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Sample records for 4t1 murine breast

  1. Effects of Combined Soy Isoflavone Extract and Docetaxel Treatment on Murine 4T1 Breast Tumor Model

    PubMed Central

    Hejazi, Ehsan; Nasrollahzadeh, Javad; Fatemi, Ramina; Barzegar-Yar Mohamadi, Leila; Saliminejad, Kioomars; Amiri, Zohre; Kimiagar, Masoud; Houshyari, Mohammad; Tavakoli, Maryam; Idali, Farah

    2015-01-01

    Background Emergence of drug resistance has brought major problems in chemotherapy. Using nutrients in combination with chemotherapy could be beneficial for improvement of sensitivity of tumors to drug resistance. Soybean-derived isoflavones have been suggested as chemopreventive agents for certain types of cancer, particularly breast cancer. In this study, the synergistic effects of soy isoflavone extract in combination with docetaxel in murine 4T1 breast tumor model were investigated. Methods In this study, mice were divided into 4 groups (15 mice per group) of control, the dietary Soy Isoflavone Extract (SIE, 100 mg/kg diet), the Docetaxel (DOCE, 10 mg/kg) injection and the combination of dietary soy isoflavone extract and intravenous docetaxel injection (DOCE+SIE). After 3 injections of docetaxel (once a week), 7 mice were sacrificed to analyze MKI67 gene and protein expressions and the rest were monitored for diet consumption, tumor growth and survival rates. Results In DOCE+SIE group, diet consumption was significantly higher than DOCE group. While lifespan showed a trend towards improvement in DOCE+SIE group, no significant difference was observed among the 4 studied groups. Tumor volume was not significantly affected in treated groups. A lower but not significant MKI67 protein expression was detected in western blot in DOCE+SIE group. The mRNA expression was not significantly different among groups. Conclusion The results suggest that the combination of soy isoflavone as an adjunct to docetaxel chemotherapy can be effective in improving diet consumption in breast cancer. PMID:25926948

  2. Secretion of N- and O-linked Glycoproteins from 4T1 Murine Mammary Carcinoma Cells

    PubMed Central

    Phang, Wai-Mei; Tan, Aik-Aun; Gopinath, Subash C.B.; Hashim, Onn H.; Kiew, Lik Voon; Chen, Yeng

    2016-01-01

    Breast cancer is one of the most common cancers that affect women globally and accounts for ~23% of all cancers diagnosed in women. Breast cancer is also one of the leading causes of death primarily due to late stage diagnoses and a lack of effective treatments. Therefore, discovering protein expression biomarkers is mandatory for early detection and thus, critical for successful therapy. Two-dimensional electrophoresis (2D-E) coupled with lectin-based analysis followed by mass spectrometry were applied to identify potential biomarkers in the secretions of a murine mammary carcinoma cell line. Comparisons of the protein profiles of the murine 4T1 mammary carcinoma cell line and a normal murine MM3MG mammary cell line indicated that cadherin-1 (CDH), collagenase 3 (MMP-13), Viral envelope protein G7e (VEP), Gag protein (GAG) and Hypothetical protein LOC433182 (LOC) were uniquely expressed by the 4T1 cells, and pigment epithelium-derived factor (PEDF) was exclusively secreted by the MM3MG cells. Further analysis by a lectin-based study revealed that aberrant O-glycosylated CDH, N-glycosylated MMP-13 and LOC were present in the 4T1 medium. These differentially expressed N- and O-linked glycoprotein candidates, which were identified by combining lectin-based analysis with 2D-E, could serve as potential diagnostic and prognostic markers for breast cancer. PMID:27226773

  3. Synthesis, Characterization and in Vitro Evaluation of Manganese Ferrite (MnFe2O4) Nanoparticles for Their Biocompatibility with Murine Breast Cancer Cells (4T1).

    PubMed

    Kanagesan, Samikannu; Aziz, Sidek Bin Ab; Hashim, Mansor; Ismail, Ismayadi; Tamilselvan, Subramani; Alitheen, Noorjahan Banu Binti Mohammed; Swamy, Mallappa Kumara; Purna Chandra Rao, Bandaru

    2016-03-11

    Manganese ferrite (MnFe2O4) magnetic nanoparticles were successfully prepared by a sol-gel self-combustion technique using iron nitrate and manganese nitrate, followed by calcination at 150 °C for 24 h. Calcined sample was systematically characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), and vibrational sample magnetometry (VSM) in order to identify the crystalline phase, functional group, morphology, particle size, shape and magnetic behavior. It was observed that the resultant spinal ferrites obtained at low temperature exhibit single phase, nanoparticle size and good magnetic behavior. The study results have revealed the existence of a potent dose dependent cytotoxic effect of MnFe2O4 nanoparticles against 4T1 cell lines at varying concentrations with IC50 values of 210, 198 and 171 μg/mL after 24 h, 48 h and 72 h of incubation, respectively. Cells exposed to higher concentrations of nanoparticles showed a progressive increase of apoptotic and necrotic activity. Below 125 μg/mL concentration the nanoparticles were biocompatible with 4T1 cells.

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

    PubMed Central

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

    2016-01-01

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

  5. 4T1 Murine Mammary Carcinoma Cells Enhance Macrophage-Mediated Innate Inflammatory Responses

    PubMed Central

    Madera, Laurence; Greenshields, Anna; Coombs, Melanie R. Power; Hoskin, David W.

    2015-01-01

    Tumor progression and the immune response are intricately linked. While it is known that cancers alter macrophage inflammatory responses to promote tumor progression, little is known regarding how cancers affect macrophage-dependent innate host defense. In this study, murine bone-marrow-derived macrophages (BMDM) were exposed to murine carcinoma-conditioned media prior to assessment of the macrophage inflammatory response. BMDMs exposed to 4T1 mammary carcinoma-conditioned medium demonstrated enhanced production of pro-inflammatory cytokines tumor necrosis factor α, interleukin-6, and CCL2 in response to lipopolysaccharide (LPS) while production of interleukin-10 remained unchanged. The increased LPS-induced production of pro-inflammatory cytokines was transient and correlated with enhanced cytokine production in response to other Toll-like receptor agonists, including peptidoglycan and flagellin. In addition, 4T1-conditioned BMDMs exhibited strengthened LPS-induced nitric oxide production and enhanced phagocytosis of Escherichia coli. 4T1-mediated augmentation of macrophage responses to LPS was partially dependent on the NFκB pathway, macrophage-colony stimulating factor, and actin polymerization, as well as the presence of 4T1-secreted extracellular vesicles. Furthermore, peritoneal macrophages obtained from 4T1 tumor-bearing mice displayed enhanced pro-inflammatory cytokine production in response to LPS. These results suggest that uptake of 4T1-secreted factors and actin-mediated ingestion of 4T1-secreted exosomes by macrophages cause a transient enhancement of innate inflammatory responses. Mammary carcinoma-mediated regulation of innate immunity may have significant implications for our understanding of host defense and cancer progression. PMID:26177198

  6. 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.

  7. 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

  8. Transfer of the IL-37b gene elicits anti-tumor responses in mice bearing 4T1 breast cancer

    PubMed Central

    Wang, Wei-qiang; Zhao, Dan; Zhou, Yu-shan; Hu, Xiao-yu; Sun, Zhi-na; Yu, Gang; Wu, Wan-tong; Chen, Song; Kuang, Jiu-long; Xu, Guo-gang; Han, Zhong-chao; Wang, Bang-mao; Yang, Jing-xian; Feng, Xiao-ming

    2015-01-01

    Aim: IL-37b has shown anti-cancer activities in addition to its anti-inflammatory properties. In this study, we investigated the effects of IL-37b on breast carcinoma growth in mice and to determine the involvement of T cell activation in the effects. Methods: IL-37b gene was transferred into mouse breast carcinoma cell line 4T1 (4T1-IL37b cells), the expression of secretory IL-37b by the cells was detected, and the effects of IL-37b expression on the cell proliferation in vitro was evaluated. After injection of 4T1 cells or 4T1-IL37b cells into immunocompetent BALB/c mice, immunodeficient BALB/c nude mice and NOD-SCID mice, the tumor growth and survival rate were measured. The proliferation of T cells in vitro was also detected. Results: IL-37b was detected in the supernatants of 4T1-IL37b cells with a concentration of 12.02±0.875 ng/mL. IL-37b expression did not affect 4T1 cell proliferation in vitro. BALB/c mice inoculated with 4T1-IL37b cells showed significant retardation of tumor growth. BALB/c mice inoculated with both 4T1 cells and mitomycin C-treated 4T1-IL37b cells also showed significant retardation of tumor growth. But the anti-cancer activity of IL-37b was abrogated in BALB/c nude mice and NOD-SCID mice inoculated with 4T1-IL37b cells. Recombinant IL-37b slightly promoted CD4+ T cell proliferation without affecting CD8+ T cell proliferation. Conclusion: IL-37b exerts anti-4T1 breast carcinoma effects in vivo by modulating the tumor microenvironment and influencing T cell activation. PMID:25832432

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

    PubMed

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

    2016-07-01

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

  10. NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells

    PubMed Central

    Jin, Won Jong; Kim, Bongjun; Kim, Darong; Park Choo, Hea-Young; Kim, Hong-Hee; Ha, Hyunil; Lee, Zang Hee

    2017-01-01

    The chemokine CXCL10 and its receptor CXCR3 play a role in breast cancer metastasis to bone and osteoclast activation. However, the mechanism of CXCL10/CXCR3-induced intracellular signaling has not been fully investigated. To evaluate CXCL10-induced cellular events in the mouse breast cancer cell line 4T1, we developed a new synthetic CXCR3 antagonist JN-2. In this study, we observed that secretion of CXCL10 in the supernatant of 4T1 cells was gradually increased during cell growth. JN-2 inhibited basal and CXCL10-induced CXCL10 expression and cell motility in 4T1 cells. Treatment of 4T1 cells with CXCL10 increased the expression of P65, a subunit of the NF-κB pathway, via activation of the NF-κB transcriptional activity. Ectopic overexpression of P65 increased CXCL10 secretion and blunted JN-2-induced suppression of CXCL10 secretion, whereas overexpression of IκBα suppressed CXCL10 secretion. These results indicate that the CXCL10/CXCR3 axis creates a positive feedback loop through the canonical NF-κB signaling pathway in 4T1 cells. In addition, treatment of osteoblasts with conditioned medium from JN-2-treated 4T1 cells inhibited the expression of RANKL, a crucial cytokine for osteoclast differentiation, which resulted in an inhibitory effect on osteoclast differentiation in the co-culture system of bone marrow-derived macrophages and osteoblasts. Direct intrafemoral injection of 4T1 cells induced severe bone destruction; however, this effect was suppressed by the CXCR3 antagonist via downregulation of P65 expression in an animal model. Collectively, these results suggest that the CXCL10/CXCR3-mediated NF-κB signaling pathway plays a role in the control of autonomous regulation of CXCL10 and malignant tumor properties in breast cancer 4T1 cells. PMID:28209986

  11. Lunasin Attenuates Obesity-Associated Metastasis of 4T1 Breast Cancer Cell through Anti-Inflammatory Property

    PubMed Central

    Hsieh, Chia-Chien; Wang, Chih-Hsuan; Huang, Yu-Shan

    2016-01-01

    Obesity prevalence is increasing worldwide and is accompanied by low-grade inflammation with macrophage infiltration, which is linked with a poorer breast cancer prognosis. Lunasin is a natural seed peptide with chemopreventive properties and multiple bioactivities. This is the first study to explore the chemopreventive effects of lunasin in the obesity-related breast cancer condition using 4T1 breast cancer cells, 3T3-L1 adipocytes, and conditioned media. An obesity-related environment, such as leptin-treatment or adipocyte-conditioned medium (Ad-CM), promoted 4T1 cell proliferation and metastasis. Lunasin treatment inhibited metastasis of breast cancer cells, partially through modestly inhibiting production of the angiogenesis-mediator vascular endothelial growth factor (VEGF) and significantly by inhibiting secretion in the Ad-CM condition. Subsequently, two adipocytes inflammation models, 3T3-L1 adipocytes were stimulated by tumor necrosis factor (TNF)-α, and RAW 264.7 cell-conditioned medium (RAW-CM) was used to mimic the obese microenvironment. Lunasin significantly inhibited interleukin (IL)-6 and macrophage chemoattractant protein (MCP)-1 secretion by TNF-α stimulation, and MCP-1 secretion in the RAW-CM model. This study highlights that lunasin suppressed 3T3-L1 adipocyte inflammation and inhibited 4T1 breast cancer cell migration. Interestingly, lunasin exerted more effective anti-metastasis activity in the obesity-related condition models, indicating that it possesses anti-inflammatory properties and blocks adipocyte-cancer cell cross-talk. PMID:27983683

  12. Extract of Azadirachta indica (Neem) Leaf Induces Apoptosis in 4T1 Breast Cancer BALB/c Mice

    PubMed Central

    Othman, Fauziah; Motalleb, Gholamreza; Lam Tsuey Peng, Sally; Rahmat, Asmah; Fakurazi, Sharida; Pei Pei, Chong

    2011-01-01

    Objective: Azadirachta indica (Neem) has been used traditionally for many centuries. Some impressive therapeutic qualities have been discovered. However, the therapeutic effect of neem leaf extract in 4T1 breast cancer has not been documented. The purpose of the present study is to investigate the therapeutic effect of ethanolic Neem leaf extract in an in vivo 4T1 breast cancer model in mice. Materials and Methods: A total of 84 female BALB/c mice were divided randomly into 7 groups (3 non-cancerous groups and 4 cancerous groups) consisting of 12 mice per group. The 3 non-cancerous groups were normal mice treated with 0.5% of Tween 20 in phosphate buffer saline (PBS) (NC), 250 mg/kg Neem (N250) or 500 mg/kg Neem (N500). The 4 cancerous groups were; cancer controls treated with 0.5% of Tween 20 in PBS (CC), and cancerous mice treated with 0.5 µg/mL tamoxifen citrate (CT), 250 mg/kg Neem leaf extract (CN 250) or 500 mg/kg Neem leaf extract (CN 500). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used to evaluate apoptosis (cell death) in the breast cancer tissues. SPSS software, version 14 was used for statistical analysis. Statistical significance was defined as p≤0.05. Non parametric analysis of variance (ANOVA) was performed with the Kruskal Wallis test for the TUNEL assays. Parametric data among the groups was compared using ANOVA. Results: TUNEL assays showed that the CN 250 and CN 500 groups had a higher incidence of apoptosis compared with the cancer controls. Conclusion: The findings showed that neem leaf extract induces apoptosis in 4T1 breast cancer BALB/c mice. PMID:23507990

  13. Anticancer Activity of Saponins from Allium chinense against the B16 Melanoma and 4T1 Breast Carcinoma Cell

    PubMed Central

    Yu, Zhihui; Zhang, Tong; Zhou, Fengjuan; Xiao, Xiuqing; Ding, Xuezhi; He, Hao; Rang, Jie; Quan, Meifang; Wang, Ting; Zuo, Mingxing; Xia, Liqiu

    2015-01-01

    The cytotoxic substance of A. chinense saponins (ACSs) was isolated using ethanol extraction and purified with the D101 macroporous adsorption resin approach. We investigated the anticancer activity of ACSs in the B16 melanoma and 4T1 breast carcinoma cell lines. Methylthioninium chloride and hematoxylin-eosin staining with Giemsa dyestuff were used when the cells were treated with ACSs. The results showed that the cells morphologies changed significantly; ACSs induced cell death in B16 and 4T1 cells based on acridine orange/ethidium bromide double fluorescence staining, with the number and degree of apoptotic tumor cells increasing as ACS concentration increased. ACSs inhibited the proliferation of B16 and 4T1 cells in a dose-dependent manner. They also inhibited cell migration and colony formation and exhibited a concentration-dependent effect. In addition, ACSs apparently inhibited the growth of melanoma in vivo. The preliminary antitumor in vivo assay revealed that early medication positively affected tumor inhibition action and effectively protected the liver and spleen of C57 BL/6 mice from injury. This study provides evidence for the cytotoxicity of ACSs and a strong foundation for further research to establish the theoretical basis for cell death and help in the design and development of new anticancer drugs. PMID:26146506

  14. The immunostimulatory effect of biogenic selenium nanoparticles on the 4T1 breast cancer model: an in vivo study.

    PubMed

    Yazdi, Mohammad Hossein; Mahdavi, Mehdi; Varastehmoradi, Bardia; Faramarzi, Mohammad Ali; Shahverdi, Ahmad Reza

    2012-10-01

    Selenium salts as well as elemental selenium nanoparticles are attracting the attention of researchers due to their excellent biological properties. The aim of the present work was to study immunomodulation by applying elemental Se NPs to stimulate the immune response of mice bearing 4 T1 breast cancer tumors. Six- to 8-week-old female inbred BALB/c mice were divided into two groups of test and control, each containing 15 mice. Every day, for 2 weeks prior to tumor induction, selenium nanoparticles were orally administered to the mice at a dose of 100 μg/day. Then, 1 × 10(6) cells from a 4 T1 cell line were injected subcutaneously to each mouse. Oral nanoparticle administration was continued daily for 3 weeks after tumor induction. Different immunological parameters were then evaluated including cytokine level, delayed type hypersensitivity (DTH) response as well as tumor growth and the survival rates in all treated or nontreated animals. The production of Th1 cytokines, such as IFN-γ and IL-12, in spleen cell culture was increased in the test mice-administered selenium nanoparticles. The DTH response of test mice also showed a significant increase when compared to the control mice. The survival rate was notably higher for the selenium nanoparticle-treated mice compared to the control mice. Our results suggest that selenium nanoparticle administration can result in considerable induction of the Th1 platform of immune response through the elevation of IFN-γ and IL-12 and may be a cause for better prognosis in mice with tumors.

  15. Comparison of the Adipose and Luminal Mammary Gland Compartment as Orthotopic Inoculation Sites in a 4T1-Based Immunocompetent Preclinical Model for Triple-Negative Breast Cancer.

    PubMed

    Steenbrugge, Jonas; Breyne, Koen; Denies, Sofie; Dekimpe, Melissa; Demeyere, Kristel; De Wever, Olivier; Vermeulen, Peter; Van Laere, Steven; Sanders, Niek N; Meyer, Evelyne

    2016-12-01

    Breast tumorigenesis is classically studied in mice by inoculating tumor cells in the fat pad, the adipose compartment of the mammary gland. Alternatively, the mammary ducts, which constitute the luminal mammary gland compartment, also provide a suitable inoculation site to induce breast cancer in murine models. The microenvironments in these compartments influence tumor cell progression, yet this effect has not been investigated in an immunocompetent context. Here, we compared both mammary gland compartments as distinct inoculation sites, taking into account the immunological aspect by inoculating 4T1 tumor cells in immunocompetent mice. Following tumor cell inoculation in the adipose compartment of non-pretreated/naive, hormonally pretreated/naive and non-pretreated/lactating mice, the primary tumors developed similarly. However, a slower onset of primary tumor growth was found after inoculations in the luminal compartment of non-pretreated/lactating mice. Despite this difference in tumor development rate, metastasis to the liver and lungs was equally observed and was accompanied by lymphatic spreading of tumor cells and progressive splenomegaly with both inoculation types. Chitinase 3-like 1 (CHI3L1) and lipocalin 2 (LCN2) served as innovative biomarkers for disease progression showing increased levels in primary tumors and sera of the non-pretreated/lactating inoculation groups. A slower increase in circulating CHI3L1 but not LCN2 levels, was observed after inoculations in the luminal compartment which corroborated the slower tumor development at this inoculation site. Our results highlight the critical impact of different mammary gland compartments on tumor development in syngeneic murine models and support the use of novel tumor progression biomarkers in an immune-competent environment.

  16. Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model

    PubMed Central

    Ware, Matthew J.; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A.; Corr, Stuart J.

    2017-01-01

    Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30–40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors. PMID:28287120

  17. Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model

    NASA Astrophysics Data System (ADS)

    Ware, Matthew J.; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A.; Corr, Stuart J.

    2017-03-01

    Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30–40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors.

  18. Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model.

    PubMed

    Ware, Matthew J; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A; Corr, Stuart J

    2017-03-13

    Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30-40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors.

  19. Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice.

    PubMed

    Cha, John; Roomi, M Waheed; Ivanov, Vadim; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2013-01-01

    Degradation of the extracellular matrix (ECM) plays a critical role in the formation of tumors and metastasis and has been found to correlate with the aggressiveness of tumor growth and invasiveness of cancer. Ascorbic acid, which is known to be essential for the structural integrity of the intercellular matrix, is not produced by humans and must be obtained from the diet. Cancer patients have been shown to have very low reserves of ascorbic acid. Our main objective was to determine the effect of ascorbate supplementation on metastasis, tumor growth and tumor immunohistochemistry in mice unable to synthesize ascorbic acid [gulonolactone oxidase (gulo) knockout (KO)] when challenged with B16FO melanoma or 4T1 breast cancer cells. Gulo KO female mice 36-38 weeks of age were deprived of or maintained on ascorbate in food and water for 4 weeks prior to and 2 weeks post intraperitoneal (IP) injection of 5x105 B16FO murine melanoma cells or to injection of 5x105 4T1 breast cancer cells into the mammary pad of mice. Ascorbate-supplemented gulo KO mice injected with B16FO melanoma cells demonstrated significant reduction (by 71%, p=0.005) in tumor metastasis compared to gulo KO mice on the control diet. The mean tumor weight in ascorbate supplemented mice injected with 4T1 cells was reduced by 28% compared to tumor weight in scorbutic mice. Scorbutic tumors demonstrated large dark cores, associated with increased necrotic areas and breaches to the tumor surface, apoptosis and matrix metalloproteinase-9 (MMP-9), and weak, disorganized or missing collagen I tumor capsule. In contrast, the ascorbate-supplemented group tumors had smaller fainter colored cores and confined areas of necrosis/apoptosis with no breaches from the core to the outside of the tumor and a robust collagen I tumor capsule. In both studies, ascorbate supplementation of gulo KO mice resulted in profoundly decreased serum inflammatory cytokine interleukin (IL)-6 (99% decrease, p=0.01 in the B16F0

  20. In Vivo Anti-Tumor Effects of Flavokawain A in 4T1 Breast Cancer Cell-Challenged Mice.

    PubMed

    Abu, Nadiah; Mohamed, Nurul Elyani; Yeap, Swee Keong; Lim, Kian Lam; Akhtar, M Nadeem; Zulfadli, Aimi Jamil; Kee, Beh Boon; Abdullah, Mohd Puad; Omar, Abdul Rahman; Alitheen, Noorjahan Banu

    2015-01-01

    Flavokawain A is a chalcone that can be found in the kava-kava plant (Piper methsyticum) extract. The kava-kava plant has been reported to possess anti-cancer, anti-inflammatory and antinociceptive activities. The state of the immune system, and the inflammatory process play vital roles in the progression of cancer. The immunomodulatary effects and the anti-inflammatory effects of flavokawain A in a breast cancer murine model have not been studied yet. Thus, this study aimed to elucidate the basic mechanism as to how flavokawain A regulates and enhance the immune system as well as impeding the inflammatory process in breast cancer-challenged mice. Based on our study, it is interesting to note that flavokawain A increased the T cell population; both Th1 cells and CTLs, aside from the natural killer cells. The levels of IFN-γ and IL-2 were also elevated in the serum of flavokawain A-treated mice. Apart from that, flavokawain A also decreased the weight and volume of the tumor, and managed to induce apoptosis in them. In terms of inflammation, flavokawain A-treated mice had reduced level of major pro-inflammatory mediators; NO, iNOS, NF-KB, ICAM and COX-2. Overall, flavokawain A has the potential to not only enhance antitumor immunity, but also prevents the inflammatory process in a cancer-prone microenvironment.

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

    PubMed Central

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

    2016-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-11-01

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

  3. Effect of Neem Leaf Extract (Azadirachta indica) on c-Myc Oncogene Expression in 4T1 Breast Cancer Cells of BALB/c Mice

    PubMed Central

    Othman, Fauziah; Motalleb, Gholamreza; Lam Tsuey Peng, Sally; Rahmat, Asmah; Basri, Rusliza; Pei Pei, Chong

    2012-01-01

    Objective: Breast cancer is the most common cause of cancer-related deaths in women both worldwide and in Malaysia. Azadirachta indica (A. Juss), commonly known as neem, is one of the most versatile medicinal plants that has gained worldwide prominence due to its medicinal properties. However, the anticancer effect of ethanolic neem leaf extract against breast cancer has not been documented. The purpose of the present study is to investigate the effect of neem leaf extract on c-Myc oncogene expression in 4T1 breast cancer BALB/c mice. Materials and Methods: In this experimental study, A total of 48 female BALB/c mice were divided randomly into four groups of 12 mice per group: i.cancer control (CC) treated with 0.5% Tween 20 in PBS, ii. 0.5 µg/mL tamoxifen citrate (CT), iii. 250 mg/kg neem leaf extract (C250), and iv. 500 mg/kg neem leaf extract (C500). in situ reverse transcription polymerase chain reaction (in situ RT-PCR) was applied to evaluate suppression of c-Myc oncogene expression in breast cancer tissue. Results: The C500 group showed significant (p<0.05) suppression of c-Myc oncogene expression compared to the CC group. Conclusion: c-Myc was found to be down regulated under the effect of 500 mg/kg ethanolic neem leaf extract. PMID:23626938

  4. Licoricidin, an Active Compound in the Hexane/Ethanol Extract of Glycyrrhiza uralensis, Inhibits Lung Metastasis of 4T1 Murine Mammary Carcinoma Cells

    PubMed Central

    Park, So Young; Kwon, Soo Jin; Lim, Soon Sung; Kim, Jin-Kyu; Lee, Ki Won; Park, Jung Han Yoon

    2016-01-01

    Licorice extracts containing glycyrrhizin exhibit anti-carcinogenic properties. Because glycyrrhizin induces severe hypokalemia and hypertension, we prepared a hexane/ethanol extract of Glycyrrhiza uralensis (HEGU) that lacks glycyrrhizin, and showed that HEGU induces apoptosis and G1 cell cycle arrest and inhibits migration of DU145 human prostate cancer cells. Our previous in vitro studies identified two active components in HEGU: isoangustone A, which induces apoptosis and G1 cycle arrest, and licoricidin, which inhibits metastasis. This study examined whether HEGU and licoricidin inhibit metastasis using the 4T1 mammary cancer model. Both HEGU and licoricidin treatment reduced pulmonary metastasis and the expression of CD45, CD31, HIF-1α, iNOS, COX-2, and VEGF-A in tumor tissues. Additionally, a decrease in protein expression of VEGF-R2, VEGF-C, VEGF-R3, and LYVE-1 was noted in tumor tissues of licoricidin-treated mice. Furthermore, the blood concentrations of MMP-9, ICAM-1, VCAM-1, and VEGF-A were decreased in HEGU-treated mice. In vitro 4T1 cell culture results showed that both HEGU and licoricidin inhibited cell migration, MMP-9 secretion, and VCAM expression. The present study demonstrates that the licoricidin in HEGU inhibits lung metastasis of 4T1 mammary carcinoma cells, which may be mediated via inhibition of cancer cell migration, tumor angiogenesis, and lymphangiogenesis. PMID:27314329

  5. Licoricidin, an Active Compound in the Hexane/Ethanol Extract of Glycyrrhiza uralensis, Inhibits Lung Metastasis of 4T1 Murine Mammary Carcinoma Cells.

    PubMed

    Park, So Young; Kwon, Soo Jin; Lim, Soon Sung; Kim, Jin-Kyu; Lee, Ki Won; Park, Jung Han Yoon

    2016-06-14

    Licorice extracts containing glycyrrhizin exhibit anti-carcinogenic properties. Because glycyrrhizin induces severe hypokalemia and hypertension, we prepared a hexane/ethanol extract of Glycyrrhiza uralensis (HEGU) that lacks glycyrrhizin, and showed that HEGU induces apoptosis and G1 cell cycle arrest and inhibits migration of DU145 human prostate cancer cells. Our previous in vitro studies identified two active components in HEGU: isoangustone A, which induces apoptosis and G1 cycle arrest, and licoricidin, which inhibits metastasis. This study examined whether HEGU and licoricidin inhibit metastasis using the 4T1 mammary cancer model. Both HEGU and licoricidin treatment reduced pulmonary metastasis and the expression of CD45, CD31, HIF-1α, iNOS, COX-2, and VEGF-A in tumor tissues. Additionally, a decrease in protein expression of VEGF-R2, VEGF-C, VEGF-R3, and LYVE-1 was noted in tumor tissues of licoricidin-treated mice. Furthermore, the blood concentrations of MMP-9, ICAM-1, VCAM-1, and VEGF-A were decreased in HEGU-treated mice. In vitro 4T1 cell culture results showed that both HEGU and licoricidin inhibited cell migration, MMP-9 secretion, and VCAM expression. The present study demonstrates that the licoricidin in HEGU inhibits lung metastasis of 4T1 mammary carcinoma cells, which may be mediated via inhibition of cancer cell migration, tumor angiogenesis, and lymphangiogenesis.

  6. Theranostic probe for simultaneous in vivo photoacoustic imaging and confined photothermolysis by pulsed laser at 1064 nm in 4T1 breast cancer model

    NASA Astrophysics Data System (ADS)

    Zhou, Min; Ku, Geng; Pageon, Laura; Li, Chun

    2014-11-01

    Here, we report that polyethylene glycol (PEG)-coated copper(ii) sulfide nanoparticles (PEG-CuS NPs) with their peak absorption tuned to 1064 nm could be used both as a contrast agent for photoacoustic tomographic imaging of mouse tumor vasculature and as a mediator for confined photothermolysis of tumor cells in an orthotopic syngeneic 4T1 breast tumor model. PEG-CuS NPs showed stronger photoacoustic signal than hollow gold nanospheres and single-wall carbon nanotubes at 1064 nm. MicroPET imaging of 4T1 tumor-bearing mice showed a gradual accumulation of the NPs in the tumor over time. About 6.5% of injected dose were taken up in each gram of tumor tissue at 24 h after intravenous injection of 64Cu-labeled PEG-CuS NPs. For both photoacoustic imaging and therapeutic studies, nanosecond (ns)-pulsed laser was delivered with Q-switched Nd:YAG at a wavelength of 1064 nm. Unlike conventional photothermal ablation therapy mediated by continuous wave laser with which heat could spread to the surrounding normal tissue, interaction of CuS NPs with short pulsed laser deliver heat rapidly to the treatment volume keeping the thermal damage confined to the target tissues. Our data demonstrated that it is possible to use a single-compartment nanoplatform to achieve both photoacoustic tomography and highly selective tumor destruction at 1064 nm in small animals.Here, we report that polyethylene glycol (PEG)-coated copper(ii) sulfide nanoparticles (PEG-CuS NPs) with their peak absorption tuned to 1064 nm could be used both as a contrast agent for photoacoustic tomographic imaging of mouse tumor vasculature and as a mediator for confined photothermolysis of tumor cells in an orthotopic syngeneic 4T1 breast tumor model. PEG-CuS NPs showed stronger photoacoustic signal than hollow gold nanospheres and single-wall carbon nanotubes at 1064 nm. MicroPET imaging of 4T1 tumor-bearing mice showed a gradual accumulation of the NPs in the tumor over time. About 6.5% of injected dose were

  7. Recognition of tumor antigens in 4T1 cells by natural IgM from three strains of mice with different susceptibilities to spontaneous breast cancer

    PubMed Central

    Díaz-Zaragoza, Mariana; Hernández-Ávila, Ricardo; Ostoa-Saloma, Pedro

    2017-01-01

    The issue of antibody responses to tumors is potentially important to cancer immunologists. Early detection of cancer represents one of the most promising approaches to reduce the growing cancer burden. Natural immunoglobulin (Ig)M antibodies have been associated with the recognition and elimination of cancerous and precancerous cells. Using natural IgM antibodies, the present study identified a set of antigens in healthy mice from three different strains and examined whether the global patterns of antibodies are able to discriminate between a condition of more or less susceptibility to breast cancer. The current study performed two-dimensional (2D) immunoblotting to detect antigens from 4T1 cells using natural IgM from serum of healthy female mice from three different strains. The t-test was used to analyze the total number of spots. There were no significant differences in the numbers of antigens recognized in each strain. However, differences in patterns were observed on 2D immunoblots among the three strains. The reactivity patterns of natural IgM antibodies to particular antigens exhibited non-random clustering, which discriminated between strains with different susceptibilities to spontaneous breast cancer. The results demonstrated that the patterns of reactivity to defined subsets of antigens are able to provide information regarding differential diagnosis associated with breast cancer sensitivity. Therefore, it may be concluded that it is possible to segregate the IgM humoral immune response toward cancer antigens according to the genetic background of individuals. In addition, it is possible to identify the recognized antigens that allow grouping or discriminate between the different IgM antibodies expressed. The possible association between a particular antigen and cancer susceptibility requires further study, but the methodology exposed in the present study may identify potential candidates for this possible association. PMID:28123554

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

    PubMed

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

    2015-08-01

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

  9. Combined effect of aerobic interval training and selenium nanoparticles on expression of IL-15 and IL-10/TNF-α ratio in skeletal muscle of 4T1 breast cancer mice with cachexia.

    PubMed

    Molanouri Shamsi, M; Chekachak, S; Soudi, S; Quinn, L S; Ranjbar, K; Chenari, J; Yazdi, M H; Mahdavi, M

    2017-02-01

    Cancer cachexia is characterized by inflammation, loss of skeletal muscle and adipose tissue mass, and functional impairment. Oxidative stress and inflammation are believed to regulate pathways controlling skeletal muscle wasting. The aim of this study was to determine the effects of aerobic interval training and the purported antioxidant treatment, selenium nanoparticle supplementation, on expression of IL-15 and inflammatory cytokines in 4T1 breast cancer-bearing mice with cachexia. Selenium nanoparticle supplementation accelerated cachexia symptoms in tumor-bearing mice, while exercise training prevented muscle wasting in tumor-bearing mice. Also, aerobic interval training enhanced the anti-inflammatory indices IL-10/TNF-α ratio and IL-15 expression in skeletal muscle in tumor-bearing mice. However, combining exercise training and antioxidant supplementation prevented cachexia and muscle wasting and additionally decreased tumor volume in 4T1 breast cancer mice. These finding suggested that combining exercise training and antioxidant supplementation could be a strategy for managing tumor volume and preventing cachexia in breast cancer.

  10. DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer.

    PubMed

    Terracina, Krista P; Graham, Laura J; Payne, Kyle K; Manjili, Masoud H; Baek, Annabel; Damle, Sheela R; Bear, Harry D

    2016-09-01

    Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model. We found that expression of neu, MHC class I molecules, and several murine cancer testis antigens (CTA) was increased by decitabine treatment of 4T1 cells in vitro. Decitabine also increased expression of multiple CTA in two human breast cancer cell lines. Decitabine-treated 4T1 cells stimulated greater IFN-gamma release from tumor-sensitized lymphocytes, implying increased immunogenicity. Expansion of CD11b + Gr1 + MDSC in 4T1 tumor-bearing mice was significantly diminished by decitabine treatment. Decitabine treatment improved the efficacy of adoptive T cell immunotherapy in mice with established 4T1 tumors, with greater inhibition of tumor growth and an increased cure rate. Decitabine may have a role in combination with existing and emerging immunotherapies for breast cancer.

  11. Curcumin improves the therapeutic efficacy of Listeria(at)-Mage-b vaccine in correlation with improved T-cell responses in blood of a triple-negative breast cancer model 4T1.

    PubMed

    Singh, Manisha; Ramos, Ilyssa; Asafu-Adjei, Denise; Quispe-Tintaya, Wilber; Chandra, Dinesh; Jahangir, Arthee; Zang, Xingxing; Aggarwal, Bharat B; Gravekamp, Claudia

    2013-08-01

    Success of cancer vaccination is strongly hampered by immune suppression in the tumor microenvironment (TME). Interleukin (IL)-6 is particularly and highly produced by triple-negative breast cancer (TNBC) cells, and has been considered as an important contributor to immune suppression in the TME. Therefore, we hypothesized that IL-6 reduction may improve efficacy of vaccination against TNBC cancer through improved T-cell responses. To prove this hypothesis, we investigated the effect of curcumin, an inhibitor of IL-6 production, on vaccination of a highly attenuated Listeria monocytogenes (Listeria(at)), encoding tumor-associated antigens (TAA) Mage-b in a TNBC model 4T1. Two therapeutic vaccination strategies with Listeria(at)-Mage-b and curcumin were tested. The first immunization strategy involved all Listeria(at)-Mage-b vaccinations and curcumin after tumor development. As curcumin has been consumed all over the world, the second immunization strategy involved curcumin before and all therapeutic vaccinations with Listeria(at)-Mage-b after tumor development. Here, we demonstrate that curcumin significantly improves therapeutic efficacy of Listeria(at)-Mage-b with both immunization strategies particularly against metastases in a TNBC model (4T1). The combination therapy was slightly but significantly more effective against the metastases when curcumin was administered before compared to after tumor development. With curcumin before tumor development in the combination therapy, the production of IL-6 was significantly decreased and IL-12 increased by myeloid-derived suppressor cells (MDSC), in correlation with improved CD4 and CD8 T-cell responses in blood. Our study suggests that curcumin improves the efficacy of Listeria(at)-Mage-b vaccine against metastases in TNBC model 4T1 through reversal of tumor-induced immune suppression.

