer are offered screening mammography and clinical breast examination every two years. Images considered non suspicious of malignancy by a first reader are re-examined by a second reader. The devices and procedures are subjected to quality controls. Participating radiologists (both public and private) are required to read at least 500 mammographies per year. The program's national participation rate was 52.7 % in 2012. When individual screening outside of the national program is taken into account (nearly 15 % of women), coverage appears close to the European recommendation of 65 %. Breast cancer mortality has been falling in France by 0.6 % per year for over 30 years, starting before mass screening was implemented, and by 1.5 % since 2005. This decline can be attributed in part to earlier diagnosis and better treatment, so that the specific impact of screening cannot easily be measured. Over-treatment, defined as the detection and treatment of low-malignancy tumors that would otherwise not have been detected in a person's lifetime, is a major negative effect of screening, but its frequency is not precisely known (reported to range from 1 % to 30 %). In view of these uncertainties, it would be advisable to modify the program in order to

  16. 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.

  17. Somatic alterations of targetable oncogenes are frequently observed in BRCA1/2 mutation negative male breast cancers

    PubMed Central

    Rizzolo, Piera; Navazio, Anna Sara; Silvestri, Valentina; Valentini, Virginia; Zelli, Veronica; Zanna, Ines; Masala, Giovanna; Bianchi, Simonetta; Scarnò, Marco; Tommasi, Stefania; Palli, Domenico; Ottini, Laura

    2016-01-01

    Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from its largely known female counterpart. We aimed at investigating whether MBC cases harbor somatic alterations of genes known as prognostic biomarkers and molecular therapeutic targets in female breast cancer. We examined 103 MBC cases, all characterized for germ-line BRCA1/2 mutations, for somatic alterations in PIK3CA, EGFR, ESR1 and CCND1 genes. Pathogenic mutations of PIK3CA were detected in 2% of MBCs. No pathogenic mutations were identified in ESR1 and EGFR. Gene copy number variations (CNVs) analysis showed amplification of PIK3CA in 8.1%, EGFR in 6.8% and CCND1 in 16% of MBCs, whereas deletion of ESR1 was detected in 15% of MBCs. Somatic mutations and gene amplification were fo