  12. Inoculated Cell Density as a Determinant Factor of the Growth Dynamics and Metastatic Efficiency of a Breast Cancer Murine Model

    PubMed Central

    Gregório, Ana C.; Fonseca, Nuno A.; Moura, Vera; Lacerda, Manuela; Figueiredo, Paulo; Simões, Sérgio; Dias, Sérgio; Moreira, João Nuno

    2016-01-01

    4T1 metastatic breast cancer model have been widely used to study stage IV human breast cancer. However, the frequent inoculation of a large number of cells, gives rise to fast growing tumors, as well as to a surprisingly low metastatic take rate. The present work aimed at establishing the conditions enabling high metastatic take rate of the triple-negative murine 4T1 syngeneic breast cancer model. An 87% 4T1 tumor incidence was observed when as few as 500 cancer cells were implanted. 4T1 cancer cells colonized primarily the lungs with 100% efficiency, and distant lesions were also commonly identified in the mesentery and pancreas. The drastic reduction of the number of inoculated cells resulted in increased tumor doubling times and decreased specific growth rates, following a Gompertzian tumor expansion. The established conditions for the 4T1 mouse model were further validated in a therapeutic study with peguilated liposomal doxorubicin, in clinical used in the setting of metastatic breast cancer. Inoculated cell density was proven to be a key methodological aspect towards the reproducible development of macrometastases in the 4T1 mouse model and a more reliable pre-clinical assessment of antimetastatic therapies. PMID:27820870

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

    PubMed

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

    2015-05-01

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

  14. Curcumin improves the therapeutic efficacy of Listeriaat-Mage-b vaccine in correlation with improved T-cell responses in blood of a triple-negative breast cancer model 4T1

    PubMed Central

    Singh, Manisha; Ramos, Ilyssa; Asafu-Adjei, Denise; Quispe-Tintaya, Wilber; Chandra, Dinesh; Jahangir, Arthee; Zang, Xingxing; Aggarwal, Bharat B; Gravekamp, Claudia

    2013-01-01

    Abstract Success of cancer vaccination is strongly hampered by immune suppression in the tumor microenvironment (TME). Interleukin (IL)-6 is particularly and highly produced by triple-negative breast cancer (TNBC) cells, and has been considered as an important contributor to immune suppression in the TME. Therefore, we hypothesized that IL-6 reduction may improve efficacy of vaccination against TNBC cancer through improved T-cell responses. To prove this hypothesis, we investigated the effect of curcumin, an inhibitor of IL-6 production, on vaccination of a highly attenuated Listeria monocytogenes (Listeriaat), encoding tumor-associated antigens (TAA) Mage-b in a TNBC model 4T1. Two therapeutic vaccination strategies with Listeriaat-Mage-b and curcumin were tested. The first immunization strategy involved all Listeriaat-Mage-b vaccinations and curcumin after tumor development. As curcumin has been consumed all over the world, the second immunization strategy involved curcumin before and all therapeutic vaccinations with Listeriaat-Mage-b after tumor development. Here, we demonstrate that curcumin significantly improves therapeutic efficacy of Listeriaat-Mage-b with both immunization strategies particularly against metastases in a TNBC model (4T1). The combination therapy was slightly but significantly more effective against the metastases when curcumin was administered before compared to after tumor development. With curcumin before tumor development in the combination therapy, the production of IL-6 was significantly decreased and IL-12 increased by myeloid-derived suppressor cells (MDSC), in correlation with improved CD4 and CD8 T-cell responses in blood. Our study suggests that curcumin improves the efficacy of Listeriaat-Mage-b vaccine against metastases in TNBC model 4T1 through reversal of tumor-induced immune suppression. This study is focused on improving cancer vaccination by reducing immune suppression. Here we demonstrate that curcumin improves vaccine

  15. Chemotherapeutic drug-specific alteration of microvascular blood flow in murine breast cancer as measured by diffuse correlation spectroscopy

    PubMed Central

    Ramirez, Gabriel; Proctor, Ashley R.; Jung, Ki Won; Wu, Tong Tong; Han, Songfeng; Adams, Russell R.; Ren, Jingxuan; Byun, Daniel K.; Madden, Kelley S.; Brown, Edward B.; Foster, Thomas H.; Farzam, Parisa; Durduran, Turgut; Choe, Regine

    2016-01-01

    The non-invasive, in vivo measurement of microvascular blood flow has the potential to enhance breast cancer therapy monitoring. Here, longitudinal blood flow of 4T1 murine breast cancer (N=125) under chemotherapy was quantified with diffuse correlation spectroscopy based on layer models. Six different treatment regimens involving doxorubicin, cyclophosphamide, and paclitaxel at clinically relevant doses were investigated. Treatments with cyclophosphamide increased blood flow as early as 3 days after administration, whereas paclitaxel induced a transient blood flow decrease at 1 day after administration. Early blood flow changes correlated strongly with the treatment outcome and distinguished treated from untreated mice individually for effective treatments. PMID:27699124

  16. A GM-CSF and CD40L bystander vaccine is effective in a murine breast cancer model

    PubMed Central

    Soliman, Hatem; Mediavilla-Varela, Melanie; Antonia, Scott J

    2015-01-01

    Background There is increasing interest in using cancer vaccines to treat breast cancer patients in the adjuvant setting to prevent recurrence in high risk situations or in combination with other immunomodulators in the advanced setting. Current peptide vaccines are limited by immunologic compatibility issues, and engineered autologous cellular vaccines are difficult to produce on a large scale. Using standardized bystander cell lines modified to secrete immune stimulating adjuvant substances can greatly enhance the ability to produce immunogenic cellular vaccines using unmodified autologous cells or allogeneic medical grade tumor cell lines as targets. We investigated the efficacy of a cellular vaccine using B78H1 bystander cell lines engineered to secrete granulocyte macrophage-colony stimulating factor and CD40 ligand (BCG) in a murine model of breast cancer. Methods Five-week-old female BALB/c mice were injected orthotopically in the mammary fat pad with 4T1 tumor cells. Treatment consisted of irradiated 4T1 ± BCG cells given subcutaneously every 4 days and was repeated three times per mouse when tumors became palpable. Tumors were measured two to three times per week for 25 days. The vaccine’s activity was confirmed in a second experiment using Lewis lung carcinoma (LLC) cells in C57BL/6 mice to exclude a model specific effect. Interferon-γ (IFN-γ) and interleukin-2 (IL-2) enzyme-linked immunospots (ELISPOTS) were performed on splenic lymphocytes incubated with 4T1 lysates along with immunohistochemistry for CD3 on tumor sections. Results Tumor growth was significantly inhibited in the 4T1-BCG and LLC-BCG treatment groups when compared to 4T1 and LLC treatment groups. There were higher levels of IL-2 and IFN-γ secreting T-cells on ELISPOT for BCG treated groups, and a trend for higher numbers of tumor infiltrating CD3+ lymphocytes. Some tumors in the 4T1-BCG demonstrated organized lymphoid structures within the tumor microenvironment as well. Conclusion

  17. An improved syngeneic orthotopic murine model of human breast cancer progression.

    PubMed

    Rashid, Omar M; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine; Schaum, Julia; Yamada, Akimitsu; Terracina, Krista P; Milstien, Sheldon; Spiegel, Sarah; Takabe, Kazuaki

    2014-10-01

    Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous (OP) injection in the area of the nipple, or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. ODV produced less variable-sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development .

  18. An Improved Syngeneic Orthotopic Murine Model of Human Breast Cancer Progression

    PubMed Central

    Rashid, Omar M.; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine; Schaum, Julia; Yamada, Akimitsu; Terracina, Krista P.; Milstien, Sheldon; Spiegel, Sarah; Takabe, Kazuaki

    2014-01-01

    Purpose Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Methods Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous injection in the area of the nipple (OP), or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. Results ODV produced less variable sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. Conclusions ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development. PMID:25200444

  19. Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer.

    PubMed

    Aliper, Alexander M; Frieden-Korovkina, Victoria P; Buzdin, Anton; Roumiantsev, Sergey A; Zhavoronkov, Alex

    2014-11-30

    In solid cancers, myeloid derived suppressor cells (MDSC) infiltrate (peri)tumoral tissues to induce immune tolerance and hence to establish a microenvironment permissive to tumor growth. Importantly, the mechanisms that facilitate such infiltration or a subsequent immune suppression are not fully understood. Hence, in this study, we aimed to delineate disparate molecular pathways which MDSC utilize in murine models of colon or breast cancer. Using pathways enrichment analysis, we completed interactome maps of multiple signaling pathways in CD11b+/Gr1(high/low) MDSC from spleens and tumor infiltrates of mice with c26GM colon cancer and tumor infiltrates of MDSC in 4T1 breast cancer. In both cancer models, infiltrating MDSC, but not CD11b+ splenic cells, have been found to be enriched in multiple signaling molecules suggestive of their enhanced proliferative and invasive phenotypes. The interactome data has been subsequently used to reconstruct a previously unexplored regulation of MDSC cell cycle by the c-myc transcription factor which was predicted by the analysis. Thus, this study represents a first interactome mapping of distinct multiple molecular pathways whereby MDSC sustain cancer progression.

  20. Poly (I: C) modulates the immunosuppressive activity of myeloid-derived suppressor cells in a murine model of breast cancer.

    PubMed

    Forghani, Parvin; Waller, Edmund K

    2015-08-01

    Polyinosinic-polycytidylic acid [Poly (I: C)], a ligand for Toll-like receptor (TLR-3), is used as an adjuvant to enhance anti-tumor immunity because of its prominent effects on CD8 T cells and NK cells. Myeloid-derived suppressor cells (MDSCs) are one of the main immunosuppressive factors in cancer, and their abnormal accumulation is correlated with the clinical stage of breast cancer and is an important mechanism of tumor immune evasion. Although Poly (I: C) is thought to have direct anti-tumor activity in different cell lines, its effect on immunosuppressive MDSCs in tumor-bearing animals has not been studied. 4T1-Luc, a metastatic breast cancer mouse cell line, was injected into the left flank of female BALB/c mice. Tumor-bearing mice were treated with i.p. injection of Poly (I: C) or PBS beginning on day 7 after tumor inoculation. WBCs and MDSCs were counted using coulter counter and stained for flow cytometry, respectively. Bioluminescent imaging was used to monitor tumor burden at multiple time points during the course of tumor growth. Poly (I: C) treatment led to a decrease in MDSC frequencies in BM, blood, and tumor compared to saline-treated control mice. Poly (I: C) treatment also abrogated the immunosuppressive function of MDSCs, concomitant with an increase in local T cell response of the immune system in a murine model of breast cancer. Poly (I: C) treatment decreases MDSC frequency and immunosuppressive function in 4T1-tumor-bearing hosts and effectively augments the activity of breast cancer immunotherapy.

  1. Expression of Cadherin-17 Promotes Metastasis in a Highly Bone Marrow Metastatic Murine Breast Cancer Model

    PubMed Central

    Kurabayashi, Atsushi; Furihata, Mutsuo

    2017-01-01

    We previously established 4T1E/M3 highly bone marrow metastatic mouse breast cancer cells through in vivo selection of 4T1 cells. But while the incidence of bone marrow metastasis of 4T1E/M3 cells was high (~80%) when injected intravenously to mice, it was rather low (~20%) when injected subcutaneously. Therefore, using 4T1E/M3 cells, we carried out further in vitro and in vivo selection steps to establish FP10SC2 cells, which show a very high incidence of metastasis to lungs (100%) and spines (85%) after subcutaneous injection into mice. qRT-PCR and western bolt analysis revealed that cadherin-17 gene and protein expression were higher in FP10SC2 cells than in parental 4T1E/M3 cells. In addition, immunostaining revealed the presence of cadherin-17 at sites of bone marrow and lung metastasis after subcutaneous injection of FP10SC2 cells into mice. Suppressing cadherin-17 expression in FP10SC2 cells using RNAi dramatically decreased the cells' anchorage-independent growth and migration in vitro and their metastasis to lung and bone marrow in vivo. These findings suggest that cadherin-17 plays a crucial role in mediating breast cancer metastasis to bone marrow. PMID:28197418

  2. Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice.

    PubMed

    Hamilton, Melisa J; Banáth, Judit P; Lam, Vivian; Lepard, Nancy E; Krystal, Gerald; Bennewith, Kevin L

    2012-05-01

    As more groups investigate the role of myeloid-derived suppressor cells (MDSCs) in promoting the growth of primary tumors and distant tumor metastases, it is imperative to ensure the accurate detection and quantification of MDSC immunosuppression ex vivo. MDSCs are defined by their ability to suppress immune responses. Although different in vitro culture conditions have been used to study MDSCs, the effect of different culture conditions on MDSC immunosuppression is unknown. We therefore isolated MDSCs from the lungs and spleens of 4T1 murine mammary tumor-bearing mice and assayed MDSC-mediated suppression of T cell responses under different culture conditions. We found that 4T1-induced MDSCs effectively suppressed T cell proliferation under serum-free conditions, but not when fetal calf serum (FCS) was present. FCS neither altered the immunosuppressive activities of other myeloid cell types (i.e., peritoneal or tumor-associated macrophages) nor modified the susceptibility of T cells to myeloid cell-mediated suppression, but instead acted directly on 4T1-induced MDSCs to significantly reduce their immunosuppressive function. Importantly, we found that bovine serum albumin was a major contributor to the antagonistic effects of FCS on 4T1-induced MDSC immunosuppression by inhibiting reactive oxygen species production from MDSCs. This work reveals that in vitro culture conditions influence the immunosuppressive properties of MDSCs and highlights the importance of testing different culture conditions on MDSC phenotype to ensure that MDSC immunosuppression is not being masked. These data have important implications for the accurate detection and identification of MDSCs, as well as for determining the influence of MDSC-mediated immunosuppression on primary and metastatic tumor growth.

  3. A novel protein with anti-metastasis activity on 4T1 carcinoma from medicinal fungus Cordyceps militaris.

    PubMed

    Yang, Qing; Yin, Yalin; Yu, Guojun; Jin, Yanxia; Ye, Xiangdong; Shrestha, Alok; Liu, Wei; Yu, Wenhui; Sun, Hui

    2015-09-01

    Cordyceps militaris is a famous fungus used in traditional Chinese medicine for nearly one thousand years. And its fruiting body is known to possess anticancer and immunomodulatory activities. This study describes the isolation, characterization, and test of antitumor activity of a C. militaris protein, called here as "C. militaris immunoregulatory protein" (CMIP). CMIP was purified through a three-step chromatographic procedure. The MS analyses showed that CMIP corresponded to an uncharacterized protein (CCM_01955) in the C. militaris transcriptional database. Circular dichroism of CMIP revealed the composition of 35.5% β-sheet, 18.5% α-helix, 17.0% turn and 29.0% random coil. No significant cytotoxicity of CMIP was observed on HeLa, HepG2 and 4T1 tumor cells. However, CMIP demonstrated anti-metastasis activity on a mouse model of 4T1 breast cancer lung metastasis. It reduced the number of tumor nodules in the lung of tumor-bearing mice and prolonged their survival time. Furthermore, proliferation of the 4T1 cells was inhibited by macrophage-CMIP conditioned media. And the mRNA levels of cytokines TNF-α, IL-1β and IL-6 were increased significantly in peritoneal macrophages treated by CMIP. These results reveal the antitumor potential of CMIP, thus reinforcing the importance of biochemical prospecting of C. militaris.

  4. Green tea (Camellia sinensis) extract inhibits both the metastasis and osteolytic components of mammary cancer 4T1 lesions in mice.

    PubMed

    Luo, Ke-Wang; Ko, Chun-Hay; Yue, Grace Gar-Lee; Lee, Julia Kin-Ming; Li, Kai-Kai; Lee, Michelle; Li, Gang; Fung, Kwok-Pui; Leung, Ping-Chung; Lau, Clara Bik-San

    2014-04-01

    Green tea (Camellia sinensis, CS), a kind of Chinese tea commonly consumed as a healthy beverage, has been demonstrated to have various biological activities, including antioxidation, antiobesity and anticancer. Our study aims to investigate the antitumor, antimetastasis and antiosteolytic effects of CS aqueous extract both in vitro and in vivo using metastasis-specific mouse mammary carcinoma 4T1 cells. Our results showed that treatment of 4T1 cells with CS aqueous extract resulted in significant inhibition of 4T1 cell proliferation. CS extract induced 4T1 apoptosis in a dose-dependent manner as assessed by annexin-V and propidium iodide staining and caspase-3 activity. Western blot analysis showed that CS increased the expression of Bax-to-Bcl-2 ratio and activated caspase-8 and caspase-3 to induce apoptosis. CS also inhibited 4T1 cell migration and invasion at 0.06-0.125 mg/ml. In addition, CS extract (0.6 g/kg, orally fed daily for 4 weeks) was effective in decreasing the tumor weight by 34.8% in female BALB/c mice against water treatment control (100%). Apart from the antitumor effect, CS extract significantly decreased lung and liver metastasis in BALB/c mice bearing 4T1 tumors by 54.5% and 72.6%, respectively. Furthermore, micro-computed tomography and in vitro osteoclast staining analysis suggested that CS extract was effective in bone protection against breast cancer-induced bone destruction. In conclusion, the present study demonstrated that the CS aqueous extract, which closely mimics green tea beverage, has potent antitumor and antimetastasis effects in breast cancer and could protect the bone from breast cancer-induced bone destruction.

  5. Antitumor and antimetastatic activities of a novel benzothiazole-2-thiol derivative in a murine model of breast cancer.

    PubMed

    Hu, XiaoLin; Li, Sen; He, Yan; Ai, Ping; Wu, Shaoyong; Su, Yonglin; Li, Xiaolin; Cai, Lei; Peng, Xingchen

    2017-01-02

    The prognosis of metastatic breast cancer is always very poor. Thus, it is urgent to develop novel drugs with less toxicity against metastatic breast cancer. A new drug (XC-591) derived from benzothiazole-2-thiol was designed and synthesized in our lab. In this study, we tried to assess effects of XC-591 treatment on primary breast cancer and pulmonary metastasis in 4T1 mice model. Furthermore, we tried to discover its possible molecular mechanism of action. MTT experiment showed XC-591 had significant anti-cancer activity on diverse cancer cells. Furthermore, XC-591 significantly suppressed the proliferation of 4T1 cells by colony formation assay. The in vivo results displayed that XC-591 could inhibit the growth and metastasis in 4T1 model. Moreover, histological analysis revealed that XC-591 treatment increased apoptosis, inhibited proliferation and angiogenesis in vivo. In addition, XC-591 did not contribute to obvious drug associated toxicity during the whole study. Molecular mechanism showed XC-591 could inhibit RhoGDI, activate caspase-3 and decrease phosphorylated Akt. The present data may be important to further explore this kind of new small-molecule inhibitor.

  6. High and low mammographic density human breast tissues maintain histological differential in murine tissue engineering chambers.

    PubMed

    Chew, G L; Huang, D; Lin, S J; Huo, C; Blick, T; Henderson, M A; Hill, P; Cawson, J; Morrison, W A; Campbell, I G; Hopper, J L; Southey, M C; Haviv, I; Thompson, E W

    2012-08-01

    Mammographic density (MD) is the area of breast tissue that appears radiologically white on mammography. Although high MD is a strong risk factor for breast cancer, independent of BRCA1/2 mutation status, the molecular basis of high MD and its associated breast cancer risk is poorly understood. MD studies will benefit from an animal model, where hormonal, gene and drug perturbations on MD can be measured in a preclinical context. High and low MD tissues were selectively sampled by stereotactic biopsy from operative specimens of high-risk women undergoing prophylactic mastectomy. The high and low MD tissues were transferred into separate vascularised biochambers in the groins of SCID mice. Chamber material was harvested after 6 weeks for histological analyses and immunohistochemistry for cytokeratins, vimentin and a human-specific mitochondrial antigen. Within-individual analysis was performed in replicate mice, eliminating confounding by age, body mass index and process-related factors, and comparisons were made to the parental human tissue. Maintenance of differential MD post-propagation was assessed radiographically. Immunohistochemical staining confirmed the preservation of human glandular and stromal components in the murine biochambers, with maintenance of radiographic MD differential. Propagated high MD regions had higher stromal (p = 0.0002) and lower adipose (p = 0.0006) composition, reflecting the findings in the original human breast tissue, although glands appeared small and non-complex in both high and low MD groups. No significant differences were observed in glandular area (p = 0.4) or count (p = 0.4) between high and low MD biochamber tissues. Human mammary glandular and stromal tissues were viably maintained in murine biochambers, with preservation of differential radiographic density and histological features. Our study provides a murine model for future studies into the biomolecular basis of MD as a risk factor for breast cancer.

  7. Adjuvant Cationic Liposomes Presenting MPL and IL-12 Induce Cell Death, Suppress Tumor Growth, and Alter the Cellular Phenotype of Tumors in a Murine Model of Breast Cancer

    PubMed Central

    2015-01-01

    Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1β and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1β, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80+ macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of Ki-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response. PMID:25179345

  8. Transmission of murine cytomegalovirus in breast milk: a model of natural infection in neonates.

    PubMed

    Wu, Carol A; Paveglio, Sara A; Lingenheld, Elizabeth G; Zhu, Li; Lefrançois, Leo; Puddington, Lynn

    2011-05-01

    Vertical transmission of viruses in breast milk can expose neonates to infectious pathogens at a time when the capacity of their immune system to control infections is limited. We developed a mouse model to study the outcomes of acquisition of murine cytomegalovirus (MCMV) when neonates are breastfed by mothers with acute or latent infection. Breast milk leukocytes collected from lactating mice were examined for the presence of MCMV IE-1 mRNA by reverse transcription-PCR (RT-PCR) with Southern analysis. As determined by this criterion, breast milk leukocytes from both acute and latent mothers were positive for MCMV. This mimics the outcome seen in humans with latent cytomegalovirus infection, where reactivation of virus occurs specifically in the lactating mammary gland. Interestingly, intraperitoneal injection of breast milk collected from mothers with latent infection was sufficient to transfer MCMV to neonatal mice, demonstrating that breast milk was a source of virus. Furthermore, we found that MCMV was transmitted from infected mothers to breastfed neonates, with MCMV IE-1 mRNA or infectious virus present in multiple organs, including the brain. In fact, 1 day of nursing was sufficient to transmit MCMV from latent mothers to breastfed neonatal mice. Together, these data validate this mouse model of vertical transmission of MCMV from mothers with acute or latent MCMV infection to breastfed neonates. Its relevance to human disease should prove useful in future studies designed to elucidate the immunological and pathological ramifications of neonatal infection acquired via this natural route.

  9. Murine Models of Breast Cancer: Assessment of the Role of c-Src in Mammary Tumorigenesis

    DTIC Science & Technology

    2004-10-01

    luc) as shown along with the HSV -TK-Renilla-luciferase reporter (A to E). The fold activation for NFAT-and AP- 1 -firefly-luciferase and actual...Vo AD Award Number: DAMD17-99- 1 -9151 TITLE: Murine Models of Breast Cancer: Assessment of the Role of c-Src in Mammary Tumorigenesis PRINCIPAL...PAGE OMB No. 074-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for

  10. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors.

    PubMed

    Cho, Robert W; Wang, Xinhao; Diehn, Maximilian; Shedden, Kerby; Chen, Grace Y; Sherlock, Gavin; Gurney, Austin; Lewicki, John; Clarke, Michael F

    2008-02-01

    In human breast cancers, a phenotypically distinct minority population of tumorigenic (TG) cancer cells (sometimes referred to as cancer stem cells) drives tumor growth when transplanted into immunodeficient mice. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. To do so, we used breast tumors of the mouse mammary tumor virus (MMTV)-Wnt-1 mice. MMTV-Wnt-1 breast tumors were harvested, dissociated into single-cell suspensions, and sorted by flow cytometry on Thy1, CD24, and CD45. Sorted cells were then injected into recipient background FVB/NJ female syngeneic mice. In six of seven tumors examined, Thy1+CD24+ cancer cells, which constituted approximately 1%-4% of tumor cells, were highly enriched for cells capable of regenerating new tumors compared with cells of the tumor that did not fit this profile ("not-Thy1+CD24+"). Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. These studies suggest that there is a cancer stem cell compartment in the MMTV-Wnt-1 murine breast tumor and that there is a clinical utility of this model for the study of cancer stem cells.

  11. Heterogeneity of Functional Properties of Clone 66 Murine Breast Cancer Cells Expressing Various Stem Cell Phenotypes

    PubMed Central

    Mukhopadhyay, Partha; Farrell, Tracy; Sharma, Gayatri; McGuire, Timothy R.; O’Kane, Barbara; Sharp, J. Graham

    2013-01-01

    Introduction Breast cancer grows, metastasizes and relapses from rare, therapy resistant cells with a stem cell phenotype (cancer stem cells/CSCs). However, there is a lack of studies comparing the functions of CSCs isolated using different phenotypes in order to determine if CSCs are homogeneous or heterogeneous. Methods Cells with various stem cell phenotypes were isolated by sorting from Clone 66 murine breast cancer cells that grow orthotopically in immune intact syngeneic mice. These populations were compared by in vitro functional assays for proliferation, growth, sphere and colony formation; and in vivo limiting dilution analysis of tumorigenesis. Results The proportion of cells expressing CD44highCD24low/neg, side population (SP) cells, ALDH1+, CD49fhigh, CD133high, and CD34high differed, suggesting heterogeneity. Differences in frequency and size of tumor spheres from these populations were observed. Higher rates of proliferation of non-SP, ALDH1+, CD34low, and CD49fhigh suggested properties of transit amplifying cells. Colony formation was higher from ALDH1− and non-SP cells than ALDH1+ and SP cells suggesting a progenitor phenotype. The frequency of clonal colonies that grew in agar varied and was differentially altered by the presence of Matrigel™. In vivo, fewer cells with a stem cell phenotype were needed for tumor formation than “non-stem” cells. Fewer SP cells were needed to form tumors than ALDH1+ cells suggesting further heterogeneities of cells with stem phenotypes. Different levels of cytokines/chemokines were produced by Clone 66 with RANTES being the highest. Whether the heterogeneity reflects soluble factor production remains to be determined. Conclusions These data demonstrate that Clone 66 murine breast cancer cells that express stem cell phenotypes are heterogeneous and exhibit different functional properties, and this may also be the case for human breast cancer stem cells. PMID:24265713

  12. Induction of Monocyte Chemoattractant Proteins in Macrophages via the Production of Granulocyte/Macrophage Colony-Stimulating Factor by Breast Cancer Cells

    PubMed Central

    Yoshimura, Teizo; Imamichi, Tomozumi; Weiss, Jonathan M.; Sato, Miwa; Li, Liangzhu; Matsukawa, Akihiro; Wang, Ji Ming

    2016-01-01

    Monocyte chemoattractant protein-1 (MCP-1)/CCL2 plays an important role in the initiation and progression of cancer. We previously reported that in 4T1 murine breast cancer, non-tumor stromal cells, including macrophages, were the major source of MCP-1. In the present study, we analyzed the potential mechanisms by which MCP-1 is upregulated in macrophages infiltrating 4T1 tumors. We found that cell-free culture supernatants of 4T1 cells (4T1-sup) markedly upregulated MCP-1 production by peritoneal inflammatory macrophages. 4T1-sup also upregulated other MCPs, such as MCP-3/CCL7 and MCP-5/CCL12, but modestly upregulated neutrophil chemotactic chemokines, such as KC/CXCL1 or MIP-2/CXCL2. Physicochemical analysis indicated that an approximately 2–3 kDa 4T1 cell product was responsible for the capacity of 4T1-sup to upregulate MCP-1 expression by macrophages. A neutralizing antibody against granulocyte/macrophage colony-stimulating factor (GM-CSF), but not macrophage CSF, almost completely abrogated MCP-1-inducing activity of 4T1-sup, and recombinant GM-CSF potently upregulated MCP-1 production by macrophages. The expression levels of GM-CSF in 4T1 tumors in vivo were higher than other tumors, such as Lewis lung carcinoma. Treatment of mice with anti-GM-CSF antibody significantly reduced the growth of 4T1 tumors at the injection sites but did not reduce MCP-1 production or lung metastasis in tumor-bearing mice. These results indicate that 4T1 cells have the capacity to directly upregulate MCP-1 production by macrophages by releasing GM-CSF; however, other mechanisms are also involved in increased MCP-1 levels in the 4T1 tumor microenvironment. PMID:26834744

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

    PubMed

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

    2014-02-01

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

  14. High and low frequency subharmonic imaging of angiogenesis in a murine breast cancer model.

    PubMed

    Dahibawkar, Manasi; Forsberg, Mark A; Gupta, Aditi; Jaffe, Samantha; Dulin, Kelly; Eisenbrey, John R; Halldorsdottir, Valgerdur G; Forsberg, Anya I; Dave, Jaydev K; Marshall, Andrew; Machado, Priscilla; Fox, Traci B; Liu, Ji-Bin; Forsberg, Flemming

    2015-09-01

    This project compared quantifiable measures of tumor vascularity obtained from contrast-enhanced high frequency (HF) and low frequency (LF) subharmonic ultrasound imaging (SHI) to 3 immunohistochemical markers of angiogenesis in a murine breast cancer model (since angiogenesis is an important marker of malignancy and the target of many novel cancer treatments). Nineteen athymic, nude, female rats were implanted with 5×10(6) breast cancer cells (MDA-MB-231) in the mammary fat pad. The contrast agent Definity (Lantheus Medical Imaging, N Billerica, MA) was injected in a tail vein (dose: 180μl/kg) and LF pulse-inversion SHI was performed with a modified Sonix RP scanner (Analogic Ultrasound, Richmond, BC, Canada) using a L9-4 linear array (transmitting/receiving at 8/4MHz in SHI mode) followed by HF imaging with a Vevo 2100 scanner (Visualsonics, Toronto, ON, Canada) using a MS250 linear array transmitting and receiving at 24MHz. The radiofrequency data was filtered using a 4th order IIR Butterworth bandpass filter (11-13MHz) to isolate the subharmonic signal. After the experiments, specimens were stained for endothelial cells (CD31), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Fractional tumor vascularity was calculated as contrast-enhanced pixels over all tumor pixels for SHI, while the relative area stained over total tumor area was calculated from specimens. Results were compared using linear regression analysis. Out of 19 rats, 16 showed tumor growth (84%) and 11 of them were successfully imaged. HF SHI demonstrated better resolution, but weaker signals than LF SHI (0.06±0.017 vs. 0.39±0.059; p<0.001). The strongest overall correlation in this breast cancer model was between HF SHI and VEGF (r=-0.38; p=0.03). In conclusion, quantifiable measures of tumor neovascularity derived from contrast-enhanced HF SHI appear to be a better method than LF SHI for monitoring angiogenesis in a murine xenograft model of breast cancer

  15. High and low frequency subharmonic imaging of angiogenesis in a murine breast cancer model

    PubMed Central

    Dahibawkar, Manasi; Forsberg, Mark A.; Gupta, Aditi; Jaffe, Samantha; Dulin, Kelly; Eisenbrey, John R.; Halldorsdottir, Valgerdur G.; Forsberg, Anya I.; Dave, Jaydev K.; Marshall, Andrew; Machado, Priscilla; Fox, Traci B.; Liu, Ji-Bin; Forsberg, Flemming

    2015-01-01

    This project compared quantifiable measures of tumor vascularity obtained from contrast-enhanced high frequency (HF) and low frequency (LF) subharmonic ultrasound imaging (SHI) to 3 immunohistochemical markers of angiogenesis in a murine breast cancer model (since angiogenesis is an important marker of malignancy and the target of many novel cancer treatments). Nineteen athymic, nude, female rats were implanted with 5×106 breast cancer cells (MDA-MB-231) in the mammary fat pad. The contrast agent Definity (Lantheus Medical Imaging, N Billerica, MA) was injected in a tail vein (dose: 180µl/kg) and low frequency pulse-inversion SHI was performed with a modified Sonix RP scanner (Analogic Ultrasound, Richmond, BC, Canada) using a L9-4 linear array (transmitting/receiving at 8/4MHz in SHI mode) followed by high frequency imaging with a Vevo 2100 scanner (Visualsonics, Toronto, ON, Canada) using a MS250 linear array transmitting and receiving at 24MHz. The radiofrequency data was filtered using a 4th order IIR Butterworth bandpass filter (11–13MHz) to isolate the subharmonic signal. After the experiments, specimens were stained for endothelial cells (CD31), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Fractional tumor vascularity was calculated as contrast enhanced pixels over all tumor pixels for SHI, while the relative area stained over total tumor area was calculated from specimens. Results were compared using linear regression analysis. Out of 19 rats, 16 showed tumor growth (84%) and 11 of them were successfully imaged. HF SHI demonstrated better resolution, but weaker signals than LF SHI (0.06±0.017 vs. 0.39±0.059; p<0.001). The strongest overall correlation in this breast cancer model was between HF SHI and VEGF (r=−0.38; p=0.03). In conclusion, quantifiable measures of tumor neovascularity derived from contrast-enhanced HF SHI appear to be a better method than LF SHI for monitoring angiogenesis in a murine xenograft model of

  16. In vivo anticancer synergy mechanism of doxorubicin and verapamil combination treatment is impaired in BALB/c mice with metastatic breast cancer.

    PubMed

    McCarthy, Michelle; Auda, Gregory; Agrawal, Suchi; Taylor, Amy; Backstrom, Zack; Mondal, Debasis; Moroz, Krzysztof; Dash, Srikanta

    2014-08-01

    The development of resistance to anticancer drugs is a major unsolved problem in the chemotherapy treatment of metastatic breast cancer. We have shown that increased expression of P-glycoprotein (P-gp) prevented nuclear entry of the doxorubicin molecules into murine breast cancer cells (4T1-R) leading to doxorubicin chemoresistance. This study was performed to test whether inhibition of P-gp using verapamil could overcome doxorubicin chemoresistance and eliminate multiorgan metastasis 4T1-R cells in BALB/c mouse. The 4T1-R cells were treated with doxorubicin alone, verapamil alone, and a combination of both. Multiorgan metastasis of 4T1-R cells in the presence and in the absence of combination treatment was determined in the BALB/c mouse model. Verapamil induced nuclear translocation of doxorubicin, G2-phase growth arrest and synergistically induced 100% cytotoxicity in 4T1-R cells in culture. However, the combination treatment using verapamil and doxorubicin did not improve the overall survival of BALB/c mice with metastatic breast cancer. Our results indicate that the combination treatment of verapamil and doxorubicin did not inhibit tumor growth in the lungs and liver indicating that the anticancer synergy mechanism of verapamil and doxorubicin is impaired in vivo in BALB/c mouse model with metastatic breast cancer. We propose that understanding the mechanisms as to why the combination of doxorubicin and verapamil treatment was impaired in the mouse model should allow novel approaches to improve chemotherapy response of metastatic breast cancer.

  17. High Resolution X-Ray Microangiography of 4T1 Tumor in Mouse Using Synchrotron Radiation

    SciTech Connect

    Sun Jianqi; Liu Ping; Gu Xiang; Liu Xiaoxia; Zhao Jun; Xiao Tiqiao; Xu, Lisa X.

    2010-07-23

    Angiogenesis is very important in tumor growth and metastasis. But in clinic, only vessels lager than 200 {mu}m in diameter, can be observed using conventional medical imaging. Synchrotron radiation (SR) phase contrast imaging, whose spatial resolution can reach as high as 1 {mu}m, has great advantages in imaging soft tissue structures, such as blood vessels and tumor tissues. In this paper, the morphology of newly formed micro-vessels in the mouse 4T1 tumor samples was firstly studied with contrast agent. Then, the angiogenesis in nude mice tumor window model was observed without contrast agent using the SR phase contrast imaging at the beamline for X-ray imaging and biomedical applications, Shanghai Synchrotron Radiation Facility (SSRF). The images of tumors showed dense, irregular and tortuous tumor micro-vessels with the smallest size of 20-30 {mu}m in diameter.

  18. Muscarinic activation enhances the anti-proliferative effect of paclitaxel in murine breast tumor cells.

    PubMed

    Español, Alejandro Javier; Jacob, Guillermina; Dmytrenko, Ganna; Sales, María Elena

    2013-10-01

    Muscarinic acetylcholine receptors (mAChR) are expressed in cells without nervous origin. mAChR are up-regulated in tumor cells and their stimulation can modulate tumor growth. In this work we investigated the ability of mAChR activation to induce tumor cell death. We studied the action of a combination of low doses of the muscarinic agonist carbachol plus paclitaxel, a chemotherapeutic agent frequently used in breast cancer treatment, in terms of effectiveness. Long term treatment with carbachol exerted anti-proliferative actions on LM2 and LM3 murine mammary adenocarcinoma cells, similarly to paclitaxel. The combination of carbachol with paclitaxel at submaximal concentrations, added during 20 h decreased tumor cell proliferation in a more potent manner than each drug added separately. This effect was reverted by the muscarinic antagonist atropine, and was due to a potentiation of tumor cell apoptosis tested by TUNEL assay. This treatment did not affect the proliferation of the non tumorigenic mammary cell line NMuMG. In conclusion, the combination of a muscarinic agonist plus paclitaxel should be tested as a useful therapeutic tool in breast cancer treatment.

  19. Protoporphyrin IX fluorescence for enhanced photodynamic diagnosis and photodynamic therapy in murine models of skin and breast cancer

    NASA Astrophysics Data System (ADS)

    Rollakanti, Kishore Reddy

    Protoporphyrin IX (PpIX) is a photosensitizing agent derived from aminolevulinic acid. PpIX accumulates specifically within target cancer cells, where it fluoresces and produces cytotoxic reactive oxygen species. Our aims were to employ PpIX fluorescence to detect squamous cell carcinoma (SCC) of the skin (Photodynamic diagnosis, PDD), and to improve treatment efficacy (Photodynamic therapy, PDT) for basal cell carcinoma (BCC) and cutaneous breast cancer. Hyperspectral imaging and a spectrometer based dosimeter system were used to detect very early SCC in UVB-irradiated murine skin, using PpIX fluorescence. Regarding PDT, we showed that low non-toxic doses of vitamin D, given before ALA application, increase tumor specific PpIX accumulation and sensitize BCC and breast cancer cells to ALA-PDT. These optical imaging methods and the combination therapy regimen (vitamin D and ALA-PDT) are promising tools for effective management of skin and breast cancer.

  20. Assessing the accuracy and reproducibility of modality independent elastography in a murine model of breast cancer

    PubMed Central

    Weis, Jared A.; Flint, Katelyn M.; Sanchez, Violeta; Yankeelov, Thomas E.; Miga, Michael I.

    2015-01-01

    Abstract. Cancer progression has been linked to mechanics. Therefore, there has been recent interest in developing noninvasive imaging tools for cancer assessment that are sensitive to changes in tissue mechanical properties. We have developed one such method, modality independent elastography (MIE), that estimates the relative elastic properties of tissue by fitting anatomical image volumes acquired before and after the application of compression to biomechanical models. The aim of this study was to assess the accuracy and reproducibility of the method using phantoms and a murine breast cancer model. Magnetic resonance imaging data were acquired, and the MIE method was used to estimate relative volumetric stiffness. Accuracy was assessed using phantom data by comparing to gold-standard mechanical testing of elasticity ratios. Validation error was <12%. Reproducibility analysis was performed on animal data, and within-subject coefficients of variation ranged from 2 to 13% at the bulk level and 32% at the voxel level. To our knowledge, this is the first study to assess the reproducibility of an elasticity imaging metric in a preclinical cancer model. Our results suggest that the MIE method can reproducibly generate accurate estimates of the relative mechanical stiffness and provide guidance on the degree of change needed in order to declare biological changes rather than experimental error in future therapeutic studies. PMID:26158120

  1. Dynamic changes in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers during various murine peripartum states and over time.

    PubMed

    Chew, G L; Huang, D; Huo, C W; Blick, T; Hill, P; Cawson, J; Frazer, H; Southey, M D; Hopper, J L; Henderson, M A; Haviv, I; Thompson, E W

    2013-07-01

    Mammographic density (MD) is a strong heritable risk factor for breast cancer, and may decrease with increasing parity. However, the biomolecular basis for MD-associated breast cancer remains unclear, and systemic hormonal effects on MD-associated risk is poorly understood. This study assessed the effect of murine peripartum states on high and low MD tissue maintained in a xenograft model of human MD. Method High and low MD human breast tissues were precisely sampled under radiographic guidance from prophylactic mastectomy specimens of women. The high and low MD tissues were maintained in separate vascularised biochambers in nulliparous or pregnant SCID mice for 4 weeks, or mice undergoing postpartum involution or lactation for three additional weeks. High and low MD biochamber material was harvested for histologic and radiographic comparisons during various murine peripartum states. High and low MD biochamber tissues in nulliparous mice were harvested at different timepoints for histologic and radiographic comparisons. Results High MD biochamber tissues had decreased stromal (p = 0.0027), increased adipose (p = 0.0003) and a trend to increased glandular tissue areas (p = 0.076) after murine postpartum involution. Stromal areas decreased (p = 0.042), while glandular (p = 0.001) and adipose areas (p = 0.009) increased in high MD biochamber tissues during lactation. A difference in radiographic density was observed in high (p = 0.0021) or low MD biochamber tissues (p = 0.004) between nulliparous, pregnant and involution groups. No differences in tissue composition were observed in high or low MD biochamber tissues maintained for different durations, although radiographic density increased over time. Conclusion High MD biochamber tissues had measurable histologic changes after postpartum involution or lactation. Alterations in radiographic density occurred in biochamber tissues between different peripartum states and over time. These findings

  2. 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

  3. 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.

  4. Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

    PubMed Central

    Mall, Christine; Sckisel, Gail D.; Proia, David A.; Mirsoian, Annie; Grossenbacher, Steven K.; Pai, Chien-Chun Steven; Chen, Mingyi; Monjazeb, Arta M.; Kelly, Karen; Blazar, Bruce R.; Murphy, William J.

    2016-01-01

    ABSTRACT Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30–60 min after 4–5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing non-inflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1high neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses toward the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation. PMID:27057446

  5. Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent

    PubMed Central

    Hanlon, Katherine E; Lozano-Ondoua, Alysia N; Umaretiya, Puja J; Symons-Liguori, Ashley M; Chandramouli, Anupama; Moy, Jamie K; Kwass, William K; Mantyh, Patrick W; Nelson, Mark A; Vanderah, Todd W

    2016-01-01

    Introduction Cannabinoid compounds, both nonspecific as well as agonists selective for either cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2), have been shown to modulate the tumor microenvironment by inducing apoptosis in tumor cells in several model systems. The mechanism of this modulation remains only partially delineated, and activity induced via the CB1 and CB2 receptors may be distinct despite significant sequence homology and structural similarity of ligands. Methods The CB2-selective agonist JWH-015 was used to investigate mechanisms downstream of CB2 activation in mouse and human breast cancer cell lines in vitro and in a murine mammary tumor model. Results JWH-015 treatment significantly reduced primary tumor burden and metastasis of luciferase-tagged murine mammary carcinoma 4T1 cells in immunocompetent mice in vivo. Furthermore, JWH-015 reduced the viability of murine 4T1 and human MCF7 mammary carcinoma cells in vitro by inducing apoptosis. JWH-015-mediated reduction of breast cancer cell viability was not dependent on Gαi signaling in vitro or modified by classical pharmacological blockade of CB1, GPR55, TRPV1, or TRPA1 receptors. JWH-015 effects were calcium dependent and induced changes in MAPK/ERK signaling. Conclusion The results of this work characterize the actions of a CB2-selective agonist on breast cancer cells in a syngeneic murine model representing how a clinical presentation of cancer progression and metastasis may be significantly modulated by a G-protein-coupled receptor. PMID:27186076

  6. Rapamycin Promotes Mouse 4T1 Tumor Metastasis that Can Be Reversed by a Dendritic Cell-Based Vaccine.

    PubMed

    Lin, Tien-Jen; Liang, Wen-Miin; Hsiao, Pei-Wen; M S, Pradeep; Wei, Wen-Chi; Lin, Hsin-Ting; Yin, Shu-Yi; Yang, Ning-Sun

    2015-01-01

    Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor-resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan's National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine.

  7. Pre-osteoblastic MC3T3-E1 cells promote breast cancer growth in bone in a murine xenograft model

    PubMed Central

    Bodenstine, Thomas M.; Beck, Benjamin H.; Cao, Xuemei; Cook, Leah M.; Ismail, Aimen; Powers, J. Kent; Mastro, Andrea M.; Welch, Danny R.

    2011-01-01

    The bones are the most common sites of breast cancer metastasis. Upon arrival within the bone microenvironment, breast cancer cells coordinate the activities of stromal cells, resulting in an increase in osteoclast activity and bone matrix degradation. In late stages of bone metastasis, breast cancer cells induce apoptosis in osteoblasts, which further exacerbates bone loss. However, in early stages, breast cancer cells induce osteoblasts to secrete inflammatory cytokines purported to drive tumor progression. To more thoroughly evaluate the role of osteoblasts in early stages of breast cancer metastasis to the bones, we used green fluorescent protein-labeled human breast cancer cell lines MDA-MB-231 and MDA-MB-435, which both induce osteolysis after intra-femoral injection in athymic mice, and the murine pre-osteoblastic cell line MC3T3-E1 to modulate osteoblast populations at the sites of breast cancer metastasis. Breast cancer cells were injected directly into the femur with or without equal numbers of MC3T3-E1 cells. Tumors grew significantly larger when co-injected with breast cancer cells and MC3T3-E1 cells than injected with breast cancer cells alone. Osteolysis was induced in both groups, indicating that MC3T3-E1 cells did not block the ability of breast cancer cells to cause bone destruction. MC3T3-E1 cells promoted tumor growth out of the bone into the extraosseous stroma. These data suggest that breast cancer cells and osteoblasts communicate during early stages of bone metastasis and promote tumor growth. PMID:21352696

  8. In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503.

    PubMed

    Wankhede, Mamta; Dedeugd, Casey; Siemann, Dietmar W; Sorg, Brian S

    2010-03-01

    4T1 mouse mammary adenocarcinomas and Caki-1 human renal cell carcinomas grown in mouse dorsal window chambers were serially treated with the vascular disrupting agent (VDA) OXi4503 and their responses compared. The real-time in vivo response was assessed using spectral imaging of microvascular hemoglobin saturation. To our knowledge this is the first use of spectral imaging technology for investigation of vascular disrupting agents. Previous research showing tumor size dependence in the treatment response to VDAs suggested that for the size of tumors used in this study only a moderate response would be observed; however, the tumors unexpectedly had very different responses to treatment. Caki-1 tumors showed little permanent vessel damage and experienced transient vessel collapse with time-dependent oxygenation changes followed by recovery starting at 6 h after treatment. Caki-1 tumors did not manifest necrotic avascular regions even after repeated treatments. These results are consistent with those obtained using other imaging modalities and histology. In contrast, similarly sized 4T1 tumors showed extensive vessel disintegration, minor vascular collapse, and a drop in tumor oxygenation up to 6 h post-treatment, after which reperfusion of collapsed vessels and extensive vascular remodeling and neovascularization of the tumor rim occurred from 8-48 h. The completely disintegrated vessels did not recover and left behind avascular and apparently necrotic regions in the tumor core. Spectral imaging appears to be a useful technique for in vivo investigation of vascular disrupting agents. The differential responses of these two tumor-types suggest that further investigation of the mechanisms of action of VDAs and individual characterization of tumor VDA-responses may be needed for optimal clinical use of these agents.

  9. Gallotannin-rich Caesalpinia spinosa fraction decreases the primary tumor and factors associated with poor prognosis in a murine breast cancer model

    PubMed Central

    2013-01-01

    Background Several treatment alternatives are available for primary breast cancer, although those for metastatic disease or inflammation associated with tumor progression are ineffective. Therefore, there is a great need for new therapeutic alternatives capable of generating an immune response against residual tumor cells, thus contributing to eradication of micrometastases and cancer stem cells. The use of complex natural products is an excellent therapeutic alternative widely used by Chinese, Hindu, Egyptian, and ancestral Latin-American Indian populations. Methods The present study evaluated cytotoxic, antitumor, and tumor progression activities of a gallotannin-rich fraction derived from Caesalpinia spinosa (P2Et). The parameters evaluated in vitro were mitochondrial membrane depolarization, phosphatidylserine externalization, caspase 3 activation, DNA fragmentation, and clonogenic activity. The parameters evaluated in vivo were tumor growth, leukocyte number, metastatic cell number, and cytokine production by flow cytometry. Results The in vitro results showed that the P2Et fraction induced apoptosis with mitochondrial membrane potential loss, phosphatidylserine externalization, caspase 3 activation, DNA fragmentation, and decreased clonogenic capacity of 4T1 cells. In vivo, the P2Et fraction induced primary tumor reduction in terms of diameter and weight in BALB/c mice transplanted with 4T1 cells and decreased numbers of metastatic cells, mainly in the spleen. Furthermore, decreases in the number of peripheral blood leukocytes (leukemoid reaction) and interleukin 6 (IL-6) serum levels were found, which are events associated with a poor prognosis. The P2Et fraction exerts its activity on the primary tumor, reduces cell migration to distant organs, and decreases IL-6 serum levels, implying tumor microenvironment mechanisms. Conclusions Overall, the P2Et fraction lessens risk factors associated with tumor progression and diminishes primary tumor size, showing

  10. Vitamin D enhances the efficacy of photodynamic therapy in a murine model of breast cancer

    PubMed Central

    Rollakanti, Kishore R; Anand, Sanjay; Maytin, Edward V

    2015-01-01

    Cutaneous metastasis occurs more frequently in breast cancer than in any other malignancy in women, causing significant morbidity. Photodynamic therapy (PDT), which combines a porphyrin-based photosensitizer and activation by light, can be employed for breast cancer (especially cutaneous metastases) but tumor control after PDT has not surpassed traditional treatments methods such as surgery, radiation, and chemotherapy up to now. Here, we report that breast cancer nodules in mice can be effectively treated by preconditioning the tumors with 1α, 25-dihydroxyvitamin D3 (calcitriol; Vit D) prior to administering 5-aminolevulinate (ALA)-based PDT. Breast carcinoma tumors (MDA-MB-231 cells implanted subcutaneously in nude mice) received systemic Vit D (1 μg/kg) for 3 days prior to receiving ALA. The addition of Vit D increased intratumoral accumulation of protoporphyrin IX (PpIX) by 3.3 ± 0.5-fold, relative to mice receiving ALA alone. Bioluminescence imaging in vivo and immunohistochemical staining confirmed that tumor-specific cell death after ALA-PDT was markedly enhanced (36.8 ± 7.4-fold increase in TUNEL-positive nuclei; radiance decreased to 14% of control) in Vit D pretreated tumors as compared to vehicle-pretreated tumors. Vit D stimulated proliferation (10.7 ± 2.8-fold) and differentiation (9.62 ± 1.7-fold) in tumor cells, underlying an augmented cellular sensitivity to ALA-PDT. The observed enhancement of tumor responses to ALA-PDT after low, nontoxic doses of Vit D supports a new combination approach that deserves consideration in the clinical setting, and offers potential for improved remission of cutaneous breast cancer metastases. PMID:25712788

  11. Targeting of interleukin (IL)-17A inhibits PDL1 expression in tumor cells and induces anticancer immunity in an estrogen receptor-negative murine model of breast cancer.

    PubMed

    Ma, Yun-Feng; Chen, Chen; Li, Dongqing; Liu, Min; Lv, Zhuang-Wei; Ji, Yanhong; Xu, Jiru

    2017-01-31

    The expression of IL-17A and programmed death ligand 1 (PDL1) is increased in estrogen receptor-negative breast cancer. IL-17A promotes tumor cell survival and invasiveness and inhibits the antitumor immune response. The PDL1-PD1 (programmed death protein 1) signaling pathway promotes escape from immune surveillance in tumor cells. The pro-tumor properties of IL-17A and PDL1 in various cancers have been previously examined; however, the relationship and roles of IL-17A and PDL1 in ER-negative breast cancer have not been evaluated. Therefore, we assessed whether IL-17A promotes PDL1 expression in tumor cells and whether targeting of IL-17A could inhibit ER-negative breast cancer progression in a murine model. Our study revealed that IL-17A promoted PDL1 expression in human and mouse cells. In the murine cancer model, targeting of IL-17A inhibited PDL1 expression in the tumor microenvironment, decreased the percentage of Treg cells in tumor-infiltrating lymphocytes, and promoted CD4+ and CD8+ T cells to secrete interferon gamma. More importantly, treatment with combined anti-IL-17A and anti-PDL1 antibodies enhanced antitumor effects in favor of tumor eradication. Thus, our study established a pro-tumor role of IL-17A in promoting tumor immune escape and supports the development of a novel cytokine immunotherapy against breast cancer.

  12. Human glandular organoid formation in murine engineering chambers after collagenase digestion and flow cytometry isolation of normal human breast tissue single cells.

    PubMed

    Huo, Cecilia W; Huang, Dexing; Chew, Grace L; Hill, Prue; Vohora, Ambika; Ingman, Wendy V; Glynn, Danielle J; Godde, Nathan; Henderson, Michael A; Thompson, Erik W; Britt, Kara L

    2016-11-01

    Women with high mammographic density (MD) are at increased risk of breast cancer (BC) after adjustment for age and body mass index. We have developed a murine biochamber model in which both high MD (HMD) and low MD (LMD) tissue can be propagated. Here, we tested whether cells isolated by collagenase digestion and fluorescence-activated cell sorting (FACS) from normal breast can be reconstituted in our biochamber model, which would allow cell-specific manipulations to be tested. Fresh breast tissue was collected from women (n = 7) undergoing prophylactic mastectomy. The tissue underwent collagenase digestion overnight and, in some cases, additional FACS enrichment to obtain mature epithelial, luminal progenitor, mammary stem, and stromal cells. Cells were then transferred bilaterally into biochambers in SCID mice (n = 5-7) and incubated for 6 weeks, before harvesting for histological analyses, and immunohistochemical staining for cytokeratins (CK), vimentin, Ki-67, murine macrophages, and Cleaved Caspase-3. Biochambers inoculated with single cells after collagenase digestion or with flow cytometry contained glandular structures of human origin (human vimentin-positive), which expressed CK-14 and pan-CK, and were proliferating (Ki-67-positive). Glandular structures from the digested tissues were smaller than those in chambers seeded with finely chopped intact mammary tissue. Mouse macrophage infiltration was higher in the chambers arising from digested tissues. Pooled single cells and FACS fractionated cells were viable in the murine biochambers and formed proliferating glandular organoids of human origin. This is among the first report to demonstrate the success of formed human glandular organoids from isolated primary mammary cells in the murine biochamber model.

  13. Downregulation of survivin expression exerts antitumoral effects on mouse breast cancer cells in vitro and in vivo

    PubMed Central

    MA, WEN-HUI; LIU, YONG-CHAO; XUE, MEI-LAN; ZHENG, ZHENG; GE, YIN-LIN

    2016-01-01

    Metastasis constantly occurs in the majority of cases of primary breast cancer at late stage or following surgical treatment. Survivin, a member of the inhibitor of apoptosis protein family, has long been recognized as a promising anticancer target, but its antitumor effects remain largely unexplored. In order to elucidate the role of survivin in breast cancer metastasis, short interfering RNA (siRNA) was used in the present study to specifically downregulate survivin expression in the murine breast cancer cell line 4T1. The results demonstrated that blocking the expression of survivin by siRNA inhibited the proliferation, migration and invasion abilities of murine breast cancer cells in vitro. Vascular endothelial growth factor (VEGF)-C is a lymphatic endothelial cell-stimulating factor that may lead to the formation of lymphatic vessels in lymph nodes. In the present study, the inhibition of survivin by siRNA was able to reduce the overexpression of VEGF-C in 4T1 cells. Furthermore, intratumoral injections of the survivin-siRNA significantly inhibited the growth of orthotopically transplanted 4T1 tumors in vivo. In addition, the number of pulmonary metastases and the microlymphatic vessel density were significantly reduced in vivo, following transfection with survivin-siRNA. The results of the present study suggested that the Akt/hypoxia-inducible factor-1α signaling pathway participates in the survivin-mediated downregulation of VEGF-C expression observed in breast cancer cells treated with survivin-siRNA. Therefore, the use of siRNA specifically targeting survivin may be a potential anticancer method in the future. PMID:26870183

  14. Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling.

    PubMed

    Feys, Lynn; Descamps, Benedicte; Vanhove, Christian; Vral, Anne; Veldeman, Liv; Vermeulen, Stefan; De Wagter, Carlos; Bracke, Marc; De Wever, Olivier

    2015-09-29

    Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.

  15. Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling

    PubMed Central

    Feys, Lynn; Descamps, Benedicte; Vanhove, Christian; Vral, Anne; Veldeman, Liv; Vermeulen, Stefan; De Wagter, Carlos; Bracke, Marc; De Wever, Olivier

    2015-01-01

    Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model. Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells. PMID:26396176

  16. Cell type-dependent pathogenic functions of overexpressed human cathepsin B in murine breast cancer progression

    PubMed Central

    Bengsch, F; Buck, A; Günther, SC; Seiz, JR; Tacke, M; Pfeifer, D; von Elverfeldt, D; Sevenich, L; Hillebrand, LE; Kern, U; Sameni, M; Peters, C; Sloane, BF; Reinheckel, T

    2014-01-01

    The cysteine protease cathepsin B (CTSB) is frequently overexpressed in human breast cancer and correlated with a poor prognosis. Genetic deficiency or pharmacological inhibition of CTSB attenuates tumor growth, invasion and metastasis in mouse models of human cancers. CTSB is expressed in both cancer cells and cells of the tumor stroma, in particular in tumor-associated macrophages (TAM). In order to evaluate the impact of tumor- or stromal cell-derived CTSB on Polyoma Middle T (PyMT)-induced breast cancer progression, we used in vivo and in vitro approaches to induce human CTSB overexpression in PyMT cancer cells or stromal cells alone or in combination. Orthotopic transplantation experiments revealed that CTSB overexpression in cancer cells rather than in the stroma affects PyMT tumor progression. In 3D cultures, primary PyMT tumor cells showed higher extracellular matrix proteolysis and enhanced collective cell invasion when CTSB was overexpressed and proteolytically active. Coculture of PyMT cells with bone marrow-derived macrophages induced a TAM-like macrophage phenotype in vitro, and the presence of such M2-polarized macrophages in 3D cultures enhanced sprouting of tumor spheroids. We employed a doxycycline (DOX)-inducible CTSB expression system to selectively overexpress human CTSB either in cancer cells or in macrophages in 3D cocultures. Tumor spheroid invasiveness was only enhanced when CTSB was overexpressed in cancer cells, whereas CTSB expression in macrophages alone did not further promote invasiveness of tumor spheroids. We conclude that CTSB overexpression in the PyMT mouse model promotes tumor progression not by a stromal effect, but by a direct, cancer cell-inherent mode of action: CTSB overexpression renders the PyMT cancers more invasive by increasing proteolytic extracellular matrix protein degradation fostering collective cell invasion into adjacent tissue. PMID:24077280

  17. Proteolysis-a characteristic of tumor-initiating cells in murine metastatic breast cancer

    PubMed Central

    Hillebrand, Larissa E.; Bengsch, Fee; Hochrein, Jochen; Hülsdünker, Jan; Bender, Julia; Follo, Marie; Busch, Hauke; Boerries, Melanie; Reinheckel, Thomas

    2016-01-01

    Tumor initiating cells (TICs) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potential, TICs are founder cells for metastasis formation and are involved in chemotherapy resistance. In this study we explored molecular pathways which enable this tumor initiating potential for a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24+CD90+CD45−, showed a high tumorigenicity compared to non-CD24+CD90+CD45− cancer cells in colony formation assays, as well as upon orthotopic transplantation into the mammary fat pad of mice. In addition, these orthotopically grown CD24+CD90+CD45− TICs metastasized to the lungs. The transcriptome of TICs freshly isolated from primary tumors by cell sorting was compared with that of sorted non-CD24+CD90+CD45− cancer cells by RNA-seq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in the TICs. Accordingly, TICs showed high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on colony morphology in 3D cell culture assays. We conclude that CD24+CD90+CD45− cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature which could very well represent a functional hallmark of metastatic TICs from mammary carcinomas. PMID:27542270

  18. Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers.

    PubMed

    Chew, G L; Huo, C W; Huang, D; Blick, T; Hill, P; Cawson, J; Frazer, H; Southey, M C; Hopper, J L; Britt, K; Henderson, M A; Haviv, I; Thompson, E W

    2014-11-01

    Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other

  19. The protective effects of paeonol against epirubicin-induced hepatotoxicity in 4T1-tumor bearing mice via inhibition of the PI3K/Akt/NF-kB pathway.

    PubMed

    Wu, Jing; Xue, Xia; Zhang, Bin; Jiang, Wen; Cao, Hongmei; Wang, Rongmei; Sun, Deqing; Guo, Ruichen

    2016-01-25

    Epirubicin is widely used for the treatment of various breast cancers; however, it has serious adverse side effects, such as hepatotoxicity, which require dose-adjustment or therapy substitution. Paeonol, an active component from Moutan Cortex, has a variety of biological activities, including preventing or reducing various toxicities induced by antineoplastics. Protection by paeonol against hepatotoxicity induced by epirubicin and the underlying mechanism of action were investigated in this study. Cytosolic enzymes in the serum and oxidative stress indices in the liver were determined. The protective effects were determined using the MTT assay in vitro or by evaluating the expression of apoptotic factors and crucial proteins in the PI3K/Akt/NF-kB pathway using western blot analysis. It is concluded that paeonol alleviates epirubicin-induced hepatotoxicity in 4T1-tumor bearing mice by inhibiting the PI3K/Akt/NF-kB pathway.

  20. CD24 Is Not Required for Tumor Initiation and Growth in Murine Breast and Prostate Cancer Models.

    PubMed

    Cremers, Natascha; Neeb, Antje; Uhle, Tanja; Dimmler, Arno; Rothley, Melanie; Allgayer, Heike; Fodde, Riccardo; Sleeman, Jonathan Paul; Thiele, Wilko

    2016-01-01

    CD24 is a small, heavily glycosylated, GPI-linked membrane protein, whose expression has been associated with the tumorigenesis and progression of several types of cancer. Here, we studied the expression of CD24 in tumors of MMTV-PyMT, Apc1572/T+ and TRAMP genetic mouse models that spontaneously develop mammary or prostate carcinoma, respectively. We found that CD24 is expressed during tumor development in all three models. In MMTV-PyMT and Apc1572T/+ breast tumors, CD24 was strongly but heterogeneously expressed during early tumorigenesis, but decreased in more advanced stages, and accordingly was increased in poorly differentiated lesions compared with well differentiated lesions. In prostate tumors developing in TRAMP mice, CD24 expression was strong within hyperplastic lesions in comparison with non-hyperplastic regions, and heterogeneous CD24 expression was maintained in advanced prostate carcinomas. To investigate whether CD24 plays a functional role in tumorigenesis in these models, we crossed CD24 deficient mice with MMTV-PyMT, Apc1572T/+ and TRAMP mice, and assessed the influence of CD24 deficiency on tumor onset and tumor burden. We found that mice negative or positive for CD24 did not significantly differ in terms of tumor initiation and burden in the genetic tumor models tested, with the exception of Apc1572T/+ mice, in which lack of CD24 reduced the mammary tumor burden slightly but significantly. Together, our data suggest that while CD24 is distinctively expressed during the early development of murine mammary and prostate tumors, it is not essential for the formation of tumors developing in MMTV-PyMT, Apc1572T/+ and TRAMP mice.

  1. A Multifaceted Role for Myd88-Dependent Signaling in Progression of Murine Mammary Carcinoma

    PubMed Central

    Higgins, Mary J.; Serrano, Antonio; Boateng, Kofi Y.; Parsons, Victoria A.; Phuong, Tiffany; Seifert, Alyssa; Ricca, Jacob M.; Tucker, Kyle C.; Eidelman, Alec S.; Carey, Maureen A.; Kurt, Robert A.

    2016-01-01

    Previous data obtained in our laboratory suggested that there may be constitutive signaling through the myeloid differentiation primary response gene 88 (Myd88)-dependent signaling cascade in murine mammary carcinoma. Here, we extended these findings by showing that, in the absence of an added Toll-like receptor (TLR) agonist, the myddosome complex was preformed in 4T1 tumor cells, and that Myd88 influenced cytoplasmic extracellular signal–regulated kinase (Erk)1/Erk2 levels, nuclear levels of nuclear factor-kappaB (NFκB) and signal transducer and activator of transcription 5 (STAT5), tumor-derived chemokine (C–C motif) ligand 2 (CCL2) expression, and in vitro and in vivo tumor growth. In addition, RNA-sequencing revealed that Myd88-dependent signaling enhanced the expression of genes that could contribute to breast cancer progression and genes previously associated with poor outcome for patients with breast cancer, in addition to suppressing the expression of genes capable of inhibiting breast cancer progression. Yet, Myd88-dependent signaling in tumor cells also suppressed expression of genes that could contribute to tumor progression. Collectively, these data revealed a multifaceted role for Myd88-dependent signaling in murine mammary carcinoma. PMID:27812285

  2. 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

  3. The effect of lipocisplatin on cisplatin efficacy and nephrotoxicity in malignant breast cancer treatment.

    PubMed

    Li, Qun; Tian, Yuantong; Li, Dandi; Sun, Jianfeng; Shi, Donglei; Fang, Lin; Gao, Yong; Liu, Haiyan

    2014-08-01

    A lipid-cisplatin conjugate was synthesized for super-molecular assembly with lipids to form a new generation of liposomal cisplatin formulation, lipocisplatin. In vitro, lipocisplatin has higher efficacy in human ovarian cancer A2780 and human breast cancer MCF-7 with the murine breast cancer cell line 4T1 which is currently an established model for stage IV breast cancer as the most sensitive strain. Moreover, lipocisplatin demonstrated a greater MTD value and relatively longer blood circulation as compared to cisplatin. Lipocisplatin preferentially accumulate drugs to the tumor site, resulting in a better tumor inhibition efficacy. Moreover, lipocisplatin exceeds the size cutoff for kidney clearance, hence it bypasses the nephrotoxicity of cisplatin which is a major curse of one of the most efficient anticancer drugs nowadays in clinic. The results here indicated lipocisplatin may be translated into a new generation of liposomal based cisplatin drug in clinic.

  4. Comparison of microwave and magnetic nanoparticle hyperthermia radiosensitization in murine breast tumors

    NASA Astrophysics Data System (ADS)

    Giustini, Andrew J.; Petryk, Alicia A.; Hoopes, Paul J.

    2011-03-01

    Hyperthermia has been shown to be an effective radiosensitizer. Its utility as a clinical modality has been limited by a minimally selective tumor sensitivity and the inability to be delivered in a tumor-specific manner. Recent in vivo studies (rodent and human) have shown that cancer cell-specific cytotoxicity can be effectively and safely delivered via iron oxide magnetic nanoparticles (mNP) and an appropriately matched noninvasive alternating magnetic field (AMF). To explore the tumor radiosensitization potential of mNP hyperthermia we used a syngeneic mouse breast cancer model, dextran-coated 110 nm hydrodynamic diameter mNP and a 169 kHz / 450 Oe (35.8 kA/m) AMF. Intradermally implanted (flank) tumors (150 +/- 40 mm3) were treated by injection of 0.04 ml mNP (7.5 mg Fe) / cm3 into the tumor and an AMF (35.8 kA/m and 169 kHz) exposure necessary to achieve a CEM (cumulative equivalent minute) thermal dose of 60 (CEM 60). Tumors were treated with mNP hyperthermia (CEM 60), radiation alone (15 Gy, single dose) and in combination. Compared to the radiation and heat alone treatments, the combined treatment resulted in a greater than two-fold increase in tumor regrowth tripling time (tumor treatment efficacy). None of the treatments resulted in significant normal tissue toxicity or morbidity. Studies were also conducted to compare the radiosensitization effect of mNP hyperthermia with that of microwave-induced hyperthermia. The effects of incubation of nanoparticles within tumors (to allow nanoparticles to be endocytosed) before application of AMF and radiation were determined. This preliminary information suggests cancer cell specific hyperthermia (i.e. antibody-directed or anatomically-directed mNP) is capable of providing significantly greater radiosensitization / therapeutic ratio enhancement than other forms of hyperthermia delivery.

  5. Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression.

    PubMed

    Zhao, Yingshe; Kumbrink, Joerg; Lin, Bor-Tyh; Bouton, Amy H; Yang, Shi; Toselli, Paul A; Kirsch, Kathrin H

    2013-12-01

    Elevated expression of p130Cas (Crk-associated substrate)/BCAR1 (breast cancer antiestrogen resistance 1) in human breast tumors is a marker of poor prognosis and poor overall survival. p130Cas is a downstream target of the tyrosine kinase c-Src. Signaling mediated by p130Cas through its phosphorylated substrate domain (SD) and interaction with effector molecules directly promotes tumor progression. We previously developed a constitutively phosphorylated p130Cas SD molecule, Src*/SD (formerly referred to as Src*/CasSD), which acts as decoy molecule and attenuates the transformed phenotype in v-crk-transformed murine fibroblasts and human breast cancer cells. To test the function of this molecule in vivo, we established mouse mammary tumor virus (MMTV)-long terminal repeat-Src*/SD transgenic mice in which mammary gland development and tumor formation were analyzed. Transgenic expression of the Src*/SD molecule under the MMTV-long terminal repeat promoter did not interfere with normal mammary gland development or induce tumors in mice observed for up to 11 months. To evaluate the effects of the Src*/SD molecule on tumor development in vivo, we utilized the MMTV-polyoma middle T-antigen (PyMT) murine breast cancer model that depends on c-Src. PyMT mice crossed with Src*/SD mice displayed accelerated tumor formation. The earlier onset of tumors can be explained by the interaction of the Src* domain with PyMT and targeting the fused phosphorylated SD to the membrane. At membrane compartments, it might integrate membrane-associated active signaling complexes leading to increased proliferation measured by phospho-Histone H3 staining. Although these results were unexpected, they emphasize the importance of preventing the membrane association of Src*/SD when employed as decoy molecule.

  6. Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression

    PubMed Central

    Zhao, Yingshe; Kumbrink, Joerg; Kirsch, Kathrin H.

    2013-01-01

    Elevated expression of p130Cas (Crk-associated substrate)/BCAR1 (breast cancer antiestrogen resistance 1) in human breast tumors is a marker of poor prognosis and poor overall survival. p130Cas is a downstream target of the tyrosine kinase c-Src. Signaling mediated by p130Cas through its phosphorylated substrate domain (SD) and interaction with effector molecules directly promotes tumor progression. We previously developed a constitutively phosphorylated p130Cas SD molecule, Src*/SD (formerly referred to as Src*/CasSD), which acts as decoy molecule and attenuates the transformed phenotype in v-crk-transformed murine fibroblasts and human breast cancer cells. To test the function of this molecule in vivo, we established mouse mammary tumor virus (MMTV)-long terminal repeat-Src*/SD transgenic mice in which mammary gland development and tumor formation were analyzed. Transgenic expression of the Src*/SD molecule under the MMTV-long terminal repeat promoter did not interfere with normal mammary gland development or induce tumors in mice observed for up to 11 months. To evaluate the effects of the Src*/SD molecule on tumor development in vivo, we utilized the MMTV-polyoma middle T-antigen (PyMT) murine breast cancer model that depends on c-Src. PyMT mice crossed with Src*/SD mice displayed accelerated tumor formation. The earlier onset of tumors can be explained by the interaction of the Src* domain with PyMT and targeting the fused phosphorylated SD to the membrane. At membrane compartments, it might integrate membrane-associated active signaling complexes leading to increased proliferation measured by phospho-Histone H3 staining. Although these results were unexpected, they emphasize the importance of preventing the membrane association of Src*/SD when employed as decoy molecule. PMID:23825155

  7. Cytotoxicity and Apoptosis Induction of Ardisia crispa and Its Solvent Partitions against Mus musculus Mammary Carcinoma Cell Line (4T1)

    PubMed Central

    Nordin, Muhammad Luqman; Zakaria, Zainul Amiruddin; Othman, Fauziah; Abdullah, Muhammad Nazrul Hakim

    2017-01-01

    This study was conducted to investigate the cytotoxicity and apoptosis effect of A. crispa extract and its solvent partition (ethyl acetate and aqueous extract) against Mus musculus mammary carcinoma cell line (4T1). The normal mouse fibroblast cell line (NIH3T3) was used as comparison for selective cytotoxicity properties. The cytotoxicity evaluation was assessed using MTT assay. AO/PI dual fluorescent staining assay and Annexin V-FITC were used for apoptosis analysis. Results showed that 80% methanol extract from leaves showed most promising antimammary cancer agent with IC50 value of 42.26 ± 1.82 μg/mL and selective index (SI) value of 10.22. Ethyl acetate was cytotoxic for both cancer and normal cell while aqueous extract exhibited poor cytotoxic effect. 4T1 cells labelled with AO/PI and Annexin V-FITC and treated with 80% methanol extract demonstrated that the extract induces apoptosis to 4T1 mammary cancer cells. In conclusion, 80% methanol extract of A. crispa was selectively cytotoxic towards 4T1 cells but less cytotoxic towards NIH3T3 cells and induced the cancerous cells into apoptotic stage as early as 6 hours.

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

    PubMed

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

    2015-01-01

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

  9. Interstitial Fluid Sphingosine-1-Phosphate in Murine Mammary Gland and Cancer and Human Breast Tissue and Cancer Determined by Novel Methods.

    PubMed

    Nagahashi, Masayuki; Yamada, Akimitsu; Miyazaki, Hiroshi; Allegood, Jeremy C; Tsuchida, Junko; Aoyagi, Tomoyoshi; Huang, Wei-Ching; Terracina, Krista P; Adams, Barbara J; Rashid, Omar M; Milstien, Sheldon; Wakai, Toshifumi; Spiegel, Sarah; Takabe, Kazuaki

    2016-06-01

    The tumor microenvironment is a determining factor for cancer biology and progression. Sphingosine-1-phosphate (S1P), produced by sphingosine kinases (SphKs), is a bioactive lipid mediator that regulates processes important for cancer progression. Despite its critical roles, the levels of S1P in interstitial fluid (IF), an important component of the tumor microenvironment, have never previously been measured due to a lack of efficient methods for collecting and quantifying IF. The purpose of this study is to clarify the levels of S1P in the IF from murine mammary glands and its tumors utilizing our novel methods. We developed an improved centrifugation method to collect IF. Sphingolipids in IF, blood, and tissue samples were measured by mass spectrometry. In mice with a deletion of SphK1, but not SphK2, levels of S1P in IF from the mammary glands were greatly attenuated. Levels of S1P in IF from mammary tumors were reduced when tumor growth was suppressed by oral administration of FTY720/fingolimod. Importantly, sphingosine, dihydro-sphingosine, and S1P levels, but not dihydro-S1P, were significantly higher in human breast tumor tissue IF than in the normal breast tissue IF. To our knowledge, this is the first reported S1P IF measurement in murine normal mammary glands and mammary tumors, as well as in human patients with breast cancer. S1P tumor IF measurement illuminates new aspects of the role of S1P in the tumor microenvironment.

  10. Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after IV administration

    PubMed Central

    Wakaskar, Rajesh R.; Bathena, Sai Praneeth R.; Tallapaka, Shailendra; Ambardekar, Vishakha V.; Gautum, Nagsen; Thakare, Rhishikesh N.; Simet, Samantha M.; Curran, Stephen M.; Singh, Rakesh K.; Dong, Yuxiang

    2014-01-01

    Purpose Determine the feasibility and potential benefit of peripherally cross-linking the shell of core-shell polymer micelles on the premature release of physically loaded hydrophobic drug in whole blood and subsequent potency against solid tumors. Methods Individual Pluronic F127 polymer micelles (F127 PM) peripherally cross-linked with ethylenediamine at 76% of total PEO blocks (X-F127 PM) were physically loaded with combretastatin A4 (CA4) by the solid dispersion method and compared to CA4 physically loaded in uncross-linked F127 PM, CA4 in DMSO in vitro, or water-soluble CA4 phosphate (CA4P) in vivo. Results X-F127 PM had similar CA4 loading and aqueous solubility as F127 PM up to 10 mg CA4 / mL at 22.9 wt% and did not aggregate in PBS or 90% (v/v) human serum at 37°C for at least 24 h. In contrast, X-F127 PM decreased the unbound fraction of CA4 in whole blood (fu) and increased the mean plasma residence time and subsequent potency of CA4 against the vascular function and growth of primary murine 4T1 breast tumors over CA4 in F127 PM and water-soluble CA4P after IV administration. Conclusions Given that decreasing the fu is an indication of decreased drug release, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded hydrophobic drug in the blood and increase subsequent potency in solid tumors. PMID:25223962

  11. Quantitative [18F]-FMISO- PET imaging shows reduction of hypoxia following trastuzumab in a murine model of HER2+ breast cancer

    PubMed Central

    Sorace, Anna G.; Syed, Anum K.; Barnes, Stephanie L.; Quarles, C. Chad; Sanchez, Violeta; Kang, Hakmook; Yankeelov, Thomas E.

    2016-01-01

    Purpose Evaluation of [18F]-FMISO-PET imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer. Procedures Mice with BT474, HER2+ tumors, were imaged with [18F]-FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging. Results [18F]-FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P < 0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P < 0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r2=0.85). Conclusions [18F]-FMISO-PET is a clinically relevant modality which provides the opportunity to 1) predict response to HER2+ therapy before changes in tumor size, and 2) identify decreases hypoxia which has the potential to guide subsequent therapy. PMID:27506906

  12. 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.

  13. Disrupting Na⁺, HCO₃⁻-cotransporter NBCn1 (Slc4a7) delays murine breast cancer development.

    PubMed

    Lee, S; Axelsen, T V; Andersen, A P; Vahl, P; Pedersen, S F; Boedtkjer, E

    2016-04-21

    Increased metabolism and insufficient blood supply cause acidic waste product accumulation in solid cancers. During carcinogenesis, cellular acid extrusion is upregulated but the underlying molecular mechanisms and their consequences for cancer growth and progression have not been established. Genome-wide association studies have indicated a possible link between the Na⁺, HCO₃⁻-cotransporter NBCn1 (SLC4A7) and breast cancer. We tested the functional consequences of NBCn1 knockout (KO) for breast cancer development. NBCn1 protein expression increased 2.5-fold during breast carcinogenesis and was responsible for the increased net acid extrusion and alkaline intracellular pH of breast cancer compared with normal breast tissue. Genetic disruption of NBCn1 delayed breast cancer development: tumor latency was ~50% increased while tumor growth rate was ~65% reduced in NBCn1 KO compared with wild-type (WT) mice. Breast cancer histopathology in NBCn1 KO mice differed from that in WT mice and included less aggressive tumor types. The extracellular tumor microenvironment in NBCn1 KO mice contained higher concentrations of glucose and lower concentrations of lactate than that in WT mice. Independently of NBCn1 genotype, the cleaved fraction of poly(ADP-ribose) polymerase (PARP)-1 and expression of monocarboxylate transporter (MCT)1 increased while phosphorylation of Akt and ERK1 decreased as functions of tumor volume. Cell proliferation, evaluated from Ki-67 and phospho-histone H₃staining, was ~60% lower in breast cancer of NBCn1 KO than that of WT mice when corrected for variations in tumor size. We conclude that NBCn1 facilitates acid extrusion from breast cancer tissue, maintains the alkaline intracellular environment and promotes aggressive cancer development and growth.

  14. Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results.

    PubMed

    Sorace, Anna G; Quarles, C Chad; Whisenant, Jennifer G; Hanker, Ariella B; McIntyre, J Oliver; Sanchez, Violeta M; Yankeelov, Thomas E

    2016-01-01

    To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter K (trans) ) and the extravascular extracellular volume fraction (v e ) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in K (trans) (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in v e (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically available imaging

  15. Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results

    PubMed Central

    Quarles, C. Chad; Whisenant, Jennifer G.; Hanker, Ariella B.; McIntyre, J. Oliver; Sanchez, Violeta M.; Yankeelov, Thomas E.

    2016-01-01

    To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter Ktrans) and the extravascular extracellular volume fraction (ve) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in Ktrans (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in ve (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically available imaging method

  16. RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation

    PubMed Central

    Leung, Hoi-Wing; Zhao, Si-Meng; Yue, Grace Gar-Lee; Lee, Julia Kin-Ming; Fung, Kwok-Pui; Leung, Ping-Chung; Tan, Ning-Hua; Lau, Clara Bik-San

    2015-01-01

    Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer. PMID:26592552

  17. TGFβ1 Inhibition Increases the Radiosensitivity of Breast Cancer Cells In Vitro and Promotes Tumor Control by Radiation In Vivo

    PubMed Central

    Bouquet, Fanny; Pal, Anupama; Pilones, Karsten A.; Demaria, Sandra; Hann, Byron; Akhurst, Rosemary J.; Babb, Jim S.; Lonning, Scott M.; DeWyngaert, J. Keith; Formenti, Silvia C.; Barcellos-Hoff, Mary Helen

    2013-01-01

    Purpose To determine whether inhibition of TGFβ signaling prior to irradiation sensitizes human and murine cancer cells in vitro and in vivo. Experimental Design TGFβ-mediated growth and Smad phosphorylation of MCF7, Hs578T, MDA-MB-231, and T47D human breast cancer cell lines were examined and correlated with clonogenic survival following graded radiation doses with and without pretreatment with LY364947, a small molecule inhibitor of the TGFβ type I receptor kinase. The DNA damage response was assessed in irradiated MDA-MB-231 cells pretreated with LY364947 in vitro and LY2109761, a pharmacokinetically stable inhibitor of TGFβ signaling, in vivo. The in vitro response of a syngeneic murine tumor, 4T1, was tested using a TGFβ neutralizing antibody, 1D11, with single or fractionated radiation doses in vivo. Results Human breast cancer cell lines pretreated with TGFβ small molecule inhibitor were radio-sensitized, irrespective of sensitivity to TGFβ growth inhibition. Consistent with increased clonogenic cell death, radiation-induced phosphorylation of H2AX and p53 was significantly reduced in MDA-MB-231 triple-negative breast cancer cells when pretreated in vitro or in vivo with a TGFfS type I receptor kinase inhibitor. Moreover, TGFβ neutralizing antibodies increased radiation sensitivity, blocked γH2AX foci formation, and significantly increased tumor growth delay in 4T1 murine mammary tumors in response to single and fractionated radiation exposures. Conclusion These results show that TGFβ inhibition prior to radiation attenuated DNA damage responses, increased clonogenic cell death, and promoted tumor growth delay, and thus may be an effective adjunct in cancer radiotherapy. PMID:22028490

  18. Targeting Stat3 induces senescence in tumor cells and elicits prophylactic and therapeutic immune responses against breast cancer growth mediated by NK cells and CD4+ T cells.

    PubMed

    Tkach, Mercedes; Coria, Lorena; Rosemblit, Cinthia; Rivas, Martín A; Proietti, Cecilia J; Díaz Flaqué, María Celeste; Beguelin, Wendy; Frahm, Isabel; Charreau, Eduardo H; Cassataro, Juliana; Elizalde, Patricia V; Schillaci, Roxana

    2012-08-01

    Aberrant Stat3 activation and signaling contribute to malignant transformation by promoting cell cycle progression, inhibiting apoptosis, and mediating tumor immune evasion. Stat3 inhibition in tumor cells induces the expression of chemokines and proinflammatory cytokines, so we proposed to apply Stat3-inhibited breast cancer cells as a source of immunogens to induce an antitumor immune response. Studies were performed in two murine breast cancer models in which Stat3 is activated: progestin-dependent C4HD cells and 4T1 cells. We immunized BALB/c mice with irradiated cancer cells previously transfected with a dominant-negative Stat3 vector (Stat3Y705F) in either a prophylactic or a therapeutic manner. Prophylactic administration of breast cancer cells transfected with Stat3Y705F (Stat3Y705F-breast cancer cells) inhibited primary tumor growth compared with administration of empty vector-transfected cells in both models. In the 4T1 model, 50% of the challenged mice were tumor free, and the incidence of metastasis decreased by 90%. In vivo assays of C4HD tumors showed that the antitumor immune response involves the participation of CD4(+) T cells and cytotoxic NK cells. Therapeutic immunization with Stat3Y705F-breast cancer cells inhibited tumor growth, promoted tumor cell differentiation, and decreased metastasis. Furthermore, inhibition of Stat3 activation in breast cancer cells induced cellular senescence, contributing to their immunogenic phenotype. In this work, we provide preclinical proof of concept that ablating Stat3 signaling in breast cancer cells results in an effective immunotherapy against breast cancer growth and metastasis. Moreover, our findings showing that Stat3 inactivation results in induction of a cellular senescence program disclose a potential mechanism for immunotherapy research.

  19. CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome

    PubMed Central

    Zhang, Qunyuan; Ye, Jian; Wang, Fang; Zhang, Yanping; Hunborg, Pamela; Varvares, Mark A.; Hoft, Daniel F.; Hsueh, Eddy C.; Peng, Guangyong

    2015-01-01

    The Cancer Immunoediting concept has provided critical insights suggesting dual functions of immune system during the cancer initiation and development. However, the dynamics and roles of CD4+ and CD8+ T cells in the pathogenesis of breast cancer remain unclear. Here we utilized two murine breast cancer models (4T1 and E0771) and demonstrated that both CD4+ and CD8+ T cells were increased and involved in immune responses, but with distinct dynamic trends in breast cancer development. In addition to cell number increases, CD4+ T cells changed their dominant subsets from Th1 in the early stages to Treg and Th17 cells in the late stages of the cancer progression. We also analyzed CD4+ and CD8+ T cell infiltration in primary breast cancer tissues from cancer patients. We observed that CD8+ T cells are the key effector cell population mediating effective anti-tumor immunity resulting in better clinical outcomes. In contrast, intra-tumoral CD4+ T cells have negative prognostic effects on breast cancer patient outcomes. These studies indicate that CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcomes, which provides new insights relevant for the development of effective cancer immunotherapeutic approaches. PMID:25968569

  20. In vivo visualization and ex vivo quantification of murine breast cancer cells in the mouse brain using MRI cell tracking and electron paramagnetic resonance.

    PubMed

    Danhier, Pierre; Magat, Julie; Levêque, Philippe; De Preter, Géraldine; Porporato, Paolo E; Bouzin, Caroline; Jordan, Bénédicte F; Demeur, Gladys; Haufroid, Vincent; Feron, Olivier; Sonveaux, Pierre; Gallez, Bernard

    2015-03-01

    Cell tracking could be useful to elucidate fundamental processes of cancer biology such as metastasis. The aim of this study was to visualize, using MRI, and to quantify, using electron paramagnetic resonance (EPR), the entrapment of murine breast cancer cells labeled with superparamagnetic iron oxide particles (SPIOs) in the mouse brain after intracardiac injection. For this purpose, luciferase-expressing murine 4 T1-luc breast cancer cells were labeled with fluorescent Molday ION Rhodamine B SPIOs. Following intracardiac injection, SPIO-labeled 4 T1-luc cells were imaged using multiple gradient-echo sequences. Ex vivo iron oxide quantification in the mouse brain was performed using EPR (9 GHz). The long-term fate of 4 T1-luc cells after injection was characterized using bioluminescence imaging (BLI), brain MRI and immunofluorescence. We observed hypointense spots due to SPIO-labeled cells in the mouse brain 4 h after injection on T2 *-weighted images. Histology studies showed that SPIO-labeled cancer cells were localized within blood vessels shortly after delivery. Ex vivo quantification of SPIOs showed that less than 1% of the injected cells were taken up by the mouse brain after injection. MRI experiments did not reveal the development of macrometastases in the mouse brain several days after injection, but immunofluorescence studies demonstrated that these cells found in the brain established micrometastases. Concerning the metastatic patterns of 4 T1-luc cells, an EPR biodistribution study demonstrated that SPIO-labeled 4 T1-luc cells were also entrapped in the lungs of mice after intracardiac injection. BLI performed 6 days after injection of 4 T1-luc cells showed that this cell line formed macrometastases in the lungs and in the bones. Conclusively, EPR and MRI were found to be complementary for cell tracking applications. MRI cell tracking at 11.7 T allowed sensitive detection of isolated SPIO-labeled cells in the mouse brain, whereas EPR

  1. 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.

  2. The CC chemokine CK beta-11/MIP-3 beta/ELC/Exodus 3 mediates tumor rejection of murine breast cancer cells through NK cells.

    PubMed

    Braun, S E; Chen, K; Foster, R G; Kim, C H; Hromas, R; Kaplan, M H; Broxmeyer, H E; Cornetta, K

    2000-04-15

    CK beta-11 chemoattracts T cells, B cells, dendritic cells, macrophage progenitors, and NK cells and facilitates dendritic cell and T cell interactions in secondary lymphoid tissues. We hypothesized that expression of CK beta-11 in tumor cells may generate antitumor immunity through these interactions. After transduction with the retroviral vector L(CK beta 11)SN, the murine breast cancer cell line C3L5 (C3L5-CK beta 11) showed expression of retroviral mRNA by Northern analysis and production of functional CK beta-11 by chemotaxis of human NK cells to C3L5-CK beta 11 supernatant. Only 10% of mice injected with C3L5-CK beta 11 developed tumors, compared with 100% of mice injected with a transduced control C3L5 line (C3L5-G1N). Importantly, the in vitro growth characteristics of the CK beta-11-transduced cell line were unaffected, suggesting the difference in growth in vivo was a result of chemokine production. Vaccination with C3L5-CK beta 11 partially protected animals from parental C3L5 challenge. Immunodepletion with anti-asialo-GM1 or anti-CD4 during C3L5-CK beta 11 vaccination significantly reduced CK beta-11 antitumor activity compared with control and anti-CD8-treated groups. Splenocytes from NK-depleted animals transferred the acquired immunity generated with C3L5-CK beta 11 vaccination, while splenocytes from the CD4-depleted animals did not. These results indicate, for the first time, that expression of CK beta-11 in a breast cancer cell line mediates rejection of the transduced tumor through a mechanism involving NK and CD4+ cells. Furthermore, CK beta-11-transduced tumor cells generate long-term antitumor immunity that requires CD4+ cells. These studies demonstrate the potential role of CK beta-11 as an adjuvant in stimulating antitumor responses.

  3. CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model.

    PubMed

    Oghumu, Steve; Varikuti, Sanjay; Terrazas, Cesar; Kotov, Dmitri; Nasser, Mohd W; Powell, Catherine A; Ganju, Ramesh K; Satoskar, Abhay R

    2014-09-01

    Tumor associated macrophages play a vital role in determining the outcome of breast cancer. We investigated the contribution of the chemokine receptor CXCR3 to antitumor immune responses using a cxcr3 deficient mouse orthotopically injected with a PyMT breast cancer cell line. We observed that cxcr3 deficient mice displayed increased IL-4 production and M2 polarization in the tumors and spleens compared to WT mice injected with PyMT cells. This was accompanied by larger tumor development in cxcr3(-/-) than in WT mice. Further, tumor-promoting myeloid derived immune cell populations accumulated in higher proportions in the spleens of cxcr3 deficient mice. Interestingly, cxcr3(-/-) macrophages displayed a deficiency in up-regulating inducible nitric oxide synthase after stimulation by either IFN-γ or PyMT supernatants. Stimulation of bone marrow derived macrophages by PyMT supernatants also resulted in greater induction of arginase-1 in cxcr3(-/-) than WT mice. Further, cxcr3(-/-) T cells activated with CD3/CD28 in vitro produced greater amounts of IL-4 and IL-10 than T cells from WT mice. Our data suggests that a greater predisposition of cxcr3 deficient macrophages towards M2 polarization contributes to an enhanced tumor promoting environment in cxcr3 deficient mice. Although CXCR3 is known to be expressed on some macrophages, this is the first report that demonstrates a role for CXCR3 in macrophage polarization and subsequent breast tumor outcomes. Targeting CXCR3 could be a potential therapeutic approach in the management of breast cancer tumors.

  4. Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro.

    PubMed

    Wang, Hai-Fang; Ning, Fen; Liu, Zong-Cai; Wu, Long; Li, Zi-Qian; Qi, Yi-Fei; Zhang, Ge; Wang, Hong-Sheng; Cai, Shao-Hui; Du, Jun

    2017-03-01

    Myeloid-derived suppressor cells (MDSC) have been identified as a population of immature myeloid cells that suppress anti-tumor immunity. MDSC are increased in tumor-bearing hosts; thus, depletion of MDSC may enhance anti-tumor immunity. Histone deacetylase inhibitors (HDACi) are chemical agents that are primarily used against hematologic malignancies. The ability of these agents to modulate anticancer immunity has recently been extensively studied. However, the effect of HDACi on MDSC has remained largely unexplored. In the present study, we provide the first demonstration that HDACi treatment decreases MDSC accumulation in the spleen, blood and tumor bed but increases the proportion of T cells (particularly the frequency of IFN-γ- or perforin-producing CD8(+) T cells) in BALB/C mice with 4T1 mammary tumors. In addition, HDACi exposure of bone marrow (BM) cells significantly eliminated the MDSC population induced by GM-CSF or the tumor burden in vitro, which was further demonstrated as functionally important to relieve the inhibitory effect of MDSC-enriched BM cells on T cell proliferation. Mechanistically, HDACi increased the apoptosis of Gr-1(+) cells (almost MDSC) compared with that of Gr-1(-) cells, which was abrogated by the ROS scavenger N-acetylcysteine, suggesting that the HDACi-induced increase in MDSC apoptosis due to increased intracellular ROS might partially account for the observed depletion of MDSC. These findings suggest that the elimination of MDSC using an HDACi may contribute to the overall anti-tumor properties of these agents, highlighting a novel property of HDACi as potent MDSC-targeting agents, which may be used to enhance the efficacy of immunotherapeutic regimens.

  5. Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer.

    PubMed

    Karginova, Olga; Siegel, Marni B; Van Swearingen, Amanda E D; Deal, Allison M; Adamo, Barbara; Sambade, Maria J; Bazyar, Soha; Nikolaishvili-Feinberg, Nana; Bash, Ryan; O'Neal, Sara; Sandison, Katie; Parker, Joel S; Santos, Charlene; Darr, David; Zamboni, William; Lee, Yueh Z; Miller, C Ryan; Anders, Carey K

    2015-04-01

    Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapeutics. Triple-negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis. TNBC frequently harbors BRCA mutations translating to platinum sensitivity potentially augmented by additional suppression of DNA repair mechanisms through PARP inhibition. We evaluated brain penetrance and efficacy of carboplatin ± the PARP inhibitor ABT888, and investigated gene-expression changes in murine intracranial TNBC models stratified by BRCA and molecular subtype status. Athymic mice were inoculated intracerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low); or BRCA-wild-type (wt): MDA-MB-468 (basal), MDA-MB-231BR (claudin-low). TNBC cells were treated with PBS control [intraperitoneal (IP), weekly], carboplatin (50 mg/kg/wk, IP), ABT888 (25 mg/kg/d, oral gavage), or their combination. DNA damage (γ-H2AX), apoptosis (cleaved caspase-3, cC3), and gene expression were measured in intracranial tumors. Carboplatin ± ABT888 significantly improved survival in BRCA-mutant intracranial models compared with control, but did not improve survival in BRCA-wt intracranial models. Carboplatin + ABT888 revealed a modest survival advantage versus carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436, but not in the SUM149 model. BRCA-mutant SUM149 expression of γ-H2AX and cC3 proteins was elevated in all treatment groups compared with control, whereas BRCA-wt MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene-expression changes in BRCA-mutant models. Carboplatin ± ABT888 penetrates the brain and improves survival in BRCA-mutant intracranial TNBC models with corresponding DNA damage and gene-expression changes. Combination therapy represents a potential promising treatment strategy for patients with TNBC brain metastases warranting further

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

    PubMed Central

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

    2016-01-01

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

  7. A Novel Gene Gun-Mediated IL-12 Gene Therapy for Breast Cancer

    DTIC Science & Technology

    1997-10-01

    immunogenic 4T1 tumor, primary tumor growth was not affected by IL-12 gene therapy , although lung metastasis was significantly reduced. The anti...metastatically effect in the 4T1 model appears to be T cell independent, and we are investigating its mechanism. These results suggest that a similar gene therapy protocol may be useful in human breast cancer treatment.

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

    PubMed

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

    2017-02-15

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

  9. Quantifying shape changes of silicone breast implants in a murine model using in vivo micro-CT.

    PubMed

    Anderson, Emily E; Perilli, Egon; Carati, Colin J; Reynolds, Karen J

    2016-04-18

    A major complication of silicone breast implants is the formation of a capsule around the implant known as capsular contracture which results in the distortion of the implant. Recently, a mouse model for studying capsular contracture was examined using micro-computed tomography (micro-CT), however, only qualitative changes were reported. The aim of this study was to develop a quantitative method for comparing the shape changes of silicone implants using in vivo micro-CT. Mice were bilaterally implanted with silicone implants and underwent ionizing radiation to induce capsular contracture. On day 28 post-surgery mice were examined in vivo using micro-CT. The reconstructed cross-section images were visually inspected to identify distortion. Measurements were taken in 2D and 3D to quantify the shape of the implants in the normal (n = 11) and distorted (n = 5) groups. The degree of anisotropy was significantly higher in the distorted implants in the transaxial view (0.99 vs. 1.19, p = 0.002) and the y-axis lengths were significantly shorter in the sagittal (9.27 mm vs. 8.55 mm, p = 0.015) and coronal (9.24 mm vs. 8.76 mm, p = 0.031) views, indicating a deviation from the circular cross-section and shortening of the long axis. The 3D analysis revealed a significantly lower average thickness (sphere-fitting method) in distorted implants (6.86 mm vs. 5.49 mm, p = 0.002), whereas the volume and surface area did not show significant changes. Statistically significant differences between normal and distorted implants were found in 2D and 3D using distance measurements performed via micro-CT. This objective analysis method can be useful for a range of studies involving deformable implants using in vivo micro-CT. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2016.

  10. Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumour actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis.

    PubMed

    Zheng, Yu; Zhou, Hong; Brennan, Karen; Blair, Julie M; Modzelewski, James R K; Seibel, Markus J; Dunstan, Colin R

    2007-02-01

    Inhibition of bone resorption either by bisphosphonate (BP) treatment or by blocking RANKL signalling with osteoprotegerin (OPG) has been shown to reduce tumour burden in bone and inhibit bone destruction in murine xenograft models of breast cancer. However, whether the anti-tumour effect of OPG or BP in bone is mediated by inhibition of bone resorption or by direct effects on tumour cells is uncertain. The current study is designed to investigate anti-tumour effects of OPG and ibandronate (IBN), dosed alone or in combination, on tumour growth to determine if there is experimental support for combination treatments and to provide evidence for the presence of direct anti-tumour effects. To this aim, 10 microl (5 x 10(6) cells/ml) of the bone-seeking MDA-MB-231 (Tx-SA) cell line was injected intra-tibially into nude mice. After 10 days, when the tumours were evident radiologically, mice were treated with vehicle, OPG (1 mg/kg/day), ibandronate (IBN) (160 microg/kg/day) or IBN and OPG at the same doses (IBN+OPG) for a week, and the effects of each treatment on lytic lesions, tumour cell growth, cell apoptosis and proliferation were measured by radiography, immunohistochemistry and histomorphometry. Compared to vehicle controls, in vivo treatment with OPG, IBN, or IBN+OPG, each prevented the expansion of osteolytic bone lesions (increase in lytic lesion area day 10 to day 17: OPG -3.2%, IBN 6.6%, IBN+OPG 3.6%, Vehicle 232.5%; p<0.01). Treatment with OPG, IBN or IBN+OPG each produced similar reductions in tumour area relative to vehicle-treated mice (OPG 52%, IBN 54%, IBNp and OPG 48%, p<0.01 vs. vehicle) OPG and IBN alone and in combination each produced a similar increase in cancer cell apoptosis (OPG 330%, IBN 342%, IBN and OPG 347%, p<0.01 vs. vehicle) and a decrease in cancer cell proliferation (OPG 59%, IBN 62%, IBN and OPG 58%, p<0.05 vs. vehicle). Our findings indicate that (i) combined treatment with OPG and a bisphosphonate is not significantly more effective

  11. Pre-osteoblastic MC3T3-E1 promote breast cancer cell growth in bone in a murine xenograft model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The bones are the most common sites of breast cancer metastasis. Upon arrival within the bone microenvironment, breast cancer cells coordinate the activities of stromal cells, resulting in an increase in osteoclast activity and bone matrix degradation. In late stages of bone metastasis, breast cance...

  12. Interleukin-7 enhances the in vivo anti-tumor activity of tumor-reactive CD8+ T cells with induction of IFN-gamma in a murine breast cancer model.

    PubMed

    Yuan, Chun-Hui; Yang, Xue-Qin; Zhu, Cheng-Liang; Liu, Shao-Ping; Wang, Bi-Cheng; Wang, Fu-Bing

    2014-01-01

    Interleukin-7 (IL-7) is a potent anti-apoptotic cytokine that enhances immune effector cell functions and is essential for lymphocyte survival. While it known to induce differentiation and proliferation in some haematological malignancies, including certain types of leukaemias and lymphomas, little is known about its role in solid tumours, including breast cancer. In the current study, we investigated whether IL-7 could enhance the in vivo antitumor activity of tumor-reactive CD8+ T cells with induction of IFN-γ in a murine breast cancer model. Human IL-7 cDNA was constructed into the eukaryotic expression plasmid pcDNA3.1, and then the recombinational pcDNA3.1-IL-7 was intratumorally injected in the TM40D BALB/C mouse graft model. Serum and intracellular IFN-γ levels were measured by ELISA and flow cytometry, respectively. CD8+ T cell-mediated cytotoxicity was analyzed using the MTT method. Our results showed that IL-7 administration significantly inhibited tumor growth from day 15 after direct intratumoral injection of pcDNA3.1-IL-7. The anti-tumor effect correlated with a marked increase in the level of IFN-γ and breast cancer cells-specific CTL cytotoxicity. In vitro cytotoxicity assays showed that IL-7-treatment could augment cytolytic activity of CD8+ T cells from tumor bearing mice, while anti-IFN-γ blocked the function of CD8+ T cells, suggesting that IFN-γ mediated the cytolytic activity of CD8+ T cells. Furthermore, in vivo neutralization of CD8+ T lymphocytes by CD8 antibodies reversed the antitumor benefit of IL-7. Thus, we demonstrated that IL-7 exerts anti-tumor activity mainly through activating CD8+ T cells and stimulating them to secrete IFN-γ in a murine breast tumor model. Based on these results, our study points to a potential novel way to treat breast cancer and may have important implications for clinical immunotherapy.

  13. Hypoxia pathway and hypoxia-mediated extensive extramedullary hematopoiesis are involved in ursolic acid's anti-metastatic effect in 4T1 tumor bearing mice

    PubMed Central

    Gao, Jian-Li; Shui, Yan-Mei; Jiang, Wei; Huang, En-Yi; Shou, Qi-Yang; Ji, Xin; He, Bai-Cheng; Lv, Gui-Yuan; He, Tong-Chuan

    2016-01-01

    Hypoxic in the tumor mass is leading to the myeloproliferative-like disease (leukemoid reaction) and anemia of body, which characterized by strong extensive extramedullary hematopoiesis (EMH) in spleen. As the key transcription factor of hypoxia, hypoxia-inducible factor-1 (HIF-1) activates the expression of genes essential for EMH processes including enhanced blood cell production and angiogenesis. We found ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, inhibited growth of breast cancer both in vivo and in vitro. The suppression was mediated through the inhibition of multiple cell pathways linked to inflammation, proliferation, angiogenesis, and metastasis. UA also suppressed the leukemoid reaction and the EMH phenomenon of the tumor bearing mice without any significant suppression on body weight (i.p. by 20 mg/kg for 28 days). This is associated with the significant decrease in white blood cells (WBC), platelets (PLT) and spleen weight. During this process, we also detected the down-regulation of cell proliferative genes (PCNA, and β-catenin), and metastatic genes (VEGF, and HIF-1α), as well as the depression of nuclear protein intensity of HIF-1α. Furthermore, the expression of E2F1, p53 and MDM2 genes were increased in UA group when the VEGF and HIF-1α was over-expressed. Cancer cells were sensitive to UA treating after the silencing of HIF-1α and the response of Hypoxic pathway reporter to UA was suppressed when HIF-1α was over expressed. Overall, our results from experimental and predictive studies suggest that the anticancer activity of UA may be at least in part caused by suppressing the cancer hypoxia and hypoxia-mediated EMH. PMID:27708244

  14. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice.

    PubMed

    Le, Hanh K; Graham, Laura; Cha, Esther; Morales, Johanna K; Manjili, Masoud H; Bear, Harry D

    2009-07-01

    Myeloid derived suppressor cells (MDSCs) accumulate in 4T1 mammary carcinoma bearing mice and present a barrier to the success of adoptive immunotherapy (AIT) by suppressing T cell immunity. In this study, we investigated the inhibition of MDSCs by gemcitabine (GEM), a chemotherapy agent that may have favorable immunologic effects. BALB/c mice were inoculated with 4T1 mammary carcinoma cells and treated with GEM either once a week starting 5 days after tumor inoculation (EARLY GEM) or as a single dose at days 20-25 (LATE GEM). Splenic mononuclear cells were isolated, activated in vitro, expanded, and stimulated with tumor antigen. T cells were then used for AIT to treat tumor-bearing mice. EARLY GEM treatment of 4T1 tumor-bearing mice significantly inhibited tumor growth, reduced splenomegaly, and significantly decreased MDSC proportion in the spleen. Support for a direct effect was demonstrated through suppression of MDSCs in spleens, bone marrow, and blood harvested 24 and 48 h after LATE GEM treatment, despite no significant decrease in tumor burden. Interestingly, treatment of tumor-bearing mice with GEM augmented in vitro expansion of splenic T cells and boosted IFN-gamma secretion in response to stimulation by tumor antigen. However, despite GEM-mediated inhibition of MDSC suppression, splenic T cells from mice with advanced tumors were ineffective in vivo against established tumors. This study provides support for direct inhibition of MDSCs and direct reduction of tumor burden by GEM in 4T1 tumor-bearing mice. GEM treatment of mice with advanced tumors improves T cell function and growth in vitro.

  15. Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1–AKT interaction

    SciTech Connect

    Fang, Xian-Ying; Chen, Wei; Fan, Jun-Ting; Song, Ran; Wang, Lu; Gu, Yan-Hong; Zeng, Guang-Zhi; Shen, Yan; Wu, Xue-Feng; Tan, Ning-Hua; Xu, Qiang; Sun, Yang

    2013-02-15

    In the present paper, we examined the effects of a natural cyclopeptide RA-V on human breast cancer cells and the underlying mechanisms. RA-V significantly inhibited the growth of human breast cancer MCF-7, MDA-MB-231 cells and murine breast cancer 4T1 cells. In addition, RA-V triggered mitochondrial apoptotic pathway which was indicated by the loss of mitochondrial membrane potential, the release of cytochrome c, and the activation of caspase cascade. Further study showed that RA-V dramatically inhibited phosphorylation of AKT and 3-phosphoinositide dependent protein kinase 1 (PDK1) in MCF-7 cells. Moreover, RA-V disrupted the interaction between PDK1 and AKT in MCF-7 cells. Furthermore, RA-V-induced apoptosis could be enhanced by phosphatidylinositol 3-kinase inhibitor or attenuated by over-expression of AKT in all the three kinds of breast cancer cells. Taken together, this study shows that RA-V, which can induce mitochondria-mediated apoptosis, exerts strong anti-tumor activity against human breast cancer. The underlying anti-cancer mechanism of RA-V is related to the blockage of the interaction between PDK1 and AKT. - Highlights: ► Plant cyclopeptide RA-V kills human breast cancer cells. ► RA-V triggered mitochondrial apoptotic pathway in human breast cancer cells. ► RA-V inhibited phosphorylation of AKT and PDK1 in breast cancer MCF-7 cells. ► Its mechanism is related to the blockage of the interaction between PDK1 and AKT.

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

    PubMed Central

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

    2013-01-01

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

  17. Murine Typhus

    PubMed Central

    Dzul-Rosado, Karla R; Zavala Velázquez, Jorge Ernesto; Zavala-Castro, Jorge

    2012-01-01

    Rickettsia typhi: is an intracellular bacteria who causes murine typhus. His importance is reflected in the high frequency founding specific antibodies against Rickettsia typhi in several worldwide seroepidemiological studies, the seroprevalence ranging between 3-36%. Natural reservoirs of R. typhi are rats (some species belonging the Rattus Genus) and fleas (Xenopsylla cheopis) are his vector. This infection is associated with overcrowding, pollution and poor hygiene. Typically presents fever, headache, rash on trunk and extremities, in some cases may occur organ-specific complications, affecting liver, kidney, lung or brain. Initially the disease is very similar to other diseases, is very common to confuse the murine typhus with Dengue fever, therefore, ignorance of the disease is a factor related to complications or non-specific treatments for the resolution of this infection. This paper presents the most relevant information to consider about the rickettsiosis caused by Rickettsia typhi. PMID:24893060

  18. Improved drug delivery and therapeutic efficacy of PEgylated liposomal doxorubicin by targeting anti-HER2 peptide in murine breast tumor model.

    PubMed

    Zahmatkeshan, Masoumeh; Gheybi, Fatemeh; Rezayat, Seyed Mahdi; Jaafari, Mahmoud Reza

    2016-04-30

    Targeted cancer therapy is a powerful therapeutic strategy to management of cancer. HER2 as an anticancer target has long been studied. Its overexpression plays an important role in the pathogenesis and progressiveness of breast and other cancers. To establish efficient and reliable drug delivery to HER2-overexpressing cells, the authors of this study have developed anti-HER2 (ErbB2) peptide-liposomal formulations of doxorubicin (DOX) by an engineered breast tumor-targeting peptide ligand, AHNP, Anti-HER2/neu peptide, (FCDGFYACYADV) with three glycine amino acids as spacer before its original sequencing. Towards this goal, PEGylated liposome doxorubicin (PLD) bearing different ligand densities of AHNP was prepared and characterized for their size, zeta potential and peptide conjugation. The AHNP functionalization and density effects on breast tumor cell uptake, selective cytotoxicity, prevention of tumor growth and the tissue biodistribution of encapsulated DOX were studied in mice bearing TUBO breast cancer tumor model. The findings demonstrated that increasing the ligand density of AHNP increases cytotoxicity and cell-uptake in SKBR3 and TUBO cells which overexpress HER2 but not in MDA-MB-231with low HER2 expression profile. The anticancer activity was also superior for targeted liposomal DOX with more AHNP densities. Overall, the results showed that optimum AHNP density functionalization of PLD can significantly improve selectivity and the therapeutic index of liposomal DOX in the treatment of HER2 positive breast cancer and merits further investigation.

  19. β-Bisabolene, a Sesquiterpene from the Essential Oil Extract of Opoponax (Commiphora guidottii), Exhibits Cytotoxicity in Breast Cancer Cell Lines.

    PubMed

    Yeo, Syn Kok; Ali, Ahmed Y; Hayward, Olivia A; Turnham, Daniel; Jackson, Troy; Bowen, Ifor D; Clarkson, Richard

    2016-03-01

    The essential oils from Commiphora species have for centuries been recognized to possess medicinal properties. Here, we performed gas chromatography-mass spectrometry on the essential oil from opoponax (Commiphora guidotti) and identified bisabolene isomers as the main constituents of this essential oil. Opoponax essential oil, a chemical component; β-bisabolene and an alcoholic analogue, α-bisabolol, were tested for their ability to selectively kill breast cancer cells. Only β-bisabolene, a sesquiterpene constituting 5% of the essential oil, exhibited selective cytotoxic activity for mouse cells (IC50 in normal Eph4: >200 µg/ml, MG1361: 65.49 µg/ml, 4T1: 48.99 µg/ml) and human breast cancer cells (IC50 in normal MCF-10A: 114.3 µg/ml, MCF-7: 66.91 µg/ml, MDA-MB-231: 98.39 µg/ml, SKBR3: 70.62 µg/ml and BT474: 74.3 µg/ml). This loss of viability was because of the induction of apoptosis as shown by Annexin V-propidium iodide and caspase-3/7 activity assay. β-bisabolene was also effective in reducing the growth of transplanted 4T1 mammary tumours in vivo (37.5% reduction in volume by endpoint). In summary, we have identified an anti-cancer agent from the essential oil of opoponax that exhibits specific cytotoxicity to both human and murine mammary tumour cells in vitro and in vivo, and this warrants further investigation into the use of β-bisabolene in the treatment of breast cancers.

  20. Umbelliprenin is Potentially Toxic Against the HT29, CT26, MCF-7, 4T1, A172, and GL26 Cell Lines, Potentially Harmful Against Bone Marrow-Derived Stem Cells, and Non-Toxic Against Peripheral Blood Mononuclear Cells

    PubMed Central

    Rashidi, Mohsen; Ziai, Seyed Ali; Moini Zanjani, Taraneh; Khalilnezhad, Ahad; Jamshidi, Hamidreza; Amani, Davar

    2016-01-01

    Background Resistance to chemotherapy is a growing concern, thus natural anticancer agents are drawing the attention of many scientists and clinicians. One natural anticancer agent, umbelliprenin, is a coumarin produced by many species of Ferula. Objectives We aimed to examine the inhibitory effect of umbelliprenin on human and mouse bone marrow-derived stem cells (BMDSCs), peripheral blood mononuclear cells (PBMCs), and different cancer cell lines. Materials and Methods In this in vitro experimental study, the HT29, CT26, MCF-7, 4T1, A172, and GL26 cancer cells and human and mouse BMDSCs and PBMCs were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), incubated at 37°C for 24 hours in a 5% CO2 atmosphere, and then were treated with different concentrations of umbelliprenin dissolved in dimethyl sulfoxide (DMSO) (3, 6, 12, 25, 50, 100, and 200 µg/mL) for 24, 48, and 72 hours at 37°C. Each experiment was performed in triplicate. Finally, the cell survival rate was assessed by MTT assay. The IC50 values were calculated based on the log values using GraphPad Prism version 5 software for windows (La Jolla CA, USA) and were expressed as mean ± SEM. Results Umbelliprenin inhibited the cancer cells in a concentration-dependent (P < 0.05) but not time-dependent manner (P > 0.05). The most sensitive and resistant cell lines at the 24-hour incubation time were 4T1 (IC50, 30.9 ± 3.1 µg/mL) and A172 (IC50, 51.9 ± 6.7 µg/mL); at the 48-hour incubation time: 4T1 (IC50, 30.6 ± 2.6 µg/mL) and CT26 (IC50, 53.2 ± 3.6 µg/mL); and at the 72-hour incubation time: HT29 (IC50, 37.1 ± 1.4 µg/mL) and 4T1 (IC50, 62.2 ± 4.8 µg/mL). Both human and mouse BMDSCs showed the highest resistance at the 24-hour incubation time (IC50s, 254.7 ± 21 and 204.4 ± 4.5 µg/mL, respectively) and the highest sensitivity at the 72-hour incubation time (IC50s, 120.4 ± 5 and 159.0 ± 7.3 µg/mL, respectively). The PBMCs of both human and mouse origin revealed very

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

    DTIC Science & Technology

    2011-09-01

    2,3-dioxygenase (IDO) in Breast Cancer Metastasis PRINCIPAL INVESTIGATOR: Courtney Smith, Ph.D...5a. CONTRACT NUMBER Investigating the Role of Indoleamine 2,3-dioxygenase (IDO) in Breast Cancer Metastasis 5b. GRANT NUMBER W81XWH-09-1-0667...the malignant 4T1 breast carcinoma cell line exhibit metastatic spread to organs similar to that seen in human breast cancer with pulmonary metastases

  2. Downregulation of CXCL12 in mesenchymal stromal cells by TGFβ promotes breast cancer metastasis

    PubMed Central

    Yu, P F; Huang, Y; Xu, C L; Lin, L Y; Han, Y Y; Sun, W H; Hu, G H; Rabson, A B; Wang, Y; Shi, Y F

    2017-01-01

    Mesenchymal stromal cells (MSCs) are one of major components of the tumour microenvironment. Recent studies have shown that MSC tumour residence and their close interactions with inflammatory factors are important factors that affect tumour progression. Among tumour-associated inflammatory factors, transforming growth factor β (TGFβ) is regarded as a key determinant of malignancy. By employing a lung metastasis model of a murine breast cancer, we show here that the prometastatic effect of MSCs was dependent on their response to TGFβ. Interestingly, we found that MSC-produced CXCL12, an important chemokine in tumour metastasis, was markedly inhibited by TGFβ. Furthermore, silencing of CXCL12 in TGFβ-unresponsive MSCs restored their ability to promote tumour metastasis. We found that 4T1 breast cancer cells expressed high levels of CXCR7, but not of CXCR4, both of which are CXCL12 receptors. In presence of CXCL12, CXCR7 expression on tumour cells was decreased. Indeed, when CXCR7 was silenced in breast cancer cells, their metastatic ability was inhibited. Therefore, our data demonstrated that sustained expression of CXCL12 by MSCs in the primary tumour site inhibits metastasis through reduction of CXCR7, while, in the presence of TGFβ, this CXCL12 effect of MSCs on tumour cells is relieved. Importantly, elevated CXCR7 and depressed CXCL12 expression levels were prominent features of clinical breast cancer lesions and were related significantly with poor survival. Our findings reveal a novel mechanism of MSC effects on malignant cells through which crosstalk between MSCs and TGFβ regulates tumour metastasis. PMID:27669436

  3. Molecular Mechanism of Lymph Node Metastasis in Breast Cancer

    DTIC Science & Technology

    2009-09-01

    inflammatory leukocytes to lymph nodes. CXCL21 is primarily expressed in LECs and functions as a chemoattractant for CCR7 -expressing dendritic cells and T...binding of HA to LYVE-1 regulates SLC production in LECs, which functions as chemoattractant for CCR7 - expressing breast cancer cells. Results...regulates SLC production in LECs, which functions as chemoattractant for CCR7 -expressing breast cancer cells. (Months 1-12) Generation of 4T1 cells

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

    DTIC Science & Technology

    2012-09-01

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

  5. Heterogeneous Blood-Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer

    PubMed Central

    Lockman, Paul R.; Mittapalli, Rajendar K.; Taskar, Kunal S.; Rudraraju, Vinay; Gril, Brunilde; Bohn, Kaci A.; Adkins, Chris E.; Roberts, Amanda; Thorsheim, Helen R.; Gaasch, Julie A.; Huang, Suyun; Palmieri, Diane; Steeg, Patricia S.; Smith, Quentin R.

    2010-01-01

    Purpose Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood-tumor barrier (BTB) is compromised in many brain metastases, however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain. Experimental Design Experimental brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy. Results Analysis of >2000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) demonstrated partial BTB permeability compromise in >89% lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14C- paclitaxel and 14C- doxorubicin was generally greater than normal brain but <15% of that of other tissues or peripheral metastases, and only reached cytotoxic concentrations in a small subset (~10%) of the most permeable metastases. Neither drug significantly decreased the experimental brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was associated with vascular remodeling and correlated with over expression of the pericyte protein, desmin. Conclusions This work demonstrates that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations. PMID:20829328

  6. Visualisation of Sentinel Lymph Node with Indium-Based near Infrared Emitting Quantum Dots in a Murine Metastatic Breast Cancer Model

    PubMed Central

    Helle, Marion; Cassette, Elsa; Bezdetnaya, Lina; Pons, Thomas; Leroux, Agnès; Plénat, François; Guillemin, François; Dubertret, Benoît; Marchal, Frédéric

    2012-01-01

    Due to its non-invasiveness, high temporal resolution and lower cost, fluorescence imaging is an interesting alternative to the current method (blue dye and radiocolloid) of sentinel lymph node (SLN) mapping in breast cancer. Near-infrared (NIR) emitting cadmium-based Quantum Dots (QDs) could be used for this purpose; however, their wide application is limited because of the toxicity of heavy metals composing the core. Our recent work demonstrated that indium-based QDs exhibit a weak acute local toxicity in vivo compared to their cadmium-based counterparts. In the present study we confirmed the weak toxicity of CuInS2/ZnS QDs in different in vitro models. Further in vivo studies in healthy mice showed that In-based QDs could be visualised in SLN in a few minutes after administration with a progressive increase in fluorescence until 8 h. The quantity of indium was assessed in selected organs and tissues by inductively coupled plasma – mass spectroscopy (ICP-MS) as a function of post-injection time. QD levels decrease rapidly at the injection point in the first hours after administration with a parallel increase in the lymph nodes and to a lesser extent in the liver and spleen. In addition, we observed that 3.5% of the injected indium dose was excreted in faeces in the first 4 days, with only trace quantities in the urine. Metastatic spread to the lymph nodes may hamper its visualisation. Therefore, we further performed non-invasive fluorescence measurement of QDs in SLN in tumour-bearing mice. Metastatic status was assessed by immunohistology and molecular techniques and revealed the utmost metastatic invasion of 36% of SLN. Fluorescence signal was the same irrespective of SLN status. Thus, near-infrared emitting cadmium-free QDs could be an excellent SLN tracer. PMID:22952979

  7. Fusion between cancer cells and macrophages occurs in a murine model of spontaneous neu+ breast cancer without increasing its metastatic potential

    PubMed Central

    Lizier, Michela; Anselmo, Achille; Mantero, Stefano; Ficara, Francesca; Paulis, Marianna; Vezzoni, Paolo; Lucchini, Franco; Pacchiana, Giovanni

    2016-01-01

    Cell fusion between neoplastic and normal cells has been suggested to play a role in the acquisition of a malignant phenotype. Several studies have pointed to the macrophage as the normal partner in this fusion, suggesting that the fused cells could acquire new invasive properties and become able to disseminate to distant organs. However, this conclusion is mainly based on studies with transplantable cell lines. We tested the occurrence of cell fusion in the MMTV-neu model of mouse mammary carcinoma. In the first approach, we generated aggregation chimeras between GFP/neu and RFP/neu embryos. Tumor cells would display both fluorescent proteins only if cell fusion with normal cells occurred. In addition, if cell fusion conferred a growth/dissemination advantage, cells with both markers should be detectable in lung metastases at increased frequency. We confirmed that fused cells are present at low but consistent levels in primary neoplasms and that the macrophage is the normal partner in the fusion events. Similar results were obtained using a second approach in which bone marrow from mice carrying the Cre transgene was transplanted into MMTV-neu/LoxP-tdTomato transgenic animals, in which the Tomato gene is activated only in the presence of CRE recombinase. However, no fused cells were detected in lung metastases in either model. We conclude that fusion between macrophages and tumor cells does not confer a selective advantage in our spontaneous model of breast cancer, although these data do not rule out a possible role in models in which an inflammation environment is prominent. PMID:27563823

  8. A novel thermal treatment modality for controlling breast tumor growth and progression.

    PubMed

    Xie, Yifan; Liu, Ping; Xu, Lisa X

    2012-01-01

    The new concept of keeping primary tumor under control in situ to suppress distant foci sheds light on the novel treatment of metastatic tumor. Hyperthermia is considered as one of the means for controlling tumor growth. In this study, a novel thermal modality was built to introduce hyperthermia effect on tumor to suppress its growth and progression using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer. A mildly raised temperature (i.e.39°C) was imposed on the skin surface of the implanted tumor using a thermal heating pad. Periodic heating (12 hours per day) was carried out for 3 days, 7 days, 14 days, and 21 days, respectively. The tumor growth rate was found significantly decreased in comparison to the control without hyperthermia. Biological evidences associated with tumor angiogenesis and metastasis were examined using histological analyses. Accordingly, the effect of mild hyperthermia on immune cell infiltration into tumors was also investigated. It was demonstrated that a delayed tumor growth and malignancy progression was achieved by mediating tumor cell apoptosis, vascular injury, degrading metastasis potential and as well as inhibiting the immunosuppressive cell myeloid derived suppressor cells (MDSCs) recruitment. Further mechanistic studies will be performed to explore the quantitative relationship between tumor progression and thermal dose in the near future.

  9. Huaier extract suppresses breast cancer via regulating tumor-associated macrophages

    PubMed Central

    Li, Yaming; Qi, Wenwen; Song, Xiaojin; Lv, Shangge; Zhang, Hanwen; Yang, Qifeng

    2016-01-01

    Macrophages in tumor microenvironment are mostly M2-polarized - and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). Here, we examined the regulatory effects of Huaier extract on TAMs using RAW264.7 murine macrophage cell line. Our data demonstrated that Huaier extract could inhibit the infiltration of macrophages into tumor microenvironment in a dose-dependent manner. By performing RT-PCR, immunofluorescence and phagocytosis assay, we were able to find that Huaier extract could regulate the polarization of macrophages, with decreased M2-polarization and increased phagocytosis of RAW264.7 cells. Moreover, we identified that Huaier extract could suppress macrophages-induced angiogenesis by using HUVEC migration assay, tube formation and chorioallantoic membrane assay. Additionally, western blotting showed decreased expression of MMP2, MMP9 and VEGF with the use of Huaier extract. Finally, we found that Huaier extract could inhibit M2-macrophages infiltration and angiogenesis through treating 4T1 tumor bearing mice with Huaier extract. Our study revealed a novel mechanism of the anti-tumor effect of Huaier extract which inhibited angiogenesis by targeting TAMs. These findings provided that Huaier was a promising drug for clinical treatment of breast cancer. PMID:26831282

  10. Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer.

    PubMed

    Wu, Sheng-Kai; Chiang, Chi-Feng; Hsu, Yu-Hone; Lin, Tzu-Hung; Liou, Houng-Chi; Fu, Wen-Mei; Lin, Win-Li

    2014-01-01

    The blood-brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers.

  11. 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

  12. SYMPATHETIC INNERVATION, NOREPINEPHRINE CONTENT, AND NOREPINEPHRINE TURNOVER IN ORTHOTOPIC AND SPONTANEOUS MODELS OF BREAST CANCER

    PubMed Central

    Dawes, Ryan P.; Madden, Kelley S.

    2016-01-01

    Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+ sympathetic nerves were limited to the periphery of the tumor. No TH+ staining was detected deeper within these tumors, even in regions with a high density of blood vessels. NE concentration was much lower in tumors compared to the more densely innervated spleen, reflecting the relative paucity of tumor TH+ innervation. Tumor and spleen NE concentration decreased with increased tissue mass. In mice treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy sympathetic nerves, tumor NE concentration was reduced approximately 50%, suggesting that the majority of tumor NE is derived from local sympathetic nerves. To evaluate NE utilization, NE turnover in orthotopic 4T1 mammary tumors was compared to spleen under baseline and stress conditions. In non-stressed mice, NE turnover was equivalent between tumor and spleen. In mice exposed to a stressor, tumor NE turnover was increased compared to spleen NE turnover, and compared to non-stressed tumor NE turnover. Together, these results demonstrate that NE in mammary tumors is derived from local sympathetic nerves that synthesize and metabolize NE. However, differences between spleen and tumor NE turnover with stressor exposure suggest that sympathetic NE release is regulated differently within the tumor microenvironment compared to the spleen. Local mammary tumor sympathetic innervation, despite its limited distribution, is responsive to stressor exposure and therefore can contribute to stress-induced tumor progression. PMID:26718447

  13. Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer.

    PubMed

    Szpunar, Mercedes J; Belcher, Elizabeth K; Dawes, Ryan P; Madden, Kelley S

    2016-03-01

    Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+ sympathetic nerves were limited to the periphery of the tumor. No TH+ staining was detected deeper within these tumors, even in regions with a high density of blood vessels. NE concentration was much lower in tumors compared to the more densely innervated spleen, reflecting the relative paucity of tumor TH+ innervation. Tumor and spleen NE concentration decreased with increased tissue mass. In mice treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy sympathetic nerves, tumor NE concentration was reduced approximately 50%, suggesting that the majority of tumor NE is derived from local sympathetic nerves. To evaluate NE utilization, NE turnover in orthotopic 4T1 mammary tumors was compared to spleen under baseline and stress conditions. In non-stressed mice, NE turnover was equivalent between tumor and spleen. In mice exposed to a stressor, tumor NE turnover was increased compared to spleen NE turnover, and compared to non-stressed tumor NE turnover. Together, these results demonstrate that NE in mammary tumors is derived from local sympathetic nerves that synthesize and metabolize NE. However, differences between spleen and tumor NE turnover with stressor exposure suggest that sympathetic NE release is regulated differently within the tumor microenvironment compared to the spleen. Local mammary tumor sympathetic innervation, despite its limited distribution, is responsive to stressor exposure and therefore can contribute to stress-induced tumor progression.

  14. 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

  15. A Novel Gene Gun-Mediated IL-12 Gene Therapy for Breast Cancer

    DTIC Science & Technology

    1999-10-01

    The overall goal of our research is to develop an immunological approach for breast cancer gene therapy . The results of the first year study...described in our previous Annual Report, show that gene gun-mediated Th-12 gene therapy is effective against breast tumors in mouse models. During the second...effect of IL-l2 gene therapy against 4T1 tumor is not mediated by T cells, but rather involves NK cells. From several different immunomodulatory genes

  16. Role of Notch/VEGF-Receptor 3 in Breast Tumor Angiogenesis and Lymphangiogenesis

    DTIC Science & Technology

    2006-05-01

    in a murine mammary tumor model. In aim 1, to study the role for notch in murine mammary tumorigenesis , progress has been made in developing two new...ACCOMPLISHMENTS • Developed a EF-1-flox-NotchIC mouse line that expresses an activated form of Notch1 with within the murine vasculature when...interaction between Notch and VEGFR-3 in breast cancer. To study the role for notch in murine mammary tumorigenesis , progress has been made in developing

  17. A Novel Gene Gun-Mediated IL-12 Gene Therapy for Breast Cancer

    DTIC Science & Technology

    1999-01-01

    gene therapy . The results of the first year study, described in our previous Annual Report, show that gene gun-mediated IL-12 gene therapy is effective against breast tumors in mouse models. During the second year of this study we demonstrated that 4T1 tumor is weakly immunogenic, and it can induce a low level immune response. However, the anti-metastatic effect of IL-12 gene therapy against 4T1 tumor is not mediated by T cells, but rather involves NK cells. From several different immunomidulatory genes tested in combination with

  18. 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 ...

  19. Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer.

    PubMed

    Adkins, Chris E; Mohammad, Afroz S; Terrell-Hall, Tori B; Dolan, Emma L; Shah, Neal; Sechrest, Emily; Griffith, Jessica; Lockman, Paul R

    2016-04-01

    The blood-brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers (14)C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases.

  20. Adoptive transfer of ex vivo expanded Vγ9Vδ2 T cells in combination with zoledronic acid inhibits cancer growth and limits osteolysis in a murine model of osteolytic breast cancer.

    PubMed

    Zysk, Aneta; DeNichilo, Mark O; Panagopoulos, Vasilios; Zinonos, Irene; Liapis, Vasilios; Hay, Shelley; Ingman, Wendy; Ponomarev, Vladimir; Atkins, Gerald; Findlay, David; Zannettino, Andrew; Evdokiou, Andreas

    2017-02-01

    Bone metastases occur in over 75% of patients with advanced breast cancer and are responsible for high levels of morbidity and mortality. In this study, ex vivo expanded cytotoxic Vγ9Vδ2 T cells isolated from human peripheral blood were tested for their anti-cancer efficacy in combination with zoledronic acid (ZOL), using a mouse model of osteolytic breast cancer. In vitro, expanded Vγ9Vδ2 T cells were cytotoxic against a panel of human breast cancer cell lines, and ZOL pre-treatment further sensitised breast cancer cells to killing by Vγ9Vδ2 T cells. Vγ9Vδ2 T cells adoptively transferred into NOD/SCID mice localised to osteolytic breast cancer lesions in the bone, and multiple infusions of Vγ9Vδ2 T cells reduced tumour growth in the bone. ZOL pre-treatment potentiated the anti-cancer efficacy of Vγ9Vδ2 T cells, with mice showing further reductions in tumour burden. Mice treated with the combination also had reduced tumour burden of secondary pulmonary metastases, and decreased bone degradation. Our data suggests that adoptive transfer of Vγ9Vδ2 T cell in combination with ZOL may prove an effective immunotherapeutic approach for the treatment of breast cancer bone metastases.

  1. Conventional murine gene targeting.

    PubMed

    Zimmermann, Albert G; Sun, Yue

    2013-01-01

    Murine gene knockout models engineered over the last two decades have continued to demonstrate their potential as invaluable tools in understanding the role of gene function in the context of normal human development and disease. The more recent elucidation of the human and mouse genomes through sequencing has opened up the capability to elucidate the function of every human gene. State-of-the-art mouse model generation allows, through a multitude of experimental steps requiring careful standardization, gene function to be reliably and predictably ablated in a live model system. The application of these standardized methodologies to directly target gene function through murine gene knockout has to date provided comprehensive and verifiable genetic models that have contributed tremendously to our understanding of the cellular and molecular pathways underlying normal and disease states in humans. The ensuing chapter provides an overview of the latest steps and procedures required to ablate gene function in a murine model.

  2. Ron in Breast Development and Cancer

    DTIC Science & Technology

    2005-10-01

    Bakhiet N. Functional analysis of mouse keratin 8 in 34. Maglione JE, Moghanaki D, Young LJ, et al. 38. Lifsted T, Le Voyer T, Williams M , et al...Waltz, S.E.; Beauman, S.; Collins, M .; Leonis, M .; Toney, K. and Peace, B.E. Ron receptor singaling augments mammary tumorigenesis in murine models of...Collins, M .; Leonis, M .; Toney, K. and Peace, B.E. Ron receptor singaling augments mammary tumorigenesis in murine models of breast cancer. Gordon

  3. Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs

    PubMed Central

    2014-01-01

    -γ production and cytolytic activity of spleen cells from treated mice. More importantly, combined treatment of anti-PD-1/GITR mAb and chemotherapeutic drugs (cisplatin or paclitaxel) further increased the antitumor efficacy with 80% of mice obtaining tumor-free long-term survival in murine ID8 ovarian cancer and 4 T1 breast cancer models. Conclusions Combined anti-PD-1/GITR mAb treatment induces a potent antitumor immunity, which can be further promoted by chemotherapeutic drugs. A combined strategy of anti-PD-1/GITR mAb plus cisplatin or paclitaxel should be considered translation into clinic. PMID:24502656

  4. Cryoablation and Meriva have strong therapeutic effect on triple-negative breast cancer

    PubMed Central

    Chandra, Dinesh; Jahangir, Arthee; Cornelis, Francois; Rombauts, Klara; Meheus, Lydie; Jorcyk, Cheryl L; Gravekamp, Claudia

    2016-01-01

    Interleukin-6, a cytokine produced particularly by triple-negative breast cancers, strongly inhibits T cell responses in the tumor microenvironment. Here we tested cryoablation combined with Meriva (a lecithin delivery system of curcumin with improved bioavailability) in mice with metastatic breast cancer (4T1). Cryoablation involves killing of tumor cells through freezing and thawing, resulting in recruitment of tumor-specific T cells, while curcumin stimulates T cells through the reduction of IL-6 in the TME. Cryoablation plus Meriva accumulated and activated CD8+ T cells to multiple tumor-associated antigens such as Mage-b and Survivin (both expressed by 4T1 tumors). This correlated with a nearly complete reduction of 4T1 primary tumors and lung metastases while little effect was observed from saline or Meriva alone (28 d after tumor cell injection). The survival rate in the group of cryoablation plus Meriva was significantly improved compared to all control groups. Using a less aggressive 4T1 model expressing luciferase (4T1.2luc3), we demonstrated that all mice receiving saline or Meriva developed metastases in the lungs and a primary tumor (38 d after tumor cell injection; and died soon after that), but not the mice receiving cryoablation or cryoablation plus Meriva. However, on day 58 the mice receiving cryoablation developed 4T1.2luc3 metastases in the lungs, while mice receiving cryoablation plus Meriva were free of metastases. These results strongly suggest that cryoablation delayed the development of lung metastases on the short-term, but Meriva administered after cryoablation was significantly better in delaying the development of lung metastases and survival on the long-term. PMID:26942057

  5. 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.

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

    PubMed Central

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

    2017-01-01

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

  7. Breast infection

    MedlinePlus

    ... female breast anatomy Breast infection Female breast References Hunt KK, Mittendorf EA. Diseases of the breast. In: ... Jacobson, MD, Professor of Obstetrics and Gynecology, Loma Linda University School of Medicine, Loma Linda Center for ...

  8. 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; ...

  9. Ron in Breast Development and Cancer

    DTIC Science & Technology

    2006-10-01

    fraction of human and feline breast cancers. To define the in vivo significance of Ron, mice were generated with a targeted ablation of the tyrosine...with known oncogenes. For example, the skin and breast tumorigenicity of transgenic mice overexpressing the polyoma middle T (36) and RAS (37...Waltz SE. Ron tyrosine kinase receptor regulates papilloma growth and malignant conversion in a murine model of skin carcinogenesis. Oncogene 2005; 24

  10. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.

    PubMed

    Benesch, Matthew G K; Tang, Xiaoyun; Dewald, Jay; Dong, Wei-Feng; Mackey, John R; Hemmings, Denise G; McMullen, Todd P W; Brindley, David N

    2015-09-01

    Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-α and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX.

  11. Harnessing the Power of Light to See and Treat Breast Cancer

    DTIC Science & Technology

    2013-10-01

    Figure 3.4: Effect of breathing hypoxic gas on vascular oxygenation and glucose uptake of 4T1 and 4T07 tumors. A and B. Representative intravital images ...therapeutic agents in vivo. 14. ABSTRACT optical spectroscopy, imaging , fiber-optic, molecular, screening, breast cancer 15. SUBJECT TERMS 16...tumor biology and assay the effect of novel therapeutic agents in vivo. a. Original Statement of Work for 5 Years Aim 1: Optical imaging of margin

  12. Influence of the Tumor Microenvironment on Genomic Changes Conferring Chemoresistance in Breast Cancer

    DTIC Science & Technology

    2013-04-01

    tumor microenvironment on clonal selection using intravital microscopy Jae-Hyun Park 1 , Miriam R. Fein 1 , Mikala Egeblad 1 1 Cold Spring Harbor...used surgically implanted mammary imaging windows in immunocompetent mice and injected “brainbow” expressing, syngeneic 4T1 breast carcinoma cells...under the windows. This allowed us to acquire multiple time- lapse imaging series by spinning disk confocal microscopy of the same tumor, done about 3

  13. Comparative study of two routes of administration of 5-aminolevulinic acid (oral and intratumoral via) and their effect on the accumulation of PpIX in tissues in murine model of breast cancer

    NASA Astrophysics Data System (ADS)

    González-Agüero, G.; Ramón-Gallegos, E.

    2012-10-01

    Protoporphyrin IX (PpIX) is a photosensitizer synthesized from 5-aminolevulinic acid (ALA) that has been used in photodynamic therapy (PDT) as a promising treatment for many types of cancer. In this work it was quantified the accumulation of PpIX in tumors and in different tissues of female mice (nu/nu) inoculated with breast cancer cells. Two routes of administration of ALA: gastric probe and intratumoral injection were used to find optimum time of accumulation and the via that induce the higher quantity of PpIX to improve the efficiency of PDT. The results show that the accumulation of PpIX using the intratumoral via is two times bigger than the oral via in tumors at 8 h of treatment. The concentrations obtained in the different tissues are not physiologically significant.

  14. Fibroadenoma - breast

    MedlinePlus

    Breast lump - fibroadenoma; Breast lump - noncancerous; Breast lump - benign ... The cause of fibroadenomas is not known. There may be a connection to a problem with genes. Fibroadenoma is the most common benign ...

  15. Breast ultrasound

    MedlinePlus

    ... Sonogram of the breast Images Female breast References Hacker NF, Friedland ML. Breast disease. In: Hacker NF, Gambone JC, Hobel CJ, eds. Hacker and Moore's Essentials of Obstetrics and Gynecology . 6th ...

  16. Breast Pain

    MedlinePlus

    ... before your period and sometimes continuing through your menstrual cycle. The pain may be moderate or severe, and ... breasts. Throughout the month, not related to your menstrual cycle. Postmenopausal women sometimes have breast pain, but breast ...

  17. Inhibitory effect of MyoD on the proliferation of breast cancer cells

    PubMed Central

    CAI, CHANGJING; QIN, XIAOQUN; WU, ZIYI; SHEN, QIXIA; YANG, WENQIAN; ZHANG, SHUJUN; DUAN, JINLING; LIANG, FENGLAN; LIU, CHI

    2016-01-01

    Skeletal muscle is rich in lymphatic vessels, with an abundant blood supply, and it is an infrequent site of cancer metastasis. Previous studies have demonstrated that enhanced secretion of MyoD may occur when skeletal muscle is injured or becomes cancerous. It was hypothesized that MyoD may act as an endogenous cytokine to inhibit the proliferation of cancer cells. To verify the possible effect of this protein on tumor cell proliferation, C2C12 mouse skeletal muscle cells and 4T1 mouse breast cancer cells were co-cultured using embedded Transwell plates. Following co-culture, cell cycle analysis revealed that C2C12 muscle cells were able to inhibit the proliferation of the breast cancer cells. Subsequently, MyoD was silenced in C2C12 cells to assess its effect on 4T1 cell proliferation. Following co-culture with MyoD-silenced cells, a 5-ethynyl-20-deoxyuridine assay indicated that MyoD silencing prevented the reduction in proliferation of 4T1 cells induced by untransfected C2C12 cells. In summary, the results indicated that MyoD inhibits the proliferation of breast cancer cells and may be a tumor suppressor factor. PMID:27284360

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

    PubMed

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

    2015-09-08

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

  19. 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 ...

  20. 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

  1. Breast Diseases

    MedlinePlus

    ... bumps, and discharges (fluids that are not breast milk). If you have a breast lump, pain, discharge or skin irritation, see your health care provider. Minor and serious breast problems have similar symptoms. Although many women fear cancer, most breast problems are not cancer. Some common ...

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

    PubMed

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

    2013-01-01

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

  3. Animal models for exploring the pharmacokinetics of breast cancer therapies

    PubMed Central

    Rashid, Omar M.; Takabe, Kazuaki

    2015-01-01

    Introduction Despite massive expenditures in research and development to cure breast cancer, few agents that pass preclinical trials demonstrate efficacy in humans. Although this endeavor relies on murine models to screen for efficacy before progressing to clinical trials, historically there has been little focus on the validation of these models, even in the era of targeted therapy where understanding the genetic signatures of tumors under study is critical. Areas covered This review includes the transgenic, xenograft, and syngeneic murine breast cancer models, the ectopic, orthotopic and intravenous methods of cell implantation, and the ethics of animal experimentation. It also includes the latest data on tumor gene expression and the issues to consider when exploring the pharmacokinetics and efficacy of breast cancer therapies. Expert opinion Breast cancer drug development is expensive and inefficient without a consensus preclinical murine model. Investigators must approach the choice of murine model with the same sophistication that is applied to the choice of in vitro assays to improve efficiency. Understanding the limitations of each model available, including the nuances of tumor gene signatures, is critical for investigators exploring the phamacokinetics and efficacy of breast cancer therapies, especially in the context of gene profiling and individualized targeted therapy. PMID:25416501

  4. Lipopolysaccharide induces inflammation and facilitates lung metastasis in a breast cancer model via the prostaglandin E2-EP2 pathway.

    PubMed

    Li, Shancheng; Xu, Xiaoya; Jiang, Man; Bi, Yuli; Xu, Jiying; Han, Mingyong

    2015-06-01

    Inflammation is a potent promoter of tumor metastasis. The aim of the present study was to explore the function of systemic inflammation in the formation of lung metastasis of breast cancer cells in a mouse model. BALB/c mice were injected intraperitoneally with lipopolysaccharide (LPS) in order to establish an inflammatory animal model and 4T1 murine breast cancer cells were injected through the tail vein to induce lung metastasis. The levels of proinflammatory cytokines were evaluated by ELISA. Metastases on the surface of the lungs were counted and histologically analyzed by hematoxylin and eosin staining. Angiogenesis in the lungs was examined by CD31 immunofluorescence. Mouse pulmonary endothelial cells (MPVECs) were isolated and used to assay endothelial tube formation and determine the protein expression levels of vascular endothelial growth factor (VEGF) in vitro. Serum levels of VEGF and prostaglandin E2 (PGE2), the number and size of metastatic lesions, and the expression levels of cyclooxygenase‑2 were significantly greater in the lungs of LPS‑treated mice, as compared with those in control mice threated with phosphate‑buffered saline. Blood vessel density was also markedly increased in the LPS‑treated mice. These increases were reversed by treatment with celecoxib. In vitro, the protein expression levels of VEGF produced by the PGE2‑treated cells were significantly increased in a concentration‑dependent manner. In addition, the production of VEGF was increased in response to treatment with the PGE2 receptor (EP2) agonist ONO‑AE1‑259‑01; however, this increase was abrogated by treatment with AH6809, an EP2 receptor antagonist. Treatment with PGE2 or VEGF alone promoted the tube formation of MPVECs and this effect was reversed by treatment with celecoxib. These results demonstrated that PGE2 may regulate the release of VEGF by MPVECs through the EP2 receptor pathway and thereby promoted pulmonary angiogenesis and breast cancer

  5. Breast Reconstruction with Implants

    MedlinePlus

    ... removes your breast to treat or prevent breast cancer. One type of breast reconstruction uses breast implants — silicone devices filled with silicone gel or salt water (saline) — to reshape your breasts. Breast reconstruction ...

  6. Inhibition of Metastatic Potential in Breast Carcinoma In Vivo and In Vitro through Targeting VEGFRs and FGFRs.

    PubMed

    Chien, Ming-Hsien; Lee, Liang-Ming; Hsiao, Michael; Wei, Lin-Hung; Chen, Chih-Hau; Lai, Tsung-Ching; Hua, Kuo-Tai; Chen, Min-Wei; Sun, Chung-Ming; Kuo, Min-Liang

    2013-01-01

    Angiogenesis and lymphangiogenesis are considered to play key roles in tumor metastasis. Targeting receptor tyrosine kinases essentially involved in the angiogenesis and lymphangiogenesis would theoretically prevent cancer metastasis. However, the optimal multikinase inhibitor for metastasis suppression has yet to be developed. In this study, we evaluated the effect of NSTPBP 0100194-A (194-A), a multikinase inhibitor of vascular endothelial growth factor receptors (VEGFRs)/fibroblast growth factor receptors (FGFRs), on lymphangiogenesis and angiogenesis in a mammary fat pad xenograft model of the highly invasive breast cancer cell line 4T1-Luc(+). We investigated the biologic effect of 194-A on various invasive breast cancer cell lines as well as endothelial and lymphatic endothelial cells. Intriguingly, we found that 194-A drastically reduced the formation of lung, liver, and lymph node metastasis of 4T1-Luc(+) and decreased primary tumor growth. This was associated with significant reductions in intratumoral lymphatic vessel length (LVL) and microvessel density (MVD). 194-A blocked VEGFRs mediated signaling on both endothelial and lymphatic endothelial cells. Moreover, 194-A significantly inhibited the invasive capacity induced by VEGF-C or FGF-2 in vitro in both 4T1 and MDA-MB231 cells. In conclusion, these experimental results demonstrate that simultaneous inhibition of VEGFRs/FGFRs kinases may be a promising strategy to prevent breast cancer metastasis.

  7. Murine typhus in travelers returning from Indonesia.

    PubMed Central

    Parola, P.; Vogelaers, D.; Roure, C.; Janbon, F.; Raoult, D.

    1998-01-01

    We report the first three documented cases of murine typhus imported into Europe from Indonesia, discuss clues for the diagnosis of the disease, and urge that murine fever be considered in the diagnosis of febrile disease in travelers. PMID:9866749

  8. Murine typhus in travelers returning from Indonesia.

    PubMed

    Parola, P; Vogelaers, D; Roure, C; Janbon, F; Raoult, D

    1998-01-01

    We report the first three documented cases of murine typhus imported into Europe from Indonesia, discuss clues for the diagnosis of the disease, and urge that murine fever be considered in the diagnosis of febrile disease in travelers.

  9. c-Abl inhibits breast cancer tumorigenesis through reactivation of p53-mediated p21 expression

    PubMed Central

    Thompson, Cheryl L.; Gilmore, Hannah L.; Chang, Jenny C.; Keri, Ruth A.; Schiemann, William P.

    2016-01-01

    We previously reported that constitutive c-Abl activity (CST-Abl) abrogates the tumorigenicity of triple-negative breast cancer cells through the combined actions of two cellular events: downregulated matrix metalloproteinase (MMP) and upregulated p21Waf1/Cip1 expression. We now find decreased c-Abl expression to be significantly associated with diminished relapse-fee survival in breast cancer patients, particularly those exhibiting invasive and basal phenotypes. Moreover, CST-Abl expression enabled 4T1 cells to persist innocuously in the mammary glands of mice, doing so by exhausting their supply of cancer stem cells. Restoring MMP-9 expression and activity in CST-Abl-expressing 4T1 cells failed to rescue their malignant phenotypes; however, rendering these same cells deficient in p21 expression not only delayed their acquisition of senescent phenotypes, but also partially restored their tumorigenicity in mice. Although 4T1 cells lacked detectable expression of p53, those engineered to express CST-Abl exhibited robust production and secretion of TGF-β1 that engendered the reactivated expression of p53. Mechanistically, TGF-β-mediated p53 expression transpired through the combined actions of Smad1/5/8 and Smad2, leading to the dramatic upregulation of p21 and its stimulation of TNBC senescence. Collectively, we identified a novel c-Abl:p53:p21 signaling axis that functions as a powerful suppressor of mammary tumorigenesis and metastatic progression. PMID:27626309

  10. IR-780 Dye as a Sonosensitizer for Sonodynamic Therapy of Breast Tumor

    PubMed Central

    Li, Yekuo; Zhou, Qunfang; Deng, Zhiting; Pan, Min; Liu, Xin; Wu, Junru; Yan, Fei; Zheng, Hairong

    2016-01-01

    Sonodynamic therapy (SDT) has become a new modality for cancer therapy through activating certain chemical sensitizers by ultrasound (US). Discovery and development of novel sonosensitizers are attracting extensive attentions. Here, we introduce IR-780 iodide, a lipophilic heptamethine dye with a peak optical absorption of 780 nm wavelength, which can function as SDT agents for breast cancer treatment. The in vitro cellular uptake, cell viability, and the generation levels of reactive oxygen species (ROS) were examined by using 4T1 breast cancer cells incubated with various concentrations of IR-780 followed by US irradiation. Our results showed a dose- and time-dependent cellular uptake of IR-780 iodide in 4T1 cancer cells. Significant lower viabilities and more necrotic/apoptotic cells were found when these cancer cells were treated with IR-780 iodide with US irradiation. Further analyzing the generation of ROS demonstrated significant increase of 1O2 level and H2O2, but not ⋅OH in the SDT-treated cells. The in vivo anti-tumor efficacy of SDT with IR-780 revealed significant tumor growth inhibition of xenografts of 4T1 cancer cells; it was further confirmed by histological analysis and TUNEL staining. Our results strongly suggest that SDT combined with IR-780 may provide a promising strategy for tumor treatment with minimal side effects. PMID:27174006

  11. Codelivery of thioridazine and doxorubicin using nanoparticles for effective breast cancer therapy

    PubMed Central

    Jin, Xun; Zou, Bingwen; Luo, Li; Zhong, Chuanhong; Zhang, Peilan; Cheng, Hao; Guo, Yanfang; Gou, Maling

    2016-01-01

    Cancer chemotherapy can benefit from the combination of different anticancer drugs. Here, we prepared doxorubicin (Dox)- and thioridazine (Thio)-coloaded methoxy poly(ethylene glycol)-poly(l-lactic acid) (MPEG-PLA) nanoparticles (NPs) for breast cancer therapy. These NPs have an average particle size of 27 nm. The drug loading efficiencies of Thio and Dox are 4.71% and 1.98%, respectively. Compared to the treatment of Thio or Dox alone, the combination of Thio and Dox exhibited a synergistic effect in inhibiting the growth of 4T1 breast cancer cells in vitro. In addition, the Thio- and Dox-coloaded MPEG-PLA NPs could efficiently suppress the growth of breast cancer cells in vivo. This study suggests that Thio- and Dox-coloaded MPEG-PLA NPs might have potential applications in breast cancer treatment. PMID:27660446

  12. Fluorescence and reflectance spectral imaging system for a murine mammary window chamber model

    PubMed Central

    Leung, Hui Min; Gmitro, Arthur F.

    2015-01-01

    A spectral imaging system was developed to study the development of breast cancer xenografts in a murine mammary window chamber model. The instrument is configured to work with either a laser to excite fluorescence or a broadband light source for diffuse reflectance imaging. Two applications were demonstrated. First, spectral imaging of fluorescence signals was demonstrated with a GFP-breast cancer tumor and fluorescein injection. Second, based on the principles of broadband reflectance spectroscopy, the instrument was used to monitor dynamic changes of tissue absorbance to yield tissue oxygenation maps at different time points during tumor progression. PMID:26309753

  13. Breast Gangrene

    PubMed Central

    2011-01-01

    Background Breast gangrene is rare in surgical practice. Gangrene of breast can be idiopathic or secondary to some causative factor. Antibiotics and debridement are used for management. Acute inflammatory infiltrate, severe necrosis of breast tissue, necrotizing arteritis, and venous thrombosis is observed on histopathology. The aim of was to study patients who had breast gangrene. Methods A prospective study of 10 patients who had breast gangrene over a period of 6 years were analyzed Results All the patients in the study group were female. Total of 10 patients were encountered who had breast gangrene. Six patients presented with breast gangrene on the right breast whereas four had on left breast. Out of 10 patients, three had breast abscess after teeth bite followed by gangrene, one had iatrogenic trauma by needle aspiration of erythematous area of breast under septic conditions. Four had history of application of belladonna on cutaneous breast abscess and had then gangrene. All were lactating female. Amongst the rest two were elderly, one of which was a diabetic who had gangrene of breast and had no application of belladonna. All except one had debridement under cover of broad spectrum antibiotics. Three patients had grafting to cover the raw area. Conclusion Breast gangrene occurs rarely. Etiology is variable and mutifactorial. Teeth bite while lactation and the iatrogenic trauma by needle aspiration of breast abscess under unsterlised conditions could be causative. Uncontrolled diabetes can be one more causative factor for the breast gangrene. Belladonna application as a topical agent could be inciting factor. Sometimes gangrene of breast can be idiopathic. Treatment is antibiotics and debridement. PMID:21854557

  14. Breast lift

    MedlinePlus

    ... Planning to have more children Talk with a plastic surgeon if you are considering cosmetic breast surgery. ... before surgery: You may need a mammogram . Your plastic surgeon will do a routine breast exam. You ...

  15. Breast Exam

    MedlinePlus

    ... Your hormone levels fluctuate each month during your menstrual cycle, which causes changes in breast tissue. Swelling begins ... changes that occur at various points in the menstrual cycles. Finding a change or lump in your breast ...

  16. Breast Cysts

    MedlinePlus

    ... discuss your symptoms, their relation to your menstrual cycle and any other relevant information. To prepare for ... one or both breasts? How does your menstrual cycle affect the breast cyst or lump? When was ...

  17. A novel histone deacetylase inhibitor augments tamoxifen-mediated attenuation of breast carcinoma growth.

    PubMed

    Restall, Christina; Doherty, Judy; Liu, Hong Bin; Genovese, Rosemary; Paiman, Lisa; Byron, Keith A; Anderson, Robin L; Dear, Anthony E

    2009-07-15

    Earlier we generated novel derivatives of the hydroxamate-based histone deacetylase inhibitor (HDACi), Oxamflatin (Ox), which demonstrate considerable HDACi activity. Here the effects of one such derivative, Metacept-1 (MCT-1), alone or in combination with tamoxifen on mammary tumour growth have been assessed in a syngeneic orthotopic model. MCT-1 alone resulted in a trend towards inhibition of growth of 4T1.2 mammary tumours. Since the combination of MCT-1 and tamoxifen up-regulates estrogen receptor expression in 4T1.2 cells in vitro, we tested this combination and found a significant reduction in primary tumour growth over tamoxifen treatment alone. Taken together, these observations suggest that the novel HDACi MCT-1 may warrant further exploration in the treatment of estrogen receptor positive breast carcinoma, particularly when used in combination with conventional agents such as tamoxifen.

  18. 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. ...

  19. Antimicrobial proteins of murine macrophages.

    PubMed Central

    Hiemstra, P S; Eisenhauer, P B; Harwig, S S; van den Barselaar, M T; van Furth, R; Lehrer, R I

    1993-01-01

    Three murine microbicidal proteins (MUMPs) were purified from cells of the murine macrophage cell line RAW264.7 that had been activated by gamma interferon. Similar proteins were also present in nonactivated RAW264.7 cells, in cells of the murine macrophage cell line J774A.1, and in resident and activated murine peritoneal macrophages. MUMP-1, MUMP-2, and MUMP-3 killed Salmonella typhimurium, Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, Mycobacterium fortuitum, and Cryptococcus neoformans in vitro. MUMP-1 resembled an H1 histone but was unusual because its N-terminal residue (serine) was not N acetylated. Although MUMP-2 was N terminally blocked, its high lysine/arginine ratio and its reactivity with an antibody to H1 histones suggested that it also belonged to the H1 histone family. MUMP-3 was identical to histone H2B in 30 of 30 amino-terminal residues. Although the antimicrobial properties of histones have been recognized for decades, this is the first evidence that such proteins may endow the lysosomal apparatus of macrophages with nonoxidative antimicrobial potential. Other MUMPs, including some with a more restricted antimicrobial spectrum and one that appeared to be induced in RAW264.7 cells after gamma interferon stimulation, were noted but remain to be characterized. Images PMID:8514411

  20. Optical redox ratio identifies metastatic potential-dependent changes in breast cancer cell metabolism

    PubMed Central

    Alhallak, Kinan; Rebello, Lisa G.; Muldoon, Timothy J.; Quinn, Kyle P.; Rajaram, Narasimhan

    2016-01-01

    The development of prognostic indicators of breast cancer metastatic risk could reduce the number of patients receiving chemotherapy for tumors with low metastatic potential. Recent evidence points to a critical role for cell metabolism in driving breast cancer metastasis. Endogenous fluorescence intensity of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) can provide a label-free method for assessing cell metabolism. We report the optical redox ratio of FAD/(FAD + NADH) of four isogenic triple-negative breast cancer cell lines with varying metastatic potential. Under normoxic conditions, the redox ratio increases with increasing metastatic potential (168FARN>4T07>4T1), indicating a shift to more oxidative metabolism in cells capable of metastasis. Reoxygenation following acute hypoxia increased the redox ratio by 43 ± 9% and 33 ± 4% in the 4T1 and 4T07 cells, respectively; in contrast, the redox ratio decreased 14 ± 7% in the non-metastatic 67NR cell line. These results demonstrate that the optical redox ratio is sensitive to the metabolic adaptability of breast cancer cells with high metastatic potential and could potentially be used to measure dynamic functional changes that are indicative of invasive or metastatic potential. PMID:27895979

  1. 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. ...

  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. 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 ...

  4. Melanin-originated carbonaceous dots for triple negative breast cancer diagnosis by fluorescence and photoacoustic dual-mode imaging.

    PubMed

    Xiao, Wei; Li, Yuan; Hu, Chuan; Huang, Yuan; He, Qin; Gao, Huile

    2017-07-01

    Carbonaceous dots exhibit increasing applications in diagnosis and drug delivery due to excellent photostability and biocompatibility properties. However, relative short excitation and emission of melanin carbonaceous dots (MCDs) limit the applicability in fluorescence bioimaging. Furthermore, the generally poor spatial resolution of fluorescence imaging limits potential in vivo applications. Due to a variety of beneficial properties, in this study, MCDs were prepared exhibiting great potential in fluorescence and photoacoustic dual-mode bioimaging. The MCDs exhibited a long excitation peak at 615nm and emission peak at 650nm, further highlighting the applicability in fluorescence imaging, while the absorbance peak at 633nm renders MCDs suitable for photoacoustic imaging. In vivo, the photoacoustic signal of MCDs was linearly correlated with the concentration of MCDs. Moreover, the MCDs were shown to be taken up into triple negative breast cancer cell line 4T1 in both a time- and concentration-dependent manner. In vivo fluorescence and photoacoustic imaging of subcutaneous 4T1 tumor demonstrated that MCDs could passively target triple negative breast cancer tissue by enhanced permeability and retention effects and may therefore be used for tumor dual-mode imaging. Furthermore, fluorescence distribution in tissue slices suggested that MCDs may distribute in 4T1 tumor with high efficacy. In conclusion, the MCDs studied offer potential application in fluorescence and photoacoustic dual-mode imaging.

  5. Breast Lumps

    MedlinePlus

    ... 2015. Raftery AT, et al. Breast lumps. In: Churchill's Pocketbook of Differential Diagnosis. 4th ed. Philadelphia, Pa.: Churchill Livingston Elsevier; 2014. http://www.clinicalkey.com. Accessed ...

  6. Breast Tomosynthesis

    MedlinePlus

    ... mammography, that uses a low-dose x-ray system and computer reconstructions to create three-dimensional images of the ... Breast tomosynthesis uses a low-dose x-ray system, electronics and a computer to convert x-ray images of the breast ...

  7. Breast Feeding.

    ERIC Educational Resources Information Center

    International Children's Centre, Paris (France).

    This set of documents consists of English, French, and Spanish translations of four pamphlets on breast-feeding. The pamphlets provide information designed for lay persons, academics and professionals, health personnel and educators, and policy-makers. The contents cover health-related differences between breast and bottle milk; patterns of…

  8. A pH-Responsive Host-guest Nanosystem Loading Succinobucol Suppresses Lung Metastasis of Breast Cancer

    PubMed Central

    Dan, Zhaoling; Cao, Haiqiang; He, Xinyu; Zhang, Zhiwen; Zou, Lili; Zeng, Lijuan; Xu, Yan; Yin, Qi; Xu, Minghua; Zhong, Dafang; Yu, Haijun; Shen, Qi; Zhang, Pengcheng; Li, Yaping

    2016-01-01

    Cancer metastasis is the leading reason for the high mortality of breast cancer. Herein, we report on a pH-responsive host-guest nanosystem of succinobucol (PHN) with pH-stimuli controlled drug release behavior to improve the therapeutic efficacy on lung metastasis of breast cancer. PHN was composed of the host polymer of β-cyclodextrin linked with multiple arms of N,N-diisopropylethylenediamine (βCD-DPA), the guest polymer of adamantyl end-capped methoxy poly(ethylene glycol) (mPEG-Ad), and the active agent of succinobucol. PHN comprises nanometer-sized homogenous spherical particles, and exhibits specific and rapid drug release in response to the intracellular acidic pH-stimuli. Then, the anti-metastatic efficacy of PHN is measured in metastatic 4T1 breast cancer cells, which effectively confirms the superior inhibitory effects on cell migration and invasion activities, VCAM-1 expression and cell-cell binding of RAW 264.7 to 4T1 cells. Moreover, PHN can be specifically delivered to the sites of metastatic nodules in lungs, and result in an obviously improved therapeutic efficacy on lung metastasis of breast cancer. Thereby, the pH-responsive host-guest nanosystem can be a promising drug delivery platform for effective treatment of cancer metastasis. PMID:26909117

  9. Host B7x promotes pulmonary metastasis of breast cancer

    PubMed Central

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

    2013-01-01

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

  10. Murine Typhus, Reunion, France, 2011–2013

    PubMed Central

    Camuset, Guillaume; Socolovschi, Cristina; Moiton, Marie-Pierre; Kuli, Barbara; Foucher, Aurélie; Poubeau, Patrice; Borgherini, Gianandrea; Wartel, Guillaume; Audin, Héla; Raoult, Didier; Filleul, Laurent; Parola, Philippe; Pagès, Fréderic

    2015-01-01

    Murine typhus case was initially identified in Reunion, France, in 2012 in a tourist. Our investigation confirmed 8 autochthonous cases that occurred during January 2011–January 2013 in Reunion. Murine typhus should be considered in local patients and in travelers returning from Reunion who have fevers of unknown origin. PMID:25625653

  11. Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis

    PubMed Central

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

    2015-01-01

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

  12. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors

    PubMed Central

    2013-01-01

    Introduction Mesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors. Methods Bone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-culture system with mouse breast cancer cell 4T1 or human prostate cancer cell DU145. Tumor cells were injected into nude mice subcutaneously either alone or coupled with BM-MSCs. The expression of cell proliferation and angiogenesis-related proteins in tumor tissues were immunofluorescence analyzed. The angiogenic effect of BM-MSCs was detected using a tube formation assay. The effects of the crosstalk between tumor cells and BM-MSCs on expression of angiogenesis related markers were examined by immunofluorescence and real-time PCR. Results Both co-culturing with mice BM-MSCs (mBM-MSCs) and treatment with mBM-MSC-conditioned medium enhanced the growth of 4T1 cells. Co-injection of 4T1 cells and mBM-MSCs into nude mice led to increased tumor size compared with injection of 4T1 cells alone. Similar experiments using DU145 cells and human BM-MSCs (hBM-MSCs) instead of 4T1 cells and mBM-MSCs obtained consistent results. Compared with tumors induced by injection of tumor cells alone, the blood vessel area was greater in tumors from co-injection of tumor cells with BM-MSCs, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. Furthermore, both conditioned medium from hBM-MSCs alone and co-cultures of hBM-MSCs with DU145 cells were able to promote tube formation ability of human umbilical vein endothelial cells. When hBM-MSCs are exposed to the DU145 cell environment, the expression of markers associated with neovascularization (macrophage

  13. IL-10 regulates murine lupus.

    PubMed

    Yin, Zhinan; Bahtiyar, Gul; Zhang, Na; Liu, Lanzhen; Zhu, Ping; Robert, Marie E; McNiff, Jennifer; Madaio, Michael P; Craft, Joe

    2002-08-15

    MRL/MpJ-Tnfrsf6(lpr) (MRL/MpJ-Fas(lpr); MRL-Fas(lpr)) mice develop a spontaneous lupus syndrome closely resembling human systemic lupus erythematosus. To define the role of IL-10 in the regulation of murine lupus, IL-10 gene-deficient (IL-10(-/-)) MRL-Fas(lpr) (MRL-Fas(lpr) IL-10(-/-)) mice were generated and their disease phenotype was compared with littermates with one or two copies of an intact IL-10 locus (MRL-Fas(lpr) IL-10(+/-) and MRL-Fas(lpr) IL-10(+/+) mice, respectively). MRL-Fas(lpr) IL-10(-/-) mice developed severe lupus, with earlier appearance of skin lesions, increased lymphadenopathy, more severe glomerulonephritis, and higher mortality than their IL-10-intact littermate controls. The increased severity of lupus in MRL-Fas(lpr) IL-10(-/-) mice was closely associated with enhanced IFN-gamma production by both CD4(+) and CD8(+) cells and increased serum concentration of IgG2a anti-dsDNA autoantibodies. The protective effect of IL-10 in this lupus model was further supported by the observation that administration of rIL-10 reduced IgG2a anti-dsDNA autoantibody production in wild-type MRL-Fas(lpr) animals. In summary, our results provide evidence that IL-10 can down-modulate murine lupus through inhibition of pathogenic Th1 cytokine responses. Modulation of the level of IL-10 may be of potential therapeutic benefit for human lupus.

  14. Breast augmentation surgery

    MedlinePlus

    ... the shape of your breasts. Talk with a plastic surgeon if you are considering breast augmentation. Discuss ... mammograms or breast x-rays before surgery. The plastic surgeon will do a routine breast exam. Several ...

  15. 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, ...

  16. Breast reconstruction - natural tissue

    MedlinePlus

    ... After a mastectomy , some women choose to have cosmetic surgery to remake their breast. This type of surgery ... augmentation surgery Breast reconstruction - implants Mastectomy Patient Instructions Cosmetic breast surgery - discharge Mastectomy and breast reconstruction - what to ask ...

  17. Breast lump

    MedlinePlus

    ... a woman are often caused by fibrocystic changes, fibroadenomas, and cysts. Fibrocystic changes are painful, lumpy breasts. ... period, and then improve after your period starts. Fibroadenomas are noncancerous lumps that feel rubbery. They move ...

  18. Breast pain

    MedlinePlus

    ... chocolate in your diet helps reduce breast pain. Vitamin E, thiamine, magnesium, and evening primrose oil are not harmful, but most studies have not shown any benefit. Talk to your health care provider before starting ...

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2014-08-01

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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2014-04-18

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

  4. A Systematic Approach to Preclinical Trials in Metastatic Breast Cancer

    PubMed Central

    Rashid, OM; Maurente, D; Takabe, K

    2016-01-01

    The process of developing new agents for therapy against breast cancer is inefficient and relies on animal models to screen for efficacy for preclinical studies. However, there has been limited validation of these models, despite the increasing costs in the rapidly growing era of personalized medicine and targeted therapy. Recently, there have been multiple studies which have critically evaluated animal models for breast cancer drug discovery. We recently reviewed the transgenic, xenograft, and syngeneic murine breast cancer models, the ectopic, orthotopic and intravenous methods of cell implantation, tumor gene expression profiles, as well as the ethics of animal experimentation, and we provide important information for investigators in this challenging field. Because of the complexities of treating breast cancer and the increasing costs of developing new agents, the choice of the appropriate murine model must carefully consider each model available, including the tumor gene expression profile. Such a critical approach to the in vivo portion of drug development will further increase the efficiency of breast cancer drug research and development. PMID:27695662

  5. A Systematic Approach to Preclinical Trials in Metastatic Breast Cancer.

    PubMed

    Rashid, O M; Maurente, D; Takabe, K

    2016-09-01

    The process of developing new agents for therapy against breast cancer is inefficient and relies on animal models to screen for efficacy for preclinical studies. However, there has been limited validation of these models, despite the increasing costs in the rapidly growing era of personalized medicine and targeted therapy. Recently, there have been multiple studies which have critically evaluated animal models for breast cancer drug discovery. We recently reviewed the transgenic, xenograft, and syngeneic murine breast cancer models, the ectopic, orthotopic and intravenous methods of cell implantation, tumor gene expression profiles, as well as the ethics of animal experimentation, and we provide important information for investigators in this challenging field. Because of the complexities of treating breast cancer and the increasing costs of developing new agents, the choice of the appropriate murine model must carefully consider each model available, including the tumor gene expression profile. Such a critical approach to the in vivo portion of drug development will further increase the efficiency of breast cancer drug research and development.

  6. 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

  7. Treatment of metastatic breast cancer by combination of chemotherapy and photothermal ablation using doxorubicin-loaded DNA wrapped gold nanorods.

    PubMed

    Wang, Dangge; Xu, Zhiai; Yu, Haijun; Chen, Xianzhi; Feng, Bing; Cui, Zhirui; Lin, Bin; Yin, Qi; Zhang, Zhiwen; Chen, Chunying; Wang, Jun; Zhang, Wen; Li, Yaping

    2014-09-01

    Despite the exciting advances in cancer therapy over past decades, tumor metastasis remains the dominate reason for cancer-related mortality. In present work, DNA-wrapped gold nanorods with doxorubicin (DOX)-loading (GNR@DOX) were developed for treatment of metastatic breast cancer via a combination of chemotherapy and photothermal ablation. The GNR@DOX nanoparticles induced significant temperature elevation and DOX release upon irradiation with near infrared (NIR) light as shown in the test tube studies. It was found that GNR@DOX nanoparticles in combination with laser irradiation caused higher cytotoxicity than free DOX in 4T1 breast cancer cells. Animal experiment with an orthotropic 4T1 mammary tumor model demonstrated that GNR@DOX nanoplatform significantly reduced the growth of primary tumors and suppressed their lung metastasis. The Hematoxylin and Eosin (H&E) and immunohistochemistry (IHC) staining assays confirmed that the tumor growth inhibition and metastasis prevention of GNR@DOX nanoparticles were attributed to their abilities to induce cellular apoptosis/necrosis and ablate intratumoral blood vessels. All these results suggested a considerable potential of GNR@DOX nanoplatform for treatment of metastatic breast cancer.

  8. Maximizing Immune Response to Carbohydrate Antigens on Breast Tumors

    DTIC Science & Technology

    2003-08-01

    antigens expressed on breast tumors. Towards this end we are developing peptide mimotopes of tumor associated carbohydrate antigens as they are T cell...dependent antigens. In our progress to date we have shown the 1) immunization with peptide mimotope activates a specific cellular response to a model murine...tumor cell line; 2) vaccination of mice with peptide eradicates established tumor; 3) Immunization with DNA format of the peptide suppresses tumor

  9. Does Lactation Mitigate Triple Negative/Basal Breast Cancer Progression?

    DTIC Science & Technology

    2012-09-01

    cells. Science 1994, 263(5146):526-529. 11. Li JH, Man YG: Dual usages of single Wilms ’ tumor 1 immunohistochemistry in evaluation of breast tumors : a...mammary tumor cells (MCF10ADCIS.com and HCC70 cell lines) directly through the intact mouse teat into the correct anatomical location for ductal...may be preferentially compromised by tumors formed in postpartum involuting mammary glands but maintained by pregnancy. Our murine mammary

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

    PubMed

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

    2005-01-01

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

  11. Breast Carcinosarcomas

    PubMed Central

    Yakan, Savaş; Sarı, Erdem; Erkan, Nazif; Yıldırım, Mehmet; Vardar, Enver; Coşkun, Ali; Çetin, Durmuş Ali; Eliyatkın, Nükhet

    2014-01-01

    Objective Carcinosarcomas of the breast are rare and aggressive breast tumors. The optimal treatment strategies and the classification of these difficult to diagnose tumors are not clear in the literature due to their very low incidence. In this study, we aimed to evaluate patients who were operated on for breast carcinosarcoma and discuss the current literature. Materials and Methods Ten patients who were treated with a diagnosis of breast carcinosarcoma between January 2000 – March 2013 at the Izmir Bozyaka Teaching and Training Hospital General Surgery Clinics were retrospectively analyzed. Results The mean age of the patients was 59.7 (±13.4) years. Eight patients underwent modified radical mastectomy, one patient lumpectomy and one patient breast conserving surgery + sentinel lymph node biopsy procedures. The TNM stage of patients were identified as stage 1 in 2 patients, stage 2 in 6 patients, and stage 3 in 2 patients. 60-month disease-free survival rate was 52.5% (±18.6). The overall survival rate was 53.3% (±20.5). Four patients died during follow-up. Conclusion It is reported that the prognosis of carcinosarcomas are as poor as triple negative epithelial tumors. In contrast to the literature, in our study the disease-free and overall survival rates according to stage were not different from epithelial tumors. In this regard, prospective studies including more patients are required.

  12. Morphine Modulates Interleukin-4- or Breast Cancer Cell-induced Pro-metastatic Activation of Macrophages.

    PubMed

    Khabbazi, Samira; Goumon, Yannick; Parat, Marie-Odile

    2015-06-16

    Interactions between cancer cells and stromal cells in the tumour microenvironment play a key role in the control of invasiveness, metastasis and angiogenesis. Macrophages display a range of activation states in specific pathological contexts and alternatively activated (M2) macrophages can promote tumour aggressiveness. Opioids are able to modulate tumour growth and metastasis. We tested whether morphine modulates the activation of macrophages induced by (i) interleukin-4 (IL-4), the prototypical M2 polarization-inducing cytokine, or (ii) coculture with breast cancer cells. We showed that IL-4 causes increased MMP-9 production and expression of the alternative activation markers arginase-1 and MRC-1. Morphine prevented IL-4-induced increase in MMP-9 in a naloxone- and methylnaltrexone-reversible fashion. Morphine also prevented IL-4-elicited alternative activation of RAW264.7 macrophages. Expression of MMP-9 and arginase-1 were increased when RAW264.7 were subjected to paracrine activation by 4T1 cells, and this effect was prevented by morphine via an opioid receptor-mediated mechanism. Morphine further decreased 4T1 breast cancer cell invasion elicited by co-culture with RAW264.7. Reduction of MMP-9 expression and alternative activation of macrophages by morphine was confirmed using mouse bone marrow-derived macrophages. Taken together, our results indicate that morphine may modulate tumour aggressiveness by regulating macrophage protease production and M2 polarization within the tumour microenvironment.

  13. Cloning of the murine counterpart of the tumor-associated antigen H-L6: Epitope mapping of the human and murine L6 antigens

    SciTech Connect

    Edwards, C.P.; Farr, A.G.; Marken, J.S. |

    1995-10-03

    The murine monoclonal antibody (mAb) L6 was raised against human lung carcinoma cells and found to recognize an antigen which is highly expressed on lung, breast, colon, and ovarian carcinomas. Promising results in phase 1 clinical studies with this antibody or its chimerized counterpart suggest the antigen recognized by mAb L6 (H-L6) is an attractive target for monoclonal antibody-based cancer therapy. Further development of L6 as an anti-tumor-targeting agent would benefit from the development of a murine model. However, initial attempts to develop such a model were hampered by our inability to generate antibodies against the murine homologue of the L6 antigen, M-L6. Here we describe the preparation of the mAb 12A8, which was raised against murine thymic epithelial cells, the tissue distribution of the murine antigen recognized by 12A8, the cloning of a cDNA encoding the 12A8 target antigen, and the demonstration that this antigen is M-L6. Using H-L6/M-L6 chimeric proteins, we show that the region of the M-L6 protein recognized by mAb 12A8 corresponds to the region of H-L6 recognized by mAb L6. There are five amino acid differences in the regions of the H-L6 and M-L6 proteins recognized by L6 and 12A8, respectively. We further mapped the protein epitope recognized by L6 by individually exchanging each of these residues in H-L6 with the corresponding residue found in M-L6. Substitution of the single H-L6 residue Leu122 with Ser resulted in the H-L6 mutant HL6-L122S which failed to bind L6. The HL6-L122S mutant also failed to bind 12A8. Substituting residue Ser122 in M-L6 with Leu did not prevent 12A8 binding and did not result in L6 binding. The availability of mAb 12A8 and the finding that it recognizes the same region of M-L6 that is recognized by L6 on H-L6 might allow the development of a murine tumor model in which the L6 antigen can be further evaluated as a therapeutic target. 31 refs., 7 figs.

  14. Photo-nano immunotherapy for metastatic breast cancer using synergistic single-walled carbon nanotubes and glycated chitosan

    NASA Astrophysics Data System (ADS)

    Zhou, Feifan; Hasanjee, Aamr; Doughty, Austin; West, Connor; Liu, Hong; Chen, Wei R.

    2015-03-01

    In our previous work, we constructed a multifunctional nano system, using single-walled carbon nanotube (SWNT) and glycated chitosan (GC), which can synergize photothermal and immunological effects. To further confirm the therapy efficacy, with a metastatic mouse mammary tumor model (4T1), we investigate the therapy effects and immune response induced by SWNT-GC, under laser irradiation. Laser+SWNT-GC treatment not only suppressed the prime tumor, but also induced antitumor immune response. It could be developed into a promising treatment modality for the metastatic breast cancer.

  15. Selenium analogues of raloxifene as promising antiproliferative agents in treatment of breast cancer.

    PubMed

    Arsenyan, Pavel; Paegle, Edgars; Domracheva, Ilona; Gulbe, Anita; Kanepe-Lapsa, Iveta; Shestakova, Irina

    2014-11-24

    Synthetic protocols for the preparation of selenium analogues of raloxifene were elaborated. General aim of the current research is to improve the positive impact of selenium atom introduction in drug design. Antiproliferative activity on CCL-8 (mouse sarcoma), MDA-MB-435s (human melanoma), MES-SA (human uterus sarcoma), MCF-7 (human breast adenocarcinoma), HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma) tumor cell lines, and normal cell line NIH 3T3 (mouse fibroblasts) was studied. Influence of aminoethoxy "tail" and benzoyl group position on SAR was discussed. Results of in vivo studies on BALB/c female mice with 4T1 cell induced breast cancer model showed that selenium analogue of raloxifene is able to suppress estrogen-depending tumor growth.

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

    PubMed Central

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

    2016-01-01

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

  17. Breast awareness and screening.

    PubMed

    Harmer, Victoria

    Breast cancer is the most commonly diagnosed cancer in the UK. Breast awareness and screening, along with better treatment, can significantly improve outcomes, and more women than ever are now surviving the disease. This article discusses breast awareness and screening, symptoms and risk factors for breast cancer, and how nurses can raise breast awareness and screening uptake.

  18. 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 ...

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

    PubMed

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

    2017-02-15

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

  20. Breast Reconstruction

    MedlinePlus

    If you need a mastectomy, you have a choice about whether or not to have surgery to rebuild the shape of the breast. Instead of ... be done at the same time as the mastectomy, or it may be done later on. If ...

  1. Breast Implants

    MedlinePlus

    ... sale in the United States: saline-filled and silicone gel-filled. Both types have a silicone outer shell. They vary in size, shell thickness, ... implant them. Provide information on saline-filled and silicone gel-filled breast implants, including data supporting a ...

  2. Breast reduction

    MedlinePlus

    ... fade. The surgeon will make every effort to place the cuts so that scars are hidden. Cuts are usually made on the underside of the breast. Most of the time, the scars should not be noticeable, even in low-cut clothing.

  3. [Breast ductoscopy].

    PubMed

    Sharon, Eran; Avin, Ilan D; Leong, Wey

    2011-02-01

    The majority of benign and malignant breast diseases originate in the ductal system. Breast ductoscopy (BD) allows direct access to this ductal system and thus holds great promise in the diagnosis and surgical management of a number of breast diseases. BD was first developed over 20 years ago to investigate nipple discharge. Indeed, till now, this remains the most common indication. However, BD technology has been further developed for a variety of new clinical applications. For example, BD-guided ductal ravage combined with molecular and genetic analysis can be a powerful screening tool for women at high-risk of breast cancer. BD can also be used during lumpectomy to identify additional radiographically occult disease. This refined intraoperative margin assessment can help surgeons to achieve clear margins at the first excision while optimizing the extent of resection. In the future, this same precise intraoperative margin assessment may facilitate a variety of local ablative techniques including laser Over time, BD is likely to evolve beyond its current technological limitations to realize its full diagnostic and therapeutic potential. The article describes the technique of BD, reviews its evolution and discusses current and future applications.

  4. Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model

    PubMed Central

    Yang, F; Hu, M; Lei, Q; Xia, Y; Zhu, Y; Song, X; Li, Y; Jie, H; Liu, C; Xiong, Y; Zuo, Z; Zeng, A; Li, Y; Yu, L; Shen, G; Wang, D; Xie, Y; Ye, T; Wei, Y

    2015-01-01

    Breast carcinoma is the most common female cancer with considerable metastatic potential. Signal transducers and activators of the transcription 3 (Stat3) signaling pathway is constitutively activated in many cancers including breast cancer and has been validated as a novel potential anticancer target. Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3. The potency of nifuroxazide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that nifuroxazide decreased the viability of three breast cancer cell lines and induced apoptosis of cancer cells in a dose-dependent manner. In addition, western blot analysis demonstrated that the occurrence of its apoptosis was associated with activation of cleaved caspases-3 and Bax, downregulation of Bcl-2. Moreover, nifuroxazide markedly blocked cancer cell migration and invasion, and the reduction of phosphorylated-Stat3Tyr705, matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 50 mg/kg/day nifuroxazide suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without detectable toxicity. Meanwhile, histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells, MMP-9-positive cells and an increase in cleaved caspase-3-positive cells upon nifuroxazide. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung. Our data indicated that nifuroxazide may potentially be a therapeutic agent for growth and metastasis of breast cancer. PMID:25811798

  5. Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model.

    PubMed

    Yang, F; Hu, M; Lei, Q; Xia, Y; Zhu, Y; Song, X; Li, Y; Jie, H; Liu, C; Xiong, Y; Zuo, Z; Zeng, A; Li, Y; Yu, L; Shen, G; Wang, D; Xie, Y; Ye, T; Wei, Y

    2015-03-26

    Breast carcinoma is the most common female cancer with considerable metastatic potential. Signal transducers and activators of the transcription 3 (Stat3) signaling pathway is constitutively activated in many cancers including breast cancer and has been validated as a novel potential anticancer target. Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3. The potency of nifuroxazide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that nifuroxazide decreased the viability of three breast cancer cell lines and induced apoptosis of cancer cells in a dose-dependent manner. In addition, western blot analysis demonstrated that the occurrence of its apoptosis was associated with activation of cleaved caspases-3 and Bax, downregulation of Bcl-2. Moreover, nifuroxazide markedly blocked cancer cell migration and invasion, and the reduction of phosphorylated-Stat3(Tyr705), matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 50 mg/kg/day nifuroxazide suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without detectable toxicity. Meanwhile, histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells, MMP-9-positive cells and an increase in cleaved caspase-3-positive cells upon nifuroxazide. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung. Our data indicated that nifuroxazide may potentially be a therapeutic agent for growth and metastasis of breast cancer.

  6. Yin-yang effect of tumor infiltrating B cells in breast cancer: From mechanism to immunotherapy.

    PubMed

    Zhang, Zhigang; Zhu, Ying; Wang, Zhen; Zhang, Ting; Wu, Pin; Huang, Jian

    2017-05-01

    Breast cancer cells secrete chemokines, such as CXCL13, and antigens or express high endothelial venules, attracting B cells to infiltrate into the tumor microenvironment and play a "yin-yang" effect. They not only enhance the anti-tumor immune effect via secreting antibodies and influencing the Fas/FasL, CXCR4/CXCL12 and perforin pathways but they also promote the tumor to form a suppressive milieu by producing immunomodulatory factors and cytokines or using cell-to-cell education to induce the generation of Tregs or myeloid-derived suppressor cells (MDSCs). Currently, most studies on breast cancer tissue have indicated that B cell infiltration could predict better survival and response to therapy, but two studies have reported opposite results. In a 4T1 tumor-bearing BALB/c mice model, B cell-based immunotherapies were administered, but the efficiency was unstable. Herein, we review the "yin-yang" effect of B cells in breast cancer and discuss B cell-based immunotherapy. B cells are complex aggregates, and breast cancer is a heterogeneous disease. Further studies are urgently required to define the B cell subsets and to discover ways to use B cell-based immunotherapy in breast cancer.

  7. 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. ...

  8. Breast Reduction Surgery

    MedlinePlus

    ... considering breast reduction surgery, consult a board-certified plastic surgeon. It's important to understand what breast reduction ... risk of complications from breast reduction surgery. Your plastic surgeon will likely: Evaluate your medical history and ...

  9. 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 ...

  10. 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 ...

  11. 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 ...

  12. Breast Lift (Mastopexy)

    MedlinePlus

    ... removed and breast tissue is reshaped to restore firmness and raise the breasts. You might choose to ... get older, your breasts change — losing elasticity and firmness. There are many causes for these kinds of ...

  13. Breast reconstruction - implants

    MedlinePlus

    ... cosmetic surgery after breast cancer can improve your sense of well-being and your quality of life. Alternative Names Breast implants surgery References Roehl KR, Wilhelmi BJ, Phillips LG. Breast reconstruction. ...

  14. Activation of antitumor cytotoxic T lymphocytes by fusions of human dendritic cells and breast carcinoma cells

    PubMed Central

    Gong, Jianlin; Avigan, David; Chen, Dongshu; Wu, Zekui; Koido, Shigeo; Kashiwaba, Masahiro; Kufe, Donald

    2000-01-01

    We have reported that fusions of murine dendritic cells (DCs) and murine carcinoma cells reverse unresponsiveness to tumor-associated antigens and induce the rejection of established metastases. In the present study, fusions were generated with primary human breast carcinoma cells and autologous DCs. Fusion cells coexpressed tumor-associated antigens and DC-derived costimulatory molecules. The fusion cells also retained the functional potency of DCs and stimulated autologous T cell proliferation. Significantly, the results show that autologous T cells are primed by the fusion cells to induce MHC class I-dependent lysis of autologous breast tumor cells. These findings demonstrate that fusions of human breast cancer cells and DCs activate T cell responses against autologous tumors. PMID:10688917

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

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

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

  16. ABC- and SLC-Transporters in Murine and Bovine Mammary Epithelium - Effects of Prochloraz

    PubMed Central

    Yagdiran, Yagmur; Oskarsson, Agneta; Knight, Christopher H.; Tallkvist, Jonas

    2016-01-01

    Some chemicals are ligands to efflux transporters which may result in high concentrations in milk. Limited knowledge is available on the influence of maternal exposure to chemicals on the expression and function of transporters in the lactating mammary gland. We determined gene expression of ABC and SLC transporters in murine mammary tissue of different gestation and lactation stages, in murine mammary cells (HC11) featuring resting and secreting phenotypes and in bovine mammary tissue and cells (BME-UV). Effects on transporter expression and function of the imidazole fungicide prochloraz, previously reported to influence BCRP in mammary cells, was investigated on transporter expression and function in the two cell lines. Transporters studied were BCRP, MDR1, MRP1, OATP1A5/OATP1A2, OCTN1 and OCT1. Gene expressions of BCRP and OCT1 in murine mammary glands were increased during gestation and lactation, whereas MDR1, MRP1, OATP1A5 and OCTN1 were decreased, compared to expressions in virgins. All transporters measured in mammary glands of mice were detected in bovine mammary tissue and in HC11 cells, while only MDR1 and MRP1 were detected in BME-UV cells. Prochloraz treatment induced MDR1 gene and protein expression in both differentiated HC11 and BME-UV cells and increased protein function in HC11 cells, resulting in decreased accumulation of the MDR1 substrate digoxin. In conclusion, our results demonstrate that murine (HC11) and bovine (BME-UV) mammary epithelial cells can be applied to characterize expression and function of transporters as well as effects of contaminants on the mammary transporters. An altered expression, induced by a drug or toxic chemical, on any of the transporters expressed in the mammary epithelial cells during lactation may modulate the well-balanced composition of nutrients and/or secretion of contaminants in milk with potential adverse effects on breast-fed infants and dairy consumers. PMID:27028005

  17. Secretome proteomics reveals candidate non-invasive biomarkers of BRCA1 deficiency in breast cancer

    PubMed Central

    van der Groep, Petra; Jaspers, Janneke E.; Smolders, Yvonne H.C.M.; de Boer, Leon; Pham, Thang V.; Piersma, Sander R.; Rottenberg, Sven; Boven, Epie; Jonkers, Jos; van Diest, Paul J.; Jimenez, Connie R.

    2016-01-01

    Breast cancer arising in female BRCA1 mutation carriers is characterized by an aggressive phenotype and early age of onset. We performed tandem mass spectrometry-based proteomics of secretomes and exosome-like extracellular vesicles from BRCA1-deficient and BRCA1-proficient murine breast tumor models to identify extracellular protein biomarkers, which can be used as an adjunct to current diagnostic modalities in patients with BRCA1-deficient breast cancer. We identified 2,107 proteins, of which 215 were highly enriched in the BRCA1-deficient secretome. We demonstrated that BRCA1-deficient secretome proteins could cluster most human BRCA1- and BRCA2-related breast carcinomas at the transcriptome level. Topoisomerase I (TOP1) and P-cadherin (CDH3) expression was investigated by immunohistochemistry on tissue microarrays of a large panel of 253 human breast carcinomas with and without BRCA1/2 mutations. We showed that expression of TOP1 and CDH3 was significantly increased in human BRCA1-related breast carcinomas relative to sporadic cases (p = 0.002 and p < 0.001, respectively). Multiple logistic regression showed that TOP1 (adjusted odds ratio [OR] 3.75; 95% confidence interval [95% CI], 1.85 - 7.71, p < 0.001) as well as CDH3 positivity (adjusted OR 2.45; 95% CI, 1.08 - 5.49, p = 0.032) were associated with BRCA1/2-related breast carcinomas after adjustment for triple-negative phenotype and age. In conclusion, proteome profiling of secretome using murine breast tumor models is a powerful strategy to identify non-invasive candidate biomarkers of BRCA1-deficient breast cancer. We demonstrate that TOP1 and CDH3 are closely associated to BRCA1-deficient breast cancer. These data merit further investigation for early detection of tumors arising in BRCA1 mutation carriers. PMID:27566577

  18. 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

  19. Tumor tropism of intravenously injected human-induced pluripotent stem cell-derived neural stem cells and their gene therapy application in a metastatic breast cancer model.

    PubMed

    Yang, Jing; Lam, Dang Hoang; Goh, Sally Sallee; Lee, Esther Xingwei; Zhao, Ying; Tay, Felix Chang; Chen, Can; Du, Shouhui; Balasundaram, Ghayathri; Shahbazi, Mohammad; Tham, Chee Kian; Ng, Wai Hoe; Toh, Han Chong; Wang, Shu

    2012-05-01

    Human pluripotent stem cells can serve as an accessible and reliable source for the generation of functional human cells for medical therapies. In this study, we used a conventional lentiviral transduction method to derive human-induced pluripotent stem (iPS) cells from primary human fibroblasts and then generated neural stem cells (NSCs) from the iPS cells. Using a dual-color whole-body imaging technology, we demonstrated that after tail vein injection, these human NSCs displayed a robust migratory capacity outside the central nervous system in both immunodeficient and immunocompetent mice and homed in on established orthotopic 4T1 mouse mammary tumors. To investigate whether the iPS cell-derived NSCs can be used as a cellular delivery vehicle for cancer gene therapy, the cells were transduced with a baculoviral vector containing the herpes simplex virus thymidine kinase suicide gene and injected through tail vein into 4T1 tumor-bearing mice. The transduced NSCs were effective in inhibiting the growth of the orthotopic 4T1 breast tumor and the metastatic spread of the cancer cells in the presence of ganciclovir, leading to prolonged survival of the tumor-bearing mice. The use of iPS cell-derived NSCs for cancer gene therapy bypasses the sensitive ethical issue surrounding the use of cells derived from human fetal tissues or human embryonic stem cells. This approach may also help to overcome problems associated with allogeneic transplantation of other types of human NSCs.

  20. Breast ultrasound.

    PubMed

    Ueno, E

    1996-03-01

    In ultrasound, ultrasonic images are formed by means of echoes among tissues with different acoustic impedance. Acoustic impedance is the product of sound speed and bulk modulus. The bulk modulus expresses the elasticity of an object, and in the human body, the value is increased by conditions such as fibrosis and calcification. The sound speed is usually high in elastic tissues and low in water. In the body, it is lowest in the fatty tissue. Ultrasound echoes are strong on the surface of bones which are hard and have a high sound speed. In organs filled with air such as the lungs, the bulk modulus is low and the sound speed is extremely low at 340 m/s, which produce strong echoes (the sound speed in solid tissues is 1,530 m/s). Human tissue is constructed of units smaller than the ultrasonic beam, and it is necessary to understand back-scattering in order to understand the ultrasonic images of these tissues. When ultrasound passes through tissue, it is absorbed as thermal energy and attenuated. Fiber is a tissue with a high absorption and attenuation rate. When the rate increases, the posterior echoes are attenuated. However, in masses with a high water content such as cysts, the posterior echoes are accentuated. This phenomenon is an important, basic finding for determining the properties of tumors. Breast cancer can be classified into two types: stellate carcinoma and circumscribed carcinoma. Since stellate carcinoma is rich in fiber, the posterior echoes are attenuated or lacking. However, circumscribed carcinoma has a high cellularity and the posterior echoes are accentuated. The same tendency is also seen in benign tumors. In immature fibroadenomas, posterior echoes are accentuated, while in fibroadenomas with hyalinosis, the posterior echoes are attenuated. Therefore, if the fundamentals of this tissue characterization and the histological features are understood, reading of ultrasound becomes easy. Color Doppler has also been developed and has contributed

  1. Commonly dysregulated genes in murine APL cells

    PubMed Central

    Yuan, Wenlin; Payton, Jacqueline E.; Holt, Matthew S.; Link, Daniel C.; Watson, Mark A.; DiPersio, John F.; Ley, Timothy J.

    2007-01-01

    To identify genes that are commonly dysregulated in a murine model of acute promyelocytic leukemia (APL), we first defined gene expression patterns during normal murine myeloid development; serial gene expression profiling studies were performed with primary murine hematopoietic progenitors that were induced to undergo myeloid maturation in vitro with G-CSF. Many genes were reproducibly expressed in restricted developmental “windows,” suggesting a structured hierarchy of expression that is relevant for the induction of developmental fates and/or differentiated cell functions. We compared the normal myeloid developmental transcriptome with that of APL cells derived from mice expressing PML-RARα under control of the murine cathepsin G locus. While many promyelocyte-specific genes were highly expressed in all APL samples, 116 genes were reproducibly dysregulated in many independent APL samples, including Fos, Jun, Egr1, Tnf, and Vcam1. However, this set of commonly dysregulated genes was expressed normally in preleukemic, early myeloid cells from the same mouse model, suggesting that dysregulation occurs as a “downstream” event during disease progression. These studies suggest that the genetic events that lead to APL progression may converge on common pathways that are important for leukemia pathogenesis. PMID:17008535

  2. 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 ...

  3. 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 ...

  4. Benign Breast Conditions

    MedlinePlus

    ... tissue.Female breasts are very complex. The female breast is filled with parts called glands (organs that produce milk in women who have ... birth), fat, and fibrous (connecting) tissue. Within each breast, there are ... of glands and fibrous tissue. Most people associate breast abnormalities ...

  5. Functions of miR-146a and miR-222 in Tumor-associated Macrophages in Breast Cancer

    PubMed Central

    Li, Yanshuang; Zhao, Lianmei; Shi, Bianhua; Ma, Sisi; Xu, Zhenbiao; Ge, Yehua; Liu, Yanxin; Zheng, Dexian; Shi, Juan

    2015-01-01

    Tumor-associated macrophages (TAMs) play critical roles in promoting tumor progression and invasion. However, the molecular mechanisms underlying TAM regulation remain to be further investigated and may make significant contributions to cancer treatment. Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression that function by repressing specific target genes mainly at the post-transcriptional level. However, systematic studies of the functions and mechanisms of miRNAs in TAMs in tumor tissues are rare. In this study, miR-146a and miR-222 were shown to be significantly decreased in TAMs associated with the up-regulated NF-κB p50 subunit. miR-146a promoted the expression of some M2 macrophage phenotype molecules, and miR-146a antagomir transfected RAW264.7 monocyte-macrophage cells inhibited 4T1 tumor growth in vivo. Meanwhile, overexpression of miR-222 inhibited TAM chemotaxis, and miR-222 in TAMs inhibited 4T1 tumor growth by targeting CXCL12 and inhibiting CXCR4. These data revealed that miRNAs influence breast tumor growth by promoting the M2 type polarization or regulating the recruitment of TAMs. These observations suggest that endogenous miRNAs may exert an important role in controlling the polarization and function of TAMs in breast cancer. PMID:26689540

  6. Potential angiogenic role of platelet-activating factor in human breast cancer.

    PubMed

    Montrucchio, G; Sapino, A; Bussolati, B; Ghisolfi, G; Rizea-Savu, S; Silvestro, L; Lupia, E; Camussi, G

    1998-11-01

    This study investigated the presence of platelet-activating factor (PAF) in the lipid extracts of 18 primary breast carcinomas and 20 control breast tissues. The amount of PAF detected in breast carcinomas was significantly higher than in controls. The mass spectrometric analysis of PAF-bioactive lipid extract from breast carcinomas showed the presence of several molecular species of PAF, including C16-alkylPAF, C18-lysophosphatidylcholine (LPC), C16-LPC, lyso-PAF, and C16-acylPAF. The amount of bioactive PAF extracted from breast specimens significantly correlated with tumor vascularization revealed by the number of CD34-and CD31-positive cells. As C16-alkylPAF was previously shown to induce angiogenesis in vivo, we evaluated whether the thin layer chromatography-purified lipid extracts of breast specimens elicited neoangiogenesis in a murine model of subcutaneous Matrigel injection. The lipid extracts from specimens of breast carcinoma containing high levels of PAF bioactivity, but not from breast carcinomas containing low levels of PAF bioactivity or from normal breast tissue, induced a significant angiogenic response. This angiogenic response was significantly inhibited by the PAF receptor antagonist WEB 2170. T47D and MCF7 breast cancer cell lines, but not an immortalized nontumor breast cell line (MCF10), released PAF in the culture medium. A significant in vivo neoangiogenic response, inhibited by WEB 2170, was elicited by T47D and MCF7 but not by MCF10 culture medium. These results indicate that an increased concentration of PAF is present in tumors with high microvessel density and that PAF may account for the neoangiogenic activity induced in mice by the lipid extracts obtained from breast cancer. A contribution of PAF in the neovascularization of human breast cancer is suggested.

  7. Potential Angiogenic Role of Platelet-Activating Factor in Human Breast Cancer

    PubMed Central

    Montrucchio, Giuseppe; Sapino, Anna; Bussolati, Benedetta; Ghisolfi, Gianpiero; Rizea-Savu, Simona; Silvestro, Luigi; Lupia, Enrico; Camussi, Giovanni

    1998-01-01

    This study investigated the presence of platelet-activating factor (PAF) in the lipid extracts of 18 primary breast carcinomas and 20 control breast tissues. The amount of PAF detected in breast carcinomas was significantly higher than in controls. The mass spectrometric analysis of PAF-bioactive lipid extract from breast carcinomas showed the presence of several molecular species of PAF, including C16-alkylPAF, C18-lysophosphatidylcholine (LPC), C16-LPC, lyso-PAF, and C16-acylPAF. The amount of bioactive PAF extracted from breast specimens significantly correlated with tumor vascularization revealed by the number of CD34- and CD31-positive cells. As C16-alkylPAF was previously shown to induce angiogenesis in vivo, we evaluated whether the thin layer chromatography-purified lipid extracts of breast specimens elicited neoangiogenesis in a murine model of subcutaneous Matrigel injection. The lipid extracts from specimens of breast carcinoma containing high levels of PAF bioactivity, but not from breast carcinomas containing low levels of PAF bioactivity or from normal breast tissue, induced a significant angiogenic response. This angiogenic response was significantly inhibited by the PAF receptor antagonist WEB 2170. T47D and MCF7 breast cancer cell lines, but not an immortalized nontumor breast cell line (MCF10), released PAF in the culture medium. A significant in vivo neoangiogenic response, inhibited by WEB 2170, was elicited by T47D and MCF7 but not by MCF10 culture medium. These results indicate that an increased concentration of PAF is present in tumors with high microvessel density and that PAF may account for the neoangiogenic activity induced in mice by the lipid extracts obtained from breast cancer. A contribution of PAF in the neovascularization of human breast cancer is suggested. PMID:9811351

  8. 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

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

    PubMed

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

    2016-02-18

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

  10. Multiple functions of CXCL12 in a syngeneic model of breast cancer

    PubMed Central

    2010-01-01

    Background A growing body of work implicates chemokines, in particular CXCL12 and its receptors, in the progression and site-specific metastasis of various cancers, including breast cancer. Various agents have been used to block the CXCL12-CXCR4 interaction as a means of inhibiting cancer metastasis. However, as a potent chemotactic factor for leukocytes, CXCL12 also has the potential to enhance anti-cancer immunity. To further elucidate its role in breast cancer progression, CXCL12 and its antagonist CXCL12(P2G) were overexpressed in the syngeneic 4T1.2 mouse model of breast carcinoma. Results While expression of CXCL12(P2G) significantly inhibited metastasis, expression of wild-type CXCL12 potently inhibited both metastasis and primary tumor growth. The effects of wild-type CXCL12 were attributed to an immune response characterized by the induction of CD8+ T cell activity, enhanced cell-mediated cytotoxicity, increased numbers of CD11c+ cells in the tumor-draining lymph nodes and reduced accumulation of myeloid-derived suppressor cells in the spleen. Conclusions This study highlights the need to consider carefully therapeutic strategies that block CXCL12 signaling. Therapies that boost CXCL12 levels at the primary tumor site may prove more effective in the treatment of metastatic breast cancer. PMID:20849618

  11. Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy.

    PubMed

    Eloy, Josimar O; Petrilli, Raquel; Topan, José Fernando; Antonio, Heriton Marcelo Ribeiro; Barcellos, Juliana Palma Abriata; Chesca, Deise L; Serafini, Luciano Neder; Tiezzi, Daniel G; Lee, Robert J; Marchetti, Juliana Maldonado

    2016-05-01

    Paclitaxel and rapamycin have been reported to act synergistically to treat breast cancer. Albeit paclitaxel is available for breast cancer treatment, the most commonly used formulation in the clinic presents side effects, limiting its use. Furthermore, both drugs present pharmacokinetics drawbacks limiting their in vivo efficacy and clinic combination. As an alternative, drug delivery systems, particularly liposomes, emerge as an option for drug combination, able to simultaneously deliver co-loaded drugs with improved therapeutic index. Therefore, the purpose of this study is to develop and characterize a co-loaded paclitaxel and rapamycin liposome and evaluate it for breast cancer efficacy both in vitro and in vivo. Results showed that a SPC/Chol/DSPE-PEG (2000) liposome was able to co-encapsulate paclitaxel and rapamycin with suitable encapsulation efficiency values, nanometric particle size, low polydispersity and neutral zeta potential. Taken together, FTIR and thermal analysis evidenced drug conversion to the more bioavailable molecular and amorphous forms, respectively, for paclitaxel and rapamycin. The pegylated liposome exhibited excellent colloidal stability and was able to retain drugs encapsulated, which were released in a slow and sustained fashion. Liposomes were more cytotoxic to 4T1 breast cancer cell line than the free drugs and drugs acted synergistically, particularly when co-loaded. Finally, in vivo therapeutic evaluation carried out in 4T1-tumor-bearing mice confirmed the in vitro results. The co-loaded paclitaxel/rapamycin pegylated liposome better controlled tumor growth compared to the solution. Therefore, we expect that the formulation developed herein might be a contribution for future studies focusing on the clinical combination of paclitaxel and rapamycin.

  12. Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy

    PubMed Central

    Eloy, Josimar O.; Petrilli, Raquel; Topan, José Fernando; Antonio, Heriton Marcelo Ribeiro; Barcellos, Juliana Palma Abriata; Chesca, Deise L.; Serafini, Luciano Neder; Tiezzi, Daniel G.; Lee, Robert J.; Marchetti, Juliana Maldonado

    2016-01-01

    Paclitaxel and rapamycin have been reported to act synergistically to treat breast cancer. Albeit paclitaxel is available for breast cancer treatment, the most commonly used formulation in the clinic presents side effects, limiting its use. Furthermore, both drugs present pharmacokinetics drawbacks limiting their in vivo efficacy and clinic combination. As an alternative, drug delivery systems, particularly liposomes, emerge as an option for drug combination, able to simultaneously deliver co-loaded drugs with improved therapeutic index. Therefore, the purpose of this study is to develop and characterize a co-loaded paclitaxel and rapamycin liposome and evaluate it for breast cancer efficacy both in vitro and in vivo. Results showed that a SPC/Chol/DSPE-PEG (2000) liposome was able to co-encapsulate paclitaxel and rapamycin with suitable encapsulation efficiency values, nanometric particle size, low polydispersity and neutral zeta potential. Taken together, FTIR and thermal analysis evidenced drug conversion to the more bioavailable molecular and amorphous forms, respectively, for paclitaxel and rapamycin. The pegylated liposome exhibited excellent colloidal stability and was able to retain drugs encapsulated, which were released in a slow and sustained fashion. Liposomes were more cytotoxic to 4T1 breast cancer cell line than the free drugs and drugs acted synergistically, particularly when co-loaded. Finally, in vivo therapeutic evaluation carried out in 4T1-tumor-bearing mice confirmed the in vitro results. The co-loaded paclitaxel/rapamycin pegylated liposome better controlled tumor growth compared to the solution. Therefore, we expect that the formulation developed herein might be a contribution for future studies focusing on the clinical combination of paclitaxel and rapamycin. PMID:26836480

  13. Diagnosis of breast tumors after breast reduction.

    PubMed

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

    1996-01-01

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

  14. 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 ...

  15. Aging changes in the breast

    MedlinePlus

    ... age, a woman's breasts lose fat, tissue, and mammary glands. Many of these changes are due to the ... to their providers about mammograms. Images Female breast Mammary gland References Davidson NE. Breast cancer and benign breast ...

  16. Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer.

    PubMed

    Cerliani, Juan P; Vanzulli, Silvia I; Piñero, Cecilia Pérez; Bottino, María C; Sahores, Ana; Nuñez, Myriam; Varchetta, Romina; Martins, Rubén; Zeitlin, Eduardo; Hewitt, Stephen M; Molinolo, Alfredo A; Lanari, Claudia; Lamb, Caroline A

    2012-06-01

    Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors which have been implicated in breast cancer. The aim of this study was to evaluate FGFR-1, -2, -3, and -4 protein expressions in normal murine mammary gland development, and in murine and human breast carcinomas. Using immunohistochemistry and Western blot, we report a hormonal regulation of FGFR during postnatal mammary gland development. Progestin treatment of adult virgin mammary glands resulted in changes in localization of FGFR-3 from the cytoplasm to the nucleus, while treatment with 17-β-estradiol induced changes in the expressions and/or localizations of FGFR-2 and -3. In murine mammary carcinomas showing different degrees of hormone dependence, we found progestin-induced increased expressions, mainly of FGFR-2 and -3. These receptors were constitutively activated in hormone-independent variants. We studied three luminal human breast cancer cell lines growing as xenografts, which particularly expressed FGFR-2 and -3, suggesting a correlation between hormonal status and FGFR expression. Most importantly, in breast cancer samples from 58 patients, we found a strong association (P < 0.01; Spearman correlation) between FGFR-2 and -3 expressions and a weaker correlation of each receptor with estrogen receptor expression. FGFR-4 correlated with c-erbB2 over expression. We conclude that FGFR-2 and -3 may be mechanistically linked and can be potential targets for treatment of estrogen receptor-positive breast cancer patients.

  17. Furanodiene enhances the anti-cancer effects of doxorubicin on ERα-negative breast cancer cells in vitro.

    PubMed

    Zhong, Zhang-Feng; Qiang, Wen-An; Wang, Chun-Ming; Tan, Wen; Wang, Yi-Tao

    2016-03-05

    Furanodiene is a natural product isolated from Rhizoma curcumae, and exhibits broad-spectrum anti-cancer activities in vitro and in vivo. Our previous study proved that furanodiene could increase growth inhibition of steroidal agent in ERα-positive breast cancer cells, but whether furanodiene can influence ER status is not clear. In this study, we confirmed that furanodiene down-regulated the ERα protein expression level and inhibited E2-induced estrogen response element (ERE)-driven reporter plasmid activity in ERα-positive MCF-7 cells. Actually, ERα-knockdown cells were more sensitive than ERα positive cells to furanodiene on the cytotoxicity effect. So the anti-cancer effects of furanodiene and non-steroidal agent in breast cancer cells still requires further investigation. Our results showed that furanodiene exposure could enhance growth inhibitory effects of doxorubicin in ERα-negative MDA-MB-231 cells and ERα-low expression 4T1 cells. However, furanodiene did not increase the cytotoxicity of doxorubicin in ERα-positive breast cancer cells, non-tumorigenic breast epithelial cells, macrophage cells, hepatocytes cells, pheochromocytoma cells and cardiac myoblasts cells. Furanodiene enhances the anti-cancer effects of doxorubicin in ERα-negative breast cancer cells through suppressing cell viability via inducing apoptosis in mitochondria-caspases-dependent and reactive oxygen species-independent manners. These results indicate that furanodiene may be a promising and safety natural agent for cancer adjuvant therapy in the future.

  18. In vivo magnetic resonance imaging investigating the development of experimental brain metastases due to triple negative breast cancer.

    PubMed

    Hamilton, Amanda M; Foster, Paula J

    2017-02-01

    Triple negative breast cancer (TNBC), when associated with poor outcome, is aggressive in nature with a high incidence of brain metastasis and the shortest median overall patient survival after brain metastasis development compared to all other breast cancer subtypes. As therapies that control primary cancer and extracranial metastatic sites improve, the incidence of brain metastases is increasing and the management of patients with breast cancer brain metastases continues to be a significant clinical challenge. Mouse models have been developed to permit in depth evaluation of breast cancer metastasis to the brain. In this study, we compare the efficiency and metastatic potential of two experimental mouse models of TNBC. Longitudinal MRI analysis and end point histology were used to quantify initial cell arrest as well as the number and volume of metastases that developed in mouse brain over time. We showed significant differences in MRI appearance, tumor progression and model efficiency between the syngeneic 4T1-BR5 model and the xenogeneic 231-BR model. Since TNBC does not respond to many standard breast cancer treatments and TNBC brain metastases lack effective targeted therapies, these preclinical TNBC models represent invaluable tools for the assessment of novel systemic therapeutic approaches. Further pursuits of therapeutics designed to bypass the blood tumor barrier and permit access to the brain parenchyma and metastatic cells within the brain will be paramount in the fight to control and treat lethal metastatic cancer.

  19. Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor.

    PubMed

    Morgan, Hayley; Tumber, Anthony; Hill, Peter A

    2004-05-01

    Breast cancer cells frequently metastasize to the skeleton, where they induce OCL formation and activity, resulting in extensive bone destruction. However, the mechanisms by which breast cancer cells mediate increased osteolysis remain unclear. To elucidate this point, we investigated how 3 human breast cancer cell lines, MDA-MB-231, MDA-MB-435 and MCF-7, induce OCL formation using a murine osteoblast-spleen cell coculture system and compared their effects with a human colorectal cancer cell line, HCT-15; a human lung cancer cell line, HT-1080; and a normal human breast cell line, HME. The breast cancer cell lines supported OCL formation only when osteoblasts were present in spleen cell cocultures, whilst the non-breast cancer cell lines and the normal breast cell line, HME, had no effect. Fractionation of BCCM by ultrafiltration established that osteoclastogenic activity was associated with factors having m.w. >3 kDa. Breast cancer cell lines produced primarily PTHrP, with lesser amounts of IL-6, IL-11 and TNF-alpha. The effect of BCCM on OCL formation in osteoblast-spleen cell cocultures was partially prevented by a neutralising antibody to human PTHrP and completely prevented by a neutralising antibody to either murine IL-11 or the murine IL-11 receptor; neutralising antibodies to human IL-6, IL-11 or TNF-alpha were without effect. BCCM or human PTHrP induced an increase in murine osteoblast IL-11 mRNA and protein production, effects that were prevented in the presence of a neutralising antibody to human PTHrP. The osteoclastogenic activity of IL-11 was mediated by enhancing osteoblast production of PGE(2) effects, which were abrogated by an inhibitor of cyclooxygenase. PGE(2) apparently enhanced OCL formation by downregulating GM-CSF production by spleen cells since recombinant murine GM-CSF inhibited OCL formation and a neutralising antibody to murine GM-CSF blocked these inhibitory effects. We conclude that breast cancer cells induce OCL formation by

  20. Murine typhus: an unrecognized suburban vectorborne disease.

    PubMed

    Civen, Rachel; Ngo, Van

    2008-03-15

    Murine typhus, an acute febrile illness caused by Rickettsia typhi, is distributed worldwide. Mainly transmitted by the fleas of rodents, it is associated with cities and ports where urban rats (Rattus rattus and Rattus norvegicus) are abundant. In the United States, cases are concentrated in suburban areas of Texas and California. Contrary to the classic rat-flea-rat cycle, the most important reservoirs of infection in these areas are opossums and cats. The cat flea, Ctenocephalides felis, has been identified as the principal vector. In Texas, murine typhus cases occur in spring and summer, whereas, in California, cases have been documented in summer and fall. Most patients present with fever, and many have rash and headache. Serologic testing with the indirect immunofluorescence assay is the preferred diagnostic method. Doxycycline is the antibiotic of choice and has been shown to shorten the course of illness.

  1. An MMP13-Selective Inhibitor Delays Primary Tumor Growth and the Onset of Tumor-Associated Osteolytic Lesions in Experimental Models of Breast Cancer

    PubMed Central

    Shah, Manisha; Huang, Dexing; Blick, Tony; Connor, Andrea; Reiter, Lawrence A.; Hardink, Joel R.; Lynch, Conor C.; Waltham, Mark; Thompson, Erik W.

    2012-01-01

    We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]phenoxy}phenoxy)-5-(2-methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also significantly inhibited subsequent growth. In contrast, no effects of Cmpd-1 were observed on soft organ metastatic burden following intracardiac or mammary fat pad inoculations of MDA-MB-231 and 4T1.2-Luc cells respectively. MMP13 immunostaining of clinical primary breast tumors and experimental mice tumors revealed intra-tumoral and stromal expression in most tumors, and vasculature expression in all. MMP13 was also detected in osteoblasts in clinical samples of breast-to-bone metastases. The data suggest that MMP13-selective inhibitors, which lack musculoskeletal side effects, may have therapeutic potential both in primary breast cancer and cancer-induced bone osteolysis. PMID:22253746

  2. Enhanced Cultivation Of Stimulated Murine B Cells

    NASA Technical Reports Server (NTRS)

    Sammons, David W.

    1994-01-01

    Method of in vitro cultivation of large numbers of stimulated murine B lymphocytes. Cells electrofused with other cells to produce hybridomas and monoclonal antibodies. Offers several advantages: polyclonally stimulated B-cell blasts cultivated for as long as 14 days, hybridomas created throughout culture period, yield of hybridomas increases during cultivation, and possible to expand polyclonally in vitro number of B cells specific for antigenic determinants first recognized in vivo.

  3. 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

  4. Anandamide inhibits adhesion and migration of breast cancer cells

    SciTech Connect

    Grimaldi, Claudia; Pisanti, Simona; Laezza, Chiara; Malfitano, Anna Maria; Santoro, Antonietta; Vitale, Mario; Caruso, Maria Gabriella; Notarnicola, Maria; Iacuzzo, Irma; Portella, Giuseppe; Di Marzo, Vincenzo . E-mail: vdimarzo@icmib.na.cnr.it; Bifulco, Maurizio . E-mail: maubiful@unina.it

    2006-02-15

    The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB{sub 1} receptors could induce a non-invasive phenotype in breast mtastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB{sub 1} antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB{sub 1} receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB{sub 1} receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo.

  5. Liposomal Nanoparticles Carrying anti-IL6R Antibody to the Tumour Microenvironment Inhibit Metastasis in Two Molecular Subtypes of Breast Cancer Mouse Models

    PubMed Central

    Guo, Chunlei; Chen, Yanan; Gao, Wenjuan; Chang, Antao; Ye, Yujie; Shen, Wenzhi; Luo, Yunping; Yang, Shengyong; Sun, Peiqing; Xiang, Rong; Li, Na

    2017-01-01

    Tumour microenvironment (TME) contributes significantly towards potentiating the stemness and metastasis properties of cancer cells. IL6-Stat3 is one of the important cell signaling pathways in mediating the communication between tumour and immune cells. Here, we have systematically developed a novel anti-CD44 antibody-mediated liposomal nanoparticle delivery system loaded with anti-IL6R antibody, which could specifically target the TME of CD44+ breast cancer cells in different mouse models for triple negative and luminal breast cancer. This nanoparticle had an enhanced and specific tumour targeting efficacy with dramatic anti-tumour metastasis effects in syngeneic BALB/c mice bearing 4T1 cells as was in the syngeneic MMTV-PyMT mice. It inhibited IL6R-Stat3 signaling and moderated the TME, characterized by the reduced expression of genes encoding Stat3, Sox2, VEGFA, MMP-9 and CD206 in the breast tissues. Furthermore, this nanoparticle reduced the subgroups of Sox2+ and CD206+ cells in the lung metastatic foci, demonstrating its inhibitory effect on the lung metastatic niche for breast cancer stem cells. Taken together, the CD44 targeted liposomal nanoparticles encapsulating anti-IL6R antibody achieved a significant effect to inhibit the metastasis of breast cancer in different molecular subtypes of breast cancer mouse models. Our results shed light on the application of nanoparticle mediated cancer immune-therapy through targeting TME. PMID:28255366

  6. Aluminium chloride promotes tumorigenesis and metastasis in normal murine mammary gland epithelial cells

    PubMed Central

    Tenan, Mirna; Ferrari, Paolo; Sappino, André‐Pascal

    2016-01-01

    Aluminium salts, present in many industrial products of frequent use like antiperspirants, anti‐acid drugs, food additives and vaccines, have been incriminated in contributing to the rise in breast cancer incidence in Western societies. However, current experimental evidence supporting this hypothesis is limited. For example, no experimental evidence that aluminium promotes tumorigenesis in cultured mammary epithelial cells exists. We report here that long‐term exposure to concentrations of aluminium—in the form of aluminium chloride (AlCl3)—in the range of those measured in the human breast, transform normal murine mammary gland (NMuMG) epithelial cells in vitro as revealed by the soft agar assay. Subcutaneous injections into three different mouse strains with decreasing immunodeficiency, namely, NOD SCID gamma (NSG), NOD SCID or nude mice, revealed that untreated NMuMG cells form tumors and metastasize, to a limited extent, in the highly immunodeficient and natural killer (NK) cell deficient NSG strain, but not in the less permissive and NK cell competent NOD SCID or nude strains. In contrast, NMuMG cells transformed in vitro by AlCl3 form large tumors and metastasize in all three mouse models. These effects correlate with a mutagenic activity of AlCl3. Our findings demonstrate for the first time that concentrations of aluminium in the range of those measured in the human breast fully transform cultured mammary epithelial cells, thus enabling them to form tumors and metastasize in well‐established mouse cancer models. Our observations provide experimental evidence that aluminium salts could be environmental breast carcinogens. PMID:27541736

  7. Loss of caveolin-1 alters extracellular matrix protein expression and ductal architecture in murine mammary glands

    PubMed Central

    Thompson, Christopher; Hielscher, Abigail

    2017-01-01

    The extracellular matrix (ECM) is abnormal in breast tumors and has been reported to contribute to breast tumor progression. One factor, which may drive ongoing matrix synthesis in breast tumors, is the loss of stromal caveolin-1 (cav-1), a scaffolding protein of caveolae, which has been linked to breast tumor aggressiveness. To determine whether loss of cav-1 results in the abnormal expression of matrix proteins, mammary glands from cav- 1-/- and cav- 1 +/+ mice were investigated for differences in expression of several ECM proteins. In addition, the presence of myofibroblasts, changes in the vessel density, and differences in duct number and size were assessed in the mammary glands of both animal models. Using immunohistochemistry, expression of fibronectin, tenascin-C, collagens and αSMA were significantly increased in the mammary glands of cav-1-/- mice. Second harmonic generation revealed more organized collagen fibers in cav-1 -/- glands and supported immunohistochemical analyses of increased collagen abundance in the glands of cav-1 -/- mice. Analysis of the ductal structure demonstrated a significant increase in the number of proliferating ducts in addition to significant increases in the duct circumference and area in cav-1 -/- glands compared to cav- 1 +/+ glands. Differences in microvessel density weren’t apparent between the animal models. In summary, we found that the loss of cav-1 resulted in increased ECM and α-SMA protein expression in murine mammary glands. Furthermore, we found that an abnormal ductal architecture accompanied the loss of cav-1. These data support a role for cav-1 in maintaining mammary gland structure. PMID:28187162

  8. Loss of caveolin-1 alters extracellular matrix protein expression and ductal architecture in murine mammary glands.

    PubMed

    Thompson, Christopher; Rahim, Sahar; Arnold, Jeremiah; Hielscher, Abigail

    2017-01-01

    The extracellular matrix (ECM) is abnormal in breast tumors and has been reported to contribute to breast tumor progression. One factor, which may drive ongoing matrix synthesis in breast tumors, is the loss of stromal caveolin-1 (cav-1), a scaffolding protein of caveolae, which has been linked to breast tumor aggressiveness. To determine whether loss of cav-1 results in the abnormal expression of matrix proteins, mammary glands from cav- 1-/- and cav- 1 +/+ mice were investigated for differences in expression of several ECM proteins. In addition, the presence of myofibroblasts, changes in the vessel density, and differences in duct number and size were assessed in the mammary glands of both animal models. Using immunohistochemistry, expression of fibronectin, tenascin-C, collagens and αSMA were significantly increased in the mammary glands of cav-1-/- mice. Second harmonic generation revealed more organized collagen fibers in cav-1 -/- glands and supported immunohistochemical analyses of increased collagen abundance in the glands of cav-1 -/- mice. Analysis of the ductal structure demonstrated a significant increase in the number of proliferating ducts in addition to significant increases in the duct circumference and area in cav-1 -/- glands compared to cav- 1 +/+ glands. Differences in microvessel density weren't apparent between the animal models. In summary, we found that the loss of cav-1 resulted in increased ECM and α-SMA protein expression in murine mammary glands. Furthermore, we found that an abnormal ductal architecture accompanied the loss of cav-1. These data support a role for cav-1 in maintaining mammary gland structure.

  9. Recovery of extracellular vesicles from human breast milk is influenced by sample collection and vesicle isolation procedures

    PubMed Central

    Zonneveld, Marijke I.; Brisson, Alain R.; van Herwijnen, Martijn J. C.; Tan, Sisareuth; van de Lest, Chris H. A.; Redegeld, Frank A.; Garssen, Johan; Wauben, Marca H. M.; Nolte-'t Hoen, Esther N. M.

    2014-01-01

    Extracellular vesicles (EV) in breast milk carry immune relevant proteins and could play an important role in the instruction of the neonatal immune system. To further analyze these EV and to elucidate their function it is important that native populations of EV can be recovered from (stored) breast milk samples in a reproducible fashion. However, the impact of isolation and storage procedures on recovery of breast milk EV has remained underexposed. Here, we aimed to define parameters important for EV recovery from fresh and stored breast milk. To compare various protocols across different donors, breast milk was spiked with a well-defined murine EV population. We found that centrifugation of EV down into density gradients largely improved density-based separation and isolation of EV, compared to floatation up into gradients after high-force pelleting of EV. Using cryo-electron microscopy, we identified different subpopulations of human breast milk EV and a not previously described population of lipid tubules. Additionally, the impact of cold storage on breast milk EV was investigated. We determined that storing unprocessed breast milk at −80°C or 4°C caused death of cells present in breast milk, leading to contamination of the breast milk EV population with storage-induced EV. Here, an alternative method is proposed to store breast milk samples for EV analysis at later time points. The proposed adaptations to the breast milk storage and EV isolation procedures can be applied for EV-based biomarker profiling of breast milk and functional analysis of the role of breast milk EV in the development of the neonatal immune system. PMID:25206958

  10. Stereotactic Image-Guided Navigation During Breast Reconstruction in Patients With Breast Cancer

    ClinicalTrials.gov

    2017-04-12

    Ductal Breast Carcinoma in Situ; Lobular Breast Carcinoma in Situ; 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. Breast radiation - discharge

    MedlinePlus

    Radiation - breast - discharge ... away around 4 to 6 weeks after the radiation treatment is over. You may notice changes in ... breast looks or feels (if you are getting radiation after a lumpectomy). These changes include: Soreness or ...

  12. Breast self-exam

    MedlinePlus

    ... hand, gently yet firmly press down using small motions to examine the entire right breast. Next, sit ... Accessed April 25, 2016. US Preventive Services Task Force. Breast cancer: screening. January 2016. www.uspreventiveservicestaskforce.org/ ...

  13. 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 ...

  14. Breastfeeding and Breast Milk

    MedlinePlus

    ... NICHD Research Information Clinical Trials Resources and Publications Breastfeeding and Breast Milk: Condition Information Skip sharing on social media links Share this: Page Content Breastfeeding and Breast Milk: Condition Information​ ​​Breastfeeding, also called ...

  15. 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. ...

  16. Risks of Breast Implants

    MedlinePlus

    ... has traveled to other parts of the body. Connective Tissue Disease The FDA has not detected any association between silicone gel-filled breast implants and connective tissue disease, breast cancer, or reproductive problems. In order ...

  17. 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 ...

  18. 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 ...

  19. Cosmetic breast surgery - discharge

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000273.htm Cosmetic breast surgery - discharge To use the sharing features on this page, please enable JavaScript. You had cosmetic breast surgery to change the size or shape ...

  20. Breast lump removal

    MedlinePlus

    Lumpectomy; Wide local excision; Breast conservation surgery; Breast-sparing surgery; Partial mastectomy ... a wire localization will be done before the surgery. A radiologist will use a mammogram or ultrasound ...

  1. Broccoli Sprout Extract in Treating Patients With Breast Cancer

    ClinicalTrials.gov

    2017-02-14

    Ductal Breast Carcinoma; Ductal Breast Carcinoma In Situ; Estrogen Receptor Negative; Estrogen Receptor Positive; Invasive Breast Carcinoma; Lobular Breast Carcinoma; Postmenopausal; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer

  2. 2’-Behenoyl-Paclitaxel Conjugate Containing Lipid Nanoparticles for the Treatment of Metastatic Breast Cancer

    PubMed Central

    Ma, Ping; Benhabbour, S. Rahima; Feng, Lan; Mumper, Russell J

    2012-01-01

    The aim of these studies was to develop a novel 2’-behenoyl-paclitaxel (C22-PX) conjugate nanoparticle (NP) formulation for the treatment of metastatic breast cancer. A lipophilic paclitaxel derivative C22-PX was synthesized and incorporated into lipid-based NPs. Free C22-PX and its NP formulation were evaluated in a series of in-vitro and in-vivo studies. The results demonstrated that C22-PX NPs were much better tolerated and had significantly higher plasma and tumor AUCs compared to Taxol at the maximum tolerated dose (MTD) in a subcutaneous 4T1 mouse mammary carcinoma model. These benefits resulted in significantly improved antitumor efficacy with the NP-based formulation. PMID:22902506

  3. 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 ...

  4. Biology of breast cancer during pregnancy using genomic profiling.

    PubMed

    Azim, Hatem A; Brohée, Sylvain; Peccatori, Fedro A; Desmedt, Christine; Loi, Sherene; Lambrechts, Diether; Dell'Orto, Patrizia; Majjaj, Samira; Jose, Vinu; Rotmensz, Nicole; Ignatiadis, Michail; Pruneri, Giancarlo; Piccart, Martine; Viale, Giuseppe; Sotiriou, Christos

    2014-08-01

    Breast cancer during pregnancy is rare and is associated with relatively poor prognosis. No information is available on its biological features at the genomic level. Using a dataset of 54 pregnant and 113 non-pregnant breast cancer patients, we evaluated the pattern of hot spot somatic mutations and did transcriptomic profiling using Sequenom and Affymetrix respectively. We performed gene set enrichment analysis to evaluate the pathways associated with diagnosis during pregnancy. We also evaluated the expression of selected cancer-related genes in pregnant and non-pregnant patients and correlated the results with changes occurring in the normal breast using a pregnant murine model. We finally investigated aberrations associated with disease-free survival (DFS). No significant differences in mutations were observed. Of the total number of patients, 18.6% of pregnant and 23% of non-pregnant patients had a PIK3CA mutation. Around 30% of tumors were basal, with no differences in the distribution of breast cancer molecular subtypes between pregnant and non-pregnant patients. Two pathways were enriched in tumors diagnosed during pregnancy: the G protein-coupled receptor pathway and the serotonin receptor pathway (FDR <0.0001). Tumors diagnosed during pregnancy had higher expression of PD1 (PDCD1; P=0.015), PDL1 (CD274; P=0.014), and gene sets related to SRC (P=0.004), IGF1 (P=0.032), and β-catenin (P=0.019). Their expression increased almost linearly throughout gestation when evaluated on the normal breast using a pregnant mouse model underscoring the potential effect of the breast microenvironment on tumor phenotype. No genes were associated with DFS in a multivariate model, which could be due to low statistical power. Diagnosis during pregnancy impacts the breast cancer transcriptome including potential cancer targets.

  5. RNAi-mediated gene silencing of vascular endothelial growth factor C suppresses growth and induces apoptosis in mouse breast cancer in vitro and in vivo

    PubMed Central

    Liu, Yong-Chao; Ma, Wen-Hui; Ge, Yin-Lin; Xue, Mei-Lan; Zhang, Zheng; Zhang, Jin-Yu; Hou, Lin; Mu, Run-Hong

    2016-01-01

    Vascular endothelial cell growth factor (VEGF)-C promotes tumorigenesis by allowing lymph node metastasis and lymphangiogenesis, among other actions. RNA interference (RNAi) is a novel technique for suppressing target gene expression and may increase the effectiveness of cancer treatments. The present study assessed the influence of VEGF-C RNAi on the apoptosis and proliferation of mouse breast cancer cells in vitro and in vivo. A total of three pairs of small interfering RNA (siRNA) targeting mouse VEGF-C were designed and synthesized prior to transfection into 4T1 cells via a liposomal approach. Reverse transcription polymerase chain reaction, western blot analysis, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Hoechst 33258 staining and flow cytometry were performed in vitro to analyze VEGF-C expression, cleaved caspase-3 protein expression and 4T1 cell proliferation and apoptosis. Experiments were also conducted in vivo on BALB/c mice with breast cancer. Tumor weight and volume were measured and the number of apoptotic cells in tumor tissues was assessed by a TUNEL assay. Immunohistochemical assays and an enzyme-linked immunosorbent assay were used to measure the expression of VEGF-C in tumor tissues. The results demonstrated that the three pairs of siRNA, particularly siV2, significantly reduced VEGF-C mRNA and protein levels in 4T1 cells. siV2 was deemed to be the most efficient siRNA and therefore was selected to be used in subsequent experiments. Furthermore, in vitro studies indicated that VEGF-C RNAi significantly decreased cell growth, induced apoptosis and upregulated the expression of cleaved caspase-3 protein. Tumor weight and volume in breast cancer in vivo models was reduced by the intratumoral injection of siV2. Antitumor efficacy was associated with decreased VEGF-C expression and increased induction of apoptosis. The present study therefore indicated that VEGF-C RNAi inhibited mouse breast cancer growth in vitro and in

  6. Breast-Conserving Surgery Followed by Radiation Therapy With MRI-Detected Stage I or Stage II Breast Cancer

    ClinicalTrials.gov

    2011-12-07

    Ductal Breast Carcinoma in Situ; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Male Breast Cancer; Medullary Ductal Breast Carcinoma With Lymphocytic Infiltrate; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Tubular Ductal Breast Carcinoma

  7. Docosahexaenoic Acid in Preventing Recurrence in Breast Cancer Survivors

    ClinicalTrials.gov

    2016-06-20

    Benign Breast Neoplasm; Ductal Breast Carcinoma In Situ; Invasive Breast Carcinoma; Lobular Breast Carcinoma In Situ; Paget Disease of the Breast; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  8. Oil-filled Lipid Nanoparticles Containing 2’-(2-bromohexadecanoyl)-docetaxel for the Treatment of Breast Cancer

    PubMed Central

    Feng, Lan; Benhabbour, Soumya R.; Mumper, Russell J.

    2013-01-01

    A docetaxel (DX) lipid conjugate 2’-(2-bromohexadecanoyl)-docetaxel (2-Br-C16-DX) is synthesized to enhance the drug loading, entrapment and retention in liquid oil-filled lipid nanoparticles (NPs). The conjugate is successfully entrapped in the previously optimized NPs with an entrapment efficiency of 56.8%. In-vitro release studies in 100% mouse plasma show an initial 45% burst release with no additional release within 8 hr. The conjugate is able to be hydrolyzed to release DX by esterases in-vitro. The conjugate is less potent than unmodified DX in DU-145 and 4T1 cells. However, NPs containing the conjugate show significantly higher cytotoxicity compared to its free form especially in 4T1 cells. In-vivo, the AUC0-∞ value of NP-formulated 2-Br-C16-DX is about 100-fold higher than DX formulated in Taxotere. Furthermore, 2-Br-C16-DX NPs improve DX AUC 4.3-fold compared to Taxotere. The high concentration and prolonged exposure of both 2-Br-C16-DX and DX from 2-Br-C16-DX NPs in circulation result in a 10-fold and 1.5-fold higher accumulation of 2-Br-C16-DX and DX, respectively, in tumors compared to Taxotere. In mice bearing syngeneic 4T1 tumors, 2-Br-C16-DX NPs show markedly greater anticancer efficacy as well as survival benefit over all controls. The results of these studies support that the oil-filled NPs containing hydrolyzable lipophilic DX prodrug 2-Br-C16-DX improve the therapeutic index of DX and are more efficacious in the treatment of breast cancer. PMID:23606545

  9. 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.

  10. Efficacy of posaconazole in murine experimental sporotrichosis.

    PubMed

    Fernández-Silva, Fabiola; Capilla, Javier; Mayayo, Emilio; Guarro, Josep

    2012-05-01

    We developed a murine model of systemic sporotrichosis by using three strains of each of the two commonest species causing sporotrichosis, i.e., Sporothrix schenckii sensu stricto and Sporothrix brasiliensis, in order to evaluate the efficacy of posaconazole (PSC). The drug was administered at a dose of 2.5 or 5 mg/kg of body weight twice a day by gavage, and one group was treated with amphotericin B (AMB) as a control treatment. Posaconazole, especially at 5 mg/kg, showed good efficacy against all the strains tested, regardless of their MICs, as measured by prolonged survival, tissue burden reduction, and histopathology.

  11. Efficacy of Posaconazole in Murine Experimental Sporotrichosis

    PubMed Central

    Fernández-Silva, Fabiola; Capilla, Javier; Mayayo, Emilio

    2012-01-01

    We developed a murine model of systemic sporotrichosis by using three strains of each of the two commonest species causing sporotrichosis, i.e., Sporothrix schenckii sensu stricto and Sporothrix brasiliensis, in order to evaluate the efficacy of posaconazole (PSC). The drug was administered at a dose of 2.5 or 5 mg/kg of body weight twice a day by gavage, and one group was treated with amphotericin B (AMB) as a control treatment. Posaconazole, especially at 5 mg/kg, showed good efficacy against all the strains tested, regardless of their MICs, as measured by prolonged survival, tissue burden reduction, and histopathology. PMID:22330929

  12. Irradiation Design for an Experimental Murine Model

    SciTech Connect

    Ballesteros-Zebadua, P.; Moreno-Jimenez, S.; Suarez-Campos, J. E.; Celis, M. A.; Larraga-Gutierrez, J. M.; Garcia-Garduno, O. A.; Rubio-Osornio, M. C.; Custodio-Ramirez, V.; Paz, C.

    2010-12-07

    In radiotherapy and stereotactic radiosurgery, small animal experimental models are frequently used, since there are still a lot of unsolved questions about the biological and biochemical effects of ionizing radiation. This work presents a method for small-animal brain radiotherapy compatible with a dedicated 6MV Linac. This rodent model is focused on the research of the inflammatory effects produced by ionizing radiation in the brain. In this work comparisons between Pencil Beam and Monte Carlo techniques, were used in order to evaluate accuracy of the calculated dose using a commercial planning system. Challenges in this murine model are discussed.

  13. Irradiation Design for an Experimental Murine Model

    NASA Astrophysics Data System (ADS)

    Ballesteros-Zebadúa, P.; Lárraga-Gutierrez, J. M.; García-Garduño, O. A.; Rubio-Osornio, M. C.; Custodio-Ramírez, V.; Moreno-Jimenez, S.; Suarez-Campos, J. E.; Paz, C.; Celis, M. A.

    2010-12-01

    In radiotherapy and stereotactic radiosurgery, small animal experimental models are frequently used, since there are still a lot of unsolved questions about the biological and biochemical effects of ionizing radiation. This work presents a method for small-animal brain radiotherapy compatible with a dedicated 6MV Linac. This rodent model is focused on the research of the inflammatory effects produced by ionizing radiation in the brain. In this work comparisons between Pencil Beam and Monte Carlo techniques, were used in order to evaluate accuracy of the calculated dose using a commercial planning system. Challenges in this murine model are discussed.

  14. Characterization of Murine Gammaherpesvirus 68 Glycoprotein B

    PubMed Central

    Lopes, Filipa B.; Colaco, Susanna; May, Janet S.; Stevenson, Philip G.

    2004-01-01

    Murine gammaherpesvirus 68 (MHV-68) glycoprotein B (gB) was identified in purified virions by immunoblotting, immunoprecipitation, and immunoelectron microscopy. It was synthesized as a 120-kDa precursor in infected cells and cleaved into 65-kDa and 55-kDa disulfide-linked subunits close to the time of virion release. The N-linked glycans on the cleaved, virion gB remained partially endoglycosidase H sensitive. The processing of MHV-68 gB therefore appears similar to that of Kaposi's sarcoma-associated herpesvirus gB and human cytomegalovirus gB. PMID:15542690

  15. Role of Activin A in Immune Response to Breast Cancer

    DTIC Science & Technology

    2015-12-01

    obstacle to the success of immunotherapy in both human and animal studies is the development of immunologic tolerance in tumor- bearing hosts. Therefore...overtime in 4T1shSCR or 4T1shInhba-tumor bearing mice treated w/o local RT (n=10 per group). Data are representative of two independent experiments...pɘ.05. (C) Survival of 4T1shSCR or 4T1shInhba-tumor bearing mice treated w/o local RT (n=7/group). Data are representative of two independent

  16. Autophagy regulation in the development and treatment of breast cancer

    PubMed Central

    Zhou, Yuting; Rucker, Edmund B.; Zhou, Binhua P.

    2016-01-01

    Autophagy is a major catabolic process in which intracellular membrane structures, protein complexes, and lysosomes are formed as lysoautophagosome to degrade and renew cytoplasmic components. Autophagy is physiologically a strategy and mechanism for cellular homeostasis as well as adaptation to stress, and thus alterations in the autophagy machinery may lead to diverse pathological conditions. The role of autophagy in cancer is complex, and the current literature reflects this as a ‘double-edged sword’. Autophagy shows promise as a novel therapeutic target in various types of breast cancer, inhibiting or increasing treatment efficacy in a context- and cell-type-dependent manner. This review aims to summarize the recent advances in the understanding of the mechanisms by which key modulators of autophagy participate in cancer metastasis, highlight different autophagy-deficient murine models for breast cancer study, and provide further impetus for the modulation of autophagy in anticancer therapy. PMID:26637829

  17. Reemergence of murine typhus in Galveston, Texas, USA, 2013.

    PubMed

    Blanton, Lucas S; Vohra, Rahat F; Bouyer, Donald H; Walker, David H

    2015-03-01

    Twelve patients with murine typhus were identified in Galveston, Texas, USA, in 2013. An isolate from 1 patient was confirmed to be Rickettsia typhi. Reemergence of murine typhus in Galveston emphasizes the importance of vector control and awareness of this disease by physicians and public health officials.

  18. An Unusual Cutaneous Manifestation in a Patient with Murine Typhus

    PubMed Central

    Blanton, Lucas S.; Lea, Alfred S.; Kelly, Brent C.; Walker, David H.

    2015-01-01

    Murine typhus is a flea-borne febrile illness caused by Rickettsia typhi. Although often accompanied by rash, an inoculation lesion has not been observed as it is with many tick- and mite-transmitted rickettsioses. We describe a patient with murine typhus and an unusual cutaneous manifestation at the site of rickettsial inoculation. PMID:26416115

  19. The future of murine sepsis and trauma research models

    PubMed Central

    Efron, Philip A.; Mohr, Alicia M.; Moore, Frederick A.; Moldawer, Lyle L.

    2015-01-01

    Recent comparisons of the murine and human transcriptome in health and disease have called into question the appropriateness of the use of murine models for human sepsis and trauma research. More specifically, researchers have debated the suitability of mouse models of severe inflammation that is intended for eventual translation to human patients. This mini-review outlines this recent research, as well as specifically defines the arguments for and against murine models of sepsis and trauma research based on these transcriptional studies. In addition, we review newer advancements in murine models of infection and injury and define what we envision as an evolving but viable future for murine studies of sepsis and trauma. PMID:26034205

  20. New potential beneficial effects of actein, a triterpene glycoside isolated from Cimicifuga species, in breast cancer treatment

    PubMed Central

    Yue, Grace Gar-Lee; Xie, Sida; Lee, Julia Kin-Ming; Kwok, Hin-Fai; Gao, Si; Nian, Yin; Wu, Xiao-Xiao; Wong, Chun-Kwok; Qiu, Ming-Hua; Lau, Clara Bik-San

    2016-01-01

    Actein is a triterpene glycoside isolated from the rhizomes of Cimicifuga foetida (Chinese herb “shengma”) which could inhibit the growth of breast cancer cells. Nevertheless, the effect of actein on angiogenesis, which is an essential step for tumor growth and metastasis, has never been reported. Hence, this study aimed to investigate the in vitro and in vivo effects of actein on angiogenesis using human microvascular endothelial cells (HMEC-1), matrigel plug and tumor-bearing mouse models. Our results showed that actein significantly inhibited the proliferation, reduced the migration and motility of endothelial cells, and it could suppress the protein expressions of VEGFR1, pJNK and pERK, suggesting that JNK/ERK pathways were involved. In vivo results showed that oral administration of actein at 10 mg/kg for 7 days inhibited blood vessel formation in the growth factor-containing matrigel plugs. Oral actein treatments (10–15 mg/kg) for 28 days resulted in decreasing mouse 4T1 breast tumor sizes and metastasis to lungs and livers. The apparent reduced angiogenic proteins (CD34 and Factor VIII) expressions and down-regulated metastasis-related VEGFR1 and CXCR4 gene expressions were observed in breast tumors. Our novel findings provide insights into the use of actein for development of anti-angiogenic agents for breast cancer. PMID:27731376

  1. Inositol 1, 4, 5-trisphosphate-dependent nuclear calcium signals regulate angiogenesis and cell motility in triple negative breast cancer.

    PubMed

    Guimarães, Erika; Machado, Rodrigo; Fonseca, Matheus de Castro; França, Andressa; Carvalho, Clarissa; Araújo E Silva, Ana Cândida; Almeida, Brígida; Cassini, Puebla; Hissa, Bárbara; Drumond, Luciana; Gonçalves, Carlos; Fernandes, Gabriel; De Brot, Marina; Moraes, Márcio; Barcelos, Lucíola; Ortega, José Miguel; Oliveira, André; Leite, M Fátima

    2017-01-01

    Increases in nuclear calcium concentration generate specific biological outcomes that differ from those resulting from increased cytoplasmic calcium. Nuclear calcium effects on tumor cell proliferation are widely appreciated; nevertheless, its involvement in other steps of tumor progression is not well understood. Therefore, we evaluated whether nuclear calcium is essential in other additional stages of tumor progression, including key steps associated with the formation of the primary tumor or with the metastatic cascade. We found that nuclear calcium buffering impaired 4T1 triple negative breast cancer growth not just by decreasing tumor cell proliferation, but also by enhancing tumor necrosis. Moreover, nuclear calcium regulates tumor angiogenesis through a mechanism that involves the upregulation of the anti-angiogenic C-X-C motif chemokine 10 (CXCL10-IP10). In addition, nuclear calcium buffering regulates breast tumor cell motility, culminating in less cell invasion, likely due to enhanced vinculin expression, a focal adhesion structural protein. Together, our results show that nuclear calcium is essential for triple breast cancer angiogenesis and cell migration and can be considered as a promising strategic target for triple negative breast cancer therapy.

  2. Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer

    PubMed Central

    2013-01-01

    Background Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Methods Mice were evaluated with regard to the treatments’ toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry. Results Regarding the treatments’ toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining. Conclusions In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report

  3. Induction of murine embryonic stem cell differentiation by medicinal plant extracts

    PubMed Central

    Reynertson, Kurt A.; Charlson, Mary E.; Gudas, Lorraine J.

    2010-01-01

    Epidemiological evidence indicates that diets high in fruits and vegetables provide a measure of cancer chemoprevention due to phytochemical constituents. Natural products are a rich source of cancer chemotherapy drugs, and primarily target rapidly-cycling tumor cells. Increasing evidence indicates that many cancers contain small populations of resistant, stem-like cells that have the capacity to regenerate tumors following chemotherapy and radiation, and have been linked to the initiation of metastases. Our goal is to discover natural product-based clinical or dietary interventions that selectively target cancer stem cells, inducing differentiation. We adapted an alkaline phosphatase (AP) stain to assay plant extracts for the capacity to induce differentiation in embryonic stem (ES) cells. AP is a characteristic marker of undifferentiated ES cells, and this represents a novel approach to screening medicinal plant extracts. Following a survey of approximately 100 fractions obtained from twelve species of ethnomedically utilized plants, we found fractions from three species that induced differentiation, decreasing AP and transcript levels of pluripotency markers (Nanog, Oct-4, Rex-1). These fractions affected proliferation of murine ES, and human embryonal, prostate, and breast carcinoma cells in a dose-dependent manner. Several phytochemical constituents were isolated; the antioxidant phytochemicals ellagic acid and gallic acid were shown to affect viability of cultured breast carcinoma cells. PMID:20955699

  4. Induction of murine embryonic stem cell differentiation by medicinal plant extracts

    SciTech Connect

    Reynertson, Kurt A.; Charlson, Mary E.; Gudas, Lorraine J.

    2011-01-01

    Epidemiological evidence indicates that diets high in fruits and vegetables provide a measure of cancer chemoprevention due to phytochemical constituents. Natural products are a rich source of cancer chemotherapy drugs, and primarily target rapidly cycling tumor cells. Increasing evidence indicates that many cancers contain small populations of resistant, stem-like cells that have the capacity to regenerate tumors following chemotherapy and radiation, and have been linked to the initiation of metastases. Our goal is to discover natural product-based clinical or dietary interventions that selectively target cancer stem cells, inducing differentiation. We adapted an alkaline phosphatase (AP) stain to assay plant extracts for the capacity to induce differentiation in embryonic stem (ES) cells. AP is a characteristic marker of undifferentiated ES cells, and this represents a novel approach to screening medicinal plant extracts. Following a survey of approximately 100 fractions obtained from 12 species of ethnomedically utilized plants, we found fractions from 3 species that induced differentiation, decreasing AP and transcript levels of pluripotency markers (Nanog, Oct-4, Rex-1). These fractions affected proliferation of murine ES, and human embryonal, prostate, and breast carcinoma cells in a dose-dependent manner. Several phytochemical constituents were isolated; the antioxidant phytochemicals ellagic acid and gallic acid were shown to affect viability of cultured breast carcinoma cells.

  5. A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models

    NASA Astrophysics Data System (ADS)

    Bhattacharyya, Jayanta; Bellucci, Joseph J.; Weitzhandler, Isaac; McDaniel, Jonathan R.; Spasojevic, Ivan; Li, Xinghai; Lin, Chao-Chieh; Chi, Jen-Tsan Ashley; Chilkoti, Ashutosh

    2015-08-01

    Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumour-specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ~60 nm near-monodisperse nanoparticles that increased the systemic exposure of PTX by sevenfold compared with free drug and twofold compared with the Food and Drug Administration-approved taxane nanoformulation (Abraxane). The tumour uptake of the CP-PTX nanoparticle was fivefold greater than free drug and twofold greater than Abraxane. In a murine cancer model of human triple-negative breast cancer and prostate cancer, CP-PTX induced near-complete tumour regression after a single dose in both tumour models, whereas at the same dose, no mice treated with Abraxane survived for >80 days (breast) and 60 days (prostate), respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for PTX delivery.

  6. A Paclitaxel-Loaded Recombinant Polypeptide Nanoparticle Outperforms Abraxane in Multiple Murine Cancer Models

    PubMed Central

    Bhattacharyya, Jayanta; Bellucci, Joseph J.; Weitzhandler, Isaac; McDaniel, Jonathan R.; Spasojevic, Ivan; Li, Xinghai; Lin, Chao-Chieh; Chi, Jen-Tsan Ashley; Chilkoti, Ashutosh

    2015-01-01

    Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumor specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ~60-nm diameter near-monodisperse nanoparticles that increased the systemic exposure of PTX by 7-fold compared to free drug and 2-fold compared to the FDA approved taxane nanoformulation (Abraxane®). The tumor uptake of the CP-PTX nanoparticle was 5-fold greater than free drug and 2-fold greater than Abraxane. In a murine cancer model of human triple negative breast cancer and prostate cancer, CP-PTX induced near complete tumor regression after a single dose in both tumor models, whereas at the same dose, no mice treated with Abraxane survived for more than 80 days (breast) and 60 days (prostate) respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for paclitaxel delivery. PMID:26239362

  7. 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 ...

  8. 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 ...

  9. Treatment of Breast Cancer during Pregnancy

    MedlinePlus

    ... During Pregnancy Breast Cancer Breast Cancer Treatment Treating Breast Cancer During Pregnancy If you are diagnosed with breast ... treatment more complicated. Is it safe to treat breast cancer during pregnancy? Pregnant women can get treatment for ...

  10. 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, ...

  11. 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 ...

  12. Pathogenesis and immunity in murine salmonellosis.

    PubMed Central

    Hsu, H S

    1989-01-01

    Salmonella is traditionally described as a facultative intracellular parasite, and host macrophages are regarded as the primary effector cells in both native and acquired immunity in mouse typhoid. This concept has not been unanimously accepted in the literature. Based on cell culture experiments and electron microscopic examinations of infected tissues, we observed that virulent Salmonella typhimurium is killed within polymorphs and macrophages of guinea pigs and mice. In a systemic disease, the organism propagates primarily in the extracellular locations of sinusoids and tissue lesions and within hepatocytes. Hence, it is more likely to be an extracellular pathogen and its virulence is directly related to its antiphagocytic property. The conspicuous absence of macrophages in the primary lesions of murine salmonellosis disputes the likelihood of their significant role in native resistance to the disease. Acquired cellular immunity is expressed as an enhanced antibacterial activity of macrophages facilitated by cytophilic antibodies rather than as an altered antibacterial action of immune macrophages. It is proposed that acquired immunity in murine salmonellosis is a synergistic manifestation of the innate capacity of polymorphs and macrophages to destroy ingested salmonellae, the activated antibacterial functions of macrophages mediated by cytophilic antibodies, the opsonic and agglutinating actions of antiserum, and the accelerated inflammation associated with delayed hypersensitivity to bacterial antigens. Unlike live attenuated vaccines, nonviable vaccines offer a significant, though not a solid, protection against subsequent challenges. Images PMID:2687679

  13. Effect of zidovudine on preimplantation murine embryos.

    PubMed Central

    Toltzis, P; Mourton, T; Magnuson, T

    1993-01-01

    It previously has been demonstrated that zidovudine (AZT) is lethal to early murine embryos. The effect of the drug on pre- and postimplantation embryos was examined to delineate the timing of this toxicity and to investigate its possible mechanisms. Embryos exposed in the whole mouse during preblastocyst development were unable to proceed beyond the blastocyst stage. Similarly, when two-cell embryos harvested from unexposed females were exposed to low-concentration (1 microM) AZT in vitro over 24 h, development beyond the blastocyst stage was inhibited. In contrast, drug exposure during in vitro blastocyst and postblastocyst development resulted in little or no morphologic toxicity. Further investigation revealed that preblastocyst AZT exposure resulted in the development of blastocysts with significantly lower cell numbers than control embryos. While embryonic exposure to AZT at the blastocyst and postblastocyst stages also resulted in retarded cell division, the effects were milder than those recorded after preblastocyst exposure. These data demonstrate that the critical period of AZT toxicity toward murine embryos is between ovulation and implantation and indicate that AZT directly suppresses cell division in the preimplantation embryo. PMID:8215271

  14. SIRT3 is a Mitochondrial Tumor Suppressor and Genetic Loss Results in a Murine Model for ER/PR-Positive Mammary Tumors Connecting Metabolism and Carcinogenesis Mitochondrial Tumor Suppressor. Revision

    DTIC Science & Technology

    2013-11-01

    breast cancer in younger women have been established by altering the expression of BRCA genes . In contrast, there are no murine models for the...overarching goal of this proposal is to determine if the mitochondrial sirtuin SIRT3 is a tumor suppressor gene (TSG) that may be used to: (1...tumors. Based on these results we initially proposed a hypothesis that longevity genes impact the process of carcinogenesis via the maintenance of

  15. Knockdown of ROS1 gene sensitizes breast tumor growth to doxorubicin in a syngeneic mouse model.

    PubMed

    Tiash, Snigdha; Chua, Ming Jang; Chowdhury, Ezharul Hoque

    2016-06-01

    Treatment of breast cancer, the second leading cause of female deaths worldwide, with classical drugs is often accompanied by treatment failure and relapse of disease condition. Development of chemoresistance and drug toxicity compels compromising the drug concentration below the threshold level with the consequence of therapeutic inefficacy. Moreover, amplification and over-activation of proto-oncogenes in tumor cells make the treatment more challenging. The oncogene, ROS1 which is highly expressed in diverse types of cancers including breast carcinoma, functions as a survival protein aiding cancer progression. Thus we speculated that selective silencing of ROS1 gene by carrier-mediated delivery of siRNA might sensitize the cancer cells to the classical drugs at a relatively low concentration. In this investigation we showed that intracellular delivery of c-ROS1-targeting siRNA using pH-sensitive inorganic nanoparticles of carbonate apatite sensitizes mouse breast cancer cells (4T1) to doxorubicin, but not to cisplatin or paclitaxel, with the highest enhancement in chemosensitivity obtained at 40 nM of the drug concentration. Although intravenous administrations of ROS1-loaded nanoparticles reduced growth of the tumor, a further substantial effect on growth retardation was noted when the mice were treated with the siRNA- and Dox-bound particles, thus suggesting that silencing of ROS1 gene could sensitize the mouse breast cancer cells both in vitro and in vivo to doxorubicin as a result of synergistic effect of the gene knockdown and the drug action, eventually preventing activation of the survival pathway protein, AKT1. Our findings therefore provide valuable insight into the potential cross-talk between the pathways of ROS1 and doxorubicin for future development of effective therapeutics for breast cancer.

  16. Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy.

    PubMed

    Lechner, Melissa G; Karimi, Saman S; Barry-Holson, Keegan; Angell, Trevor E; Murphy, Katherine A; Church, Connor H; Ohlfest, John R; Hu, Peisheng; Epstein, Alan L

    2013-01-01

    Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are to identify likely responders to immunotherapy regimens among individuals with cancer and to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here, the immune profiles of 6 murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to 2 immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (regulatory T cells and myeloid-derived suppressor cells), to analyze intratumoral and draining lymphoid tissues. Tumors were stratified as highly or poorly immunogenic, with highly immunogenic tumors showing a significantly greater presence of T-cell costimulatory molecules and immune suppression in the tumor microenvironment. An absence of tumor-infiltrating cytotoxic T lymphocytes and mature dendritic cells was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine+/-dendritic cells vaccine immunotherapy were associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with the overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens.

  17. Accelerated Radiation Therapy After Surgery in Treating Patients With Breast Cancer

    ClinicalTrials.gov

    2017-01-20

    Inflammatory Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Tubular Ductal Breast Carcinoma

  18. 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 ...

  19. Breast Implants: Saline vs. Silicone

    MedlinePlus

    ... to women of any age for breast reconstruction. Silicone breast implants Silicone implants are pre-filled with ... likely be inserted at the same time. Ruptured silicone implant If a silicone breast implant ruptures, you ...

  20. 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 ...

  1. Carboplatin and Eribulin Mesylate in Triple Negative Breast Cancer Patients

    ClinicalTrials.gov

    2016-06-30

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative 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; Triple-negative Breast Cancer

  2. Glucosylceramides stimulate mitogenesis in aged murine epidermis.

    PubMed

    Marchell, N L; Uchida, Y; Brown, B E; Elias, P M; Holleran, W M

    1998-04-01

    Glucosylceramides (GlcCer) and ceramides (Cer) appear to have opposite effects on epidermal growth and differentiation. Whereas Cer inhibit mitosis and induce terminal differentiation and apoptosis in cultured keratinocytes, GlcCer is mitogenic in young murine epidermis. Using a recently described murine model of chronologic senescence we explored whether GlcCer is mitogenic in aged epidermis. Epidermal GlcCer content increases following topical applications of either conduritol-B epoxide (CBE), an inhibitor of GlcCer hydrolysis, or exogenous GlcCer in a penetration-enhancing vehicle. During chronologic aging in the hairless mouse, baseline epidermal DNA synthesis rates remain normal until 18 mo, but decline significantly at 24 mo. Topical CBE stimulates a 1.5- to 1.9-fold increase in epidermal DNA synthesis in all age groups (i.e., 1-2, 18, and 24 mo). Although the CBE induced increase in [3H]thymidine incorporation in 24 mo old animals is significant (p < 0.01), it is not sufficient to reach the absolute levels reached in similarly treated, younger mouse epidermis. Moreover, topical GlcCer induced mitogenesis is both dose dependent and hexose specific in young (1-2 mo old) animals, and remains effective in aged (< or = 24 mo old) animals. Furthermore, the CBE induced increase in DNA synthesis in aged epidermis is sufficient to produce epidermal hyperplasia. Finally, although an increased GlcCer:Cer ratio can alter stratum corneum barrier function and membrane structure, neither stratum corneum function nor extracellular membrane structure change under these experimental conditions, and therefore the mitogenic effects of increased epidermal GlcCer cannot be attributed to effects on the stratum corneum. These results show that: (i) elevations in endogenous GlcCer are mitogenic for aged as well as young murine epidermis; (ii) topical GlcCer is also mitogenic when delivered in an enhancing vehicle; and (iii) despite the putative importance of epidermal DNA synthesis

  3. Myofibroblastoma of the Breast

    PubMed Central

    Aytaç, Hüseyin Özgür; Bolat, Filiz Aka; Canpolat, Tuba; Pourbagher, Ayşin

    2015-01-01

    This study aimed presenting a case of a 64-year-old woman with a rare diagnosis of myofibroblastoma (MFB). MFB is one of the rare, benign, spindle-like stromal tumors arising from the connective tissue of the breast. MFBs are often confused with fibroadenomas and hamartomas because of their benign characteristic appearance on breast imaging and are diagnosed after excisional biopsies. Their differential diagnosis with malignant neoplasia of the breast is important because of their wide morphological spectrum. Our case also demonstrated a breast mass with benign imaging characteristics and a needle core biopsy revealing a benign, spindle-like stromal tumor. The pathological examination performed after the excision of the lump demonstrated a collagenous-/fibrous-type MFB. This case report emphasizes the rare but important place of MFB variants of the breast in the differential diagnosis of breast mass.

  4. Breast Reconstruction after Mastectomy

    PubMed Central

    Schmauss, Daniel; Machens, Hans-Günther; Harder, Yves

    2016-01-01

    Breast cancer is the leading cause of cancer death in women worldwide. Its surgical approach has become less and less mutilating in the last decades. However, the overall number of breast reconstructions has significantly increased lately. Nowadays, breast reconstruction should be individualized at its best, first of all taking into consideration not only the oncological aspects of the tumor, neo-/adjuvant treatment, and genetic predisposition, but also its timing (immediate versus delayed breast reconstruction), as well as the patient’s condition and wish. This article gives an overview over the various possibilities of breast reconstruction, including implant- and expander-based reconstruction, flap-based reconstruction (vascularized autologous tissue), the combination of implant and flap, reconstruction using non-vascularized autologous fat, as well as refinement surgery after breast reconstruction. PMID:26835456

  5. [Combination of TLR7 agonist T7-ethacrynic acid conjugate with ROR1 has a stronger anti-breast cancer effect].

    PubMed

    Zhang, Na; Jin, Guangyi; Jin, Zhenchao; Liu, Bing; Peng, Boya; Gao, Ningning; Hu, Yunlong; Tang, Li

    2016-07-01

    Objective To investigate the synergistic anti-breast cancer effect of Toll-like receptor 7 agonist T7-ethacrynic acid conjugate (T7-EA) in combination with receptor-tyrosine-kinase-like orphan receptor 1 (ROR1). Methods ROR1 cytotoxic T lymphocyte (CTL) epitope was predicted using Syfpeithi online software. Mouse spleen lymphocytes and bone marrow dendritic cells (DCs) were separately stimulated with 4 μmol/L T7-EA and 4 μmol/L ROR1 alone or in combination. ELISA assay was used to measure the levels of interferon-γ (IFN-γ), interleukin 12 (IL-12) and tumor necrosis factor-α (TNF-α). Xenograft model was established via subcutaneous injection of mouse breast cancer 4T1 cells. The mice were weekly treated through intraperitoneal administration of 3 mg/kg T7-EA, 15 mg/kg ROR1 or the combination of T7-EA and ROR1. After four rounds of treatment, tumor tissues were weighed. Serum level of anti-4T1 tumor protein IgG was measured by ELISA. Specific CTL activity was detected by lactate dehydrogenase (LDH) assay. Results The peptide PYCDETSSV was chosen as an antigen epitope of breast cancer. The T7-EA highly activated in vitro lymphocytes in a dose-dependent manner, which wasn't affected by other relevant peptides. The combination of T7-EA and ROR1 stimulated the secretion of IFN-γ and IL-12 by lymphocytes and TNF-α by bone marrow DCs. The growth of tumor in vivo was significantly inhibited by T7-EA combined with ROR1 compared with T7-EA or ROR1 alone. The specific CTL activity triggered by T7-EA combined with ROR1 was much stronger than that triggered by T7-EA or ROR1 alone. The titer of anti-4T1 tumor protein IgG induced by T7-EA combined with ROR1 was higher than that induced by T7-EA or ROR1. Conclusion The combination of T7-EA and ROR1 has a better killing effect on breast cancer.

  6. Kisspeptin 10 inhibits the Warburg effect in breast cancer through the Smad signaling pathway: both in vitro and in vivo

    PubMed Central

    Song, Guo-Qing; Zhao, Yi

    2016-01-01

    Breast cancer is the most frequently diagnosed cancer in females. Warburg effect could enhance tumorigenesis and has garnered attention as a target for tumor treatment. In this study, we found that the mRNA and protein levels of hexokinase 2 (HK2), pyruvate kinase (PKM2), and pyruvate dehydrogenase kinase (PDK1) in breast cancer tissues were higher than those in corresponding noncancerous tissues. HK2, PKM2, and PDK1 expression was correlated statistically with the survival rate of the patients with breast cancer. We also demonstrated a shorter fragment of KISS1, Kisspeptin-10 (KP-10), inhibited the Warburg effect and induced mitochondrial injury in human breast cancer cell line, MDA-MB-231. We confirmed that KP-10-inhibited the Warburg effect by activating Smad pathway. The effects and related mechanisms of these treatments were also confirmed in murine xenografts. However, additional studies are needed to confirm these results in other cell types. PMID:27069552

  7. Glucocorticoid receptors in murine erythroleukaemic cells

    SciTech Connect

    Hammond, K.D.; Torrance, J.M.; DiDomenico, M.

    1987-01-01

    Glucocorticoid receptors in murine erythroleukaemic cells were studied in relation to hexamethylene bisacetamide (HMBA) induced differentiation. Specific binding of dexamethasone was measured. A single class of saturable, high affinity binding sites was demonstrated in intact cells; with cell homogenates or fractions binding was low and could not be reliably quantified. Receptor binding in whole cell suspensions was lower in cells which had been treated with HMBA (36.5 +/- 8.2 pmol/g protein) than in untreated controls (87.9 +/- 23.6 pmol/g protein); dissociation constants were similar in treated (2.7 nM) and untreated cells (2.5 nM). Dexamethasone, hydrocortisone, corticosterone and progesterone competed with tritium-labelled dexamethasone for receptor binding sites; cortisone, deoxycorticosterone and oestradiol had little effect.

  8. Monoclonal antibodies reacting with murine teratocarcinoma cells.

    PubMed Central

    Goodfellow, P N; Levinson, J R; Williams, V E; McDevitt, H O

    1979-01-01

    Monoclonal antibodies were produced in vitro by fusing mouse myeloma cells with spleen cells from a rat immunized with the C3H mouse teratocarcinoma C86-S1. After the fusion two clones were chosen for further analysis. The first clone, 3C4-10, produced an antibody recognizing an antigen with a distribution restricted to teratocarcinoma cell lines, an endoderm cell line, and a neuroblastoma. The second clone, 4A1-9, produced an antibody that reacted with all cultured murine cells tested and adult brain. Neither antibody reacted with preimplantation embryos. The 3C4-10 antibody recognized an antigen associated with proteins. The apparent molecular weight of the 3C4-10 antigen was greater than 100,000. PMID:284353

  9. Accessory Breast Carcinoma

    PubMed Central

    Youn, Hyun Jo; Jung, Sung Hoo

    2009-01-01

    Summary Background Ectopic breast tissue usually develops along the mammary ridges, and the incidence has been reported to be 2–6% of the general population. Occurrence of primary carcinoma in ectopic breast tissue is rare. Case Report We report the case of 59-year-old woman with accessory breast carcinoma in her left axilla. Conclusion Because an accessory areola or nipple is often missing and awareness of physicians and patients about these unsuspicious masses is lacking, clinical diagnosis of accessory breast carcinoma is frequently delayed. Therefore, a mass along the ‘milk line’ should be examined carefully, and any suspicious lesions should be evaluated. PMID:20847887

  10. [Breast reconstruction after mastectomy].

    PubMed

    Ho Quoc, C; Delay, E

    2013-02-01

    The mutilating surgery for breast cancer causes deep somatic and psychological sequelae. Breast reconstruction can mitigate these effects and permit the patient to help rebuild their lives. The purpose of this paper is to focus on breast reconstruction techniques and on factors involved in breast reconstruction. The methods of breast reconstruction are presented: objectives, indications, different techniques, operative risks, and long-term monitoring. Many different techniques can now allow breast reconstruction in most patients. Clinical cases are also presented in order to understand the results we expect from a breast reconstruction. Breast reconstruction provides many benefits for patients in terms of rehabilitation, wellness, and quality of life. In our mind, breast reconstruction should be considered more as an opportunity and a positive choice (the patient can decide to do it), than as an obligation (that the patient would suffer). The consultation with the surgeon who will perform the reconstruction is an important step to give all necessary informations. It is really important that the patient could speak again with him before undergoing reconstruction, if she has any doubt. The quality of information given by medical doctors is essential to the success of psychological intervention. This article was written in a simple, and understandable way to help gynecologists giving the best information to their patients. It is maybe also possible to let them a copy of this article, which would enable them to have a written support and would facilitate future consultation with the surgeon who will perform the reconstruction.

  11. Breast milk jaundice

    MedlinePlus

    Hyperbilirubinemia - breastfeeding; Breast-non-feeding jaundice; Breastfeeding failure jaundice ... of jaundice that is caused by too little breastfeeding by making sure your baby is getting enough ...

  12. Expression and function of the protein tyrosine phosphatase receptor J (PTPRJ) in normal mammary epithelial cells and breast tumors.

    PubMed

    Smart, Chanel E; Askarian Amiri, Marjan E; Wronski, Ania; Dinger, Marcel E; Crawford, Joanna; Ovchinnikov, Dmitry A; Vargas, Ana Cristina; Reid, Lynne; Simpson, Peter T; Song, Sarah; Wiesner, Christiane; French, Juliet D; Dave, Richa K; da Silva, Leonard; Purdon, Amy; Andrew, Megan; Mattick, John S; Lakhani, Sunil R; Brown, Melissa A; Kellie, Stuart

    2012-01-01

    The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years. Immunohistochemistry of PTPRJ protein in normal human breast tissue revealed a distinctive apical localisation in the luminal cells of alveoli and ducts. Qualitative analysis of a cohort of invasive ductal carcinomas revealed retention of normal apical PTPRJ localization where tubule formation was maintained but that tumors mostly exhibited diffuse cytoplasmic staining, indicating that dysregulation of localisation associated with loss of tissue architecture in tumorigenesis. The murine ortholog, Ptprj, exhibited a similar localisation in normal mammary gland, and was differentially regulated throughout lactational development, and in an in vitro model of mammary epithelial differentiation. Furthermore, ectopic expression of human PTPRJ in HC11 murine mammary epithelial cells inhibited dome formation. These data indicate that PTPRJ may regulate differentiation of normal mammary epithelia and that dysregulation of protein localisation may be associated with tumorigenesis.

  13. Synchronous bilateral breast cancer in a male

    PubMed Central

    Rubio Hernández, María Caridad; Díaz Prado, Yenia Ivet; Pérez, Suanly Rodríguez; Díaz, Ronald Rodríguez; Aleaga, Zaili Gutiérrez

    2013-01-01

    Male breast cancer, which represents only 1% of all breast cancers, is occasionally associated with a family history of breast cancer. Sporadic male breast cancers presenting with another primary breast cancer are extremely rare. In this article, we report on a 70-year-old male patient with bilateral multifocal and synchronous breast cancer and without a family history of breast cancer. PMID:24319497

  14. Breast cancer statistics, 2011.

    PubMed

    DeSantis, Carol; Siegel, Rebecca; Bandi, Priti; Jemal, Ahmedin

    2011-01-01

    In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including trends in incidence, mortality, survival, and screening. Approximately 230,480 new cases of invasive breast cancer and 39,520 breast cancer deaths are expected to occur among US women in 2011. Breast cancer incidence rates were stable among all racial/ethnic groups from 2004 to 2008. Breast cancer death rates have been declining since the early 1990s for all women except American Indians/Alaska Natives, among whom rates have remained stable. Disparities in breast cancer death rates are evident by state, socioeconomic status, and race/ethnicity. While significant declines in mortality rates were observed for 36 states and the District of Columbia over the past 10 years, rates for 14 states remained level. Analyses by county-level poverty rates showed that the decrease in mortality rates began later and was slower among women residing in poor areas. As a result, the highest breast cancer death rates shifted from the affluent areas to the poor areas in the early 1990s. Screening rates continue to be lower in poor women compared with non-poor women, despite much progress in increasing mammography utilization. In 2008, 51.4% of poor women had undergone a screening mammogram in the past 2 years compared with 72.8% of non-poor women. Encouraging patients aged 40 years and older to have annual mammography and a clinical breast examination is the single most important step that clinicians can take to reduce suffering and death from breast cancer. Clinicians should also ensure that patients at high risk of breast cancer are identified and offered appropriate screening and follow-up. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high-quality screening, diagnosis, and treatment to all segments of the population.

  15. Girls' Attitudes toward Breast Care and Breast Self-Examination.

    ERIC Educational Resources Information Center

    Hadranyi, B. T.

    A study explored girls' emerging attitudes toward breast care and breast self-exam (BSE) and the extent to which girls had given thought to these issues. Analyses focused specifically on individual differences related to age, stage of breast development, perceived normalcy of breast development, and body image. The sample consisted of 43 white,…

  16. The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer

    PubMed Central

    Law, Emily K.; Sieuwerts, Anieta M.; LaPara, Kelly; Leonard, Brandon; Starrett, Gabriel J.; Molan, Amy M.; Temiz, Nuri A.; Vogel, Rachel Isaksson; Meijer-van Gelder, Marion E.; Sweep, Fred C. G. J.; Span, Paul N.; Foekens, John A.; Martens, John W. M.; Yee, Douglas; Harris, Reuben S.

    2016-01-01

    Breast tumors often display extreme genetic heterogeneity characterized by hundreds of gross chromosomal aberrations and tens of thousands of somatic mutations. Tumor evolution is thought to be ongoing and driven by multiple mutagenic processes. A major outstanding question is whether primary tumors have preexisting mutations for therapy resistance or whether additional DNA damage and mutagenesis are necessary. Drug resistance is a key measure of tumor evolvability. If a resistance mutation preexists at the time of primary tumor presentation, then the intended therapy is likely to fail. However, if resistance does not preexist, then ongoing mutational processes still have the potential to undermine therapeutic efficacy. The antiviral enzyme APOBEC3B (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3B) preferentially deaminates DNA C-to-U, which results in signature C-to-T and C-to-G mutations commonly observed in breast tumors. We use clinical data and xenograft experiments to ask whether APOBEC3B contributes to ongoing breast tumor evolution and resistance to the selective estrogen receptor modulator, tamoxifen. First, APOBEC3B levels in primary estrogen receptor–positive (ER+) breast tumors inversely correlate with the clinical benefit of tamoxifen in the treatment of metastatic ER+ disease. Second, APOBEC3B depletion in an ER+ breast cancer cell line results in prolonged tamoxifen responses in murine xenograft experiments. Third, APOBEC3B overexpression accelerates the development of tamoxifen resistance in murine xenograft experiments by a mechanism that requires the enzyme’s catalytic activity. These studies combine to indicate that APOBEC3B promotes drug resistance in breast cancer and that inhibiting APOBEC3B-dependent tumor evolvability may be an effective strategy to improve efficacies of targeted cancer therapies. PMID:27730215

  17. Cultivation and characterization of three strains of murine rotavirus.

    PubMed Central

    Greenberg, H B; Vo, P T; Jones, R

    1986-01-01

    Three distinct strains of murine rotavirus were adapted to growth in cell culture. These strains are genetically related but not identical; they are serotypically heterogeneous. The cultivatable strains were substantially more infectious (approximately 10(6)-fold) for suckling mice than heterologous simian rotaviruses were. Homologous murine rotavirus strains spread from inoculated to uninoculated litter mates and caused diarrhea, while heterologous rotaviruses did not spread and cause illness. Images PMID:3003390

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

    PubMed

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

    2015-04-01

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

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

    PubMed Central

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

    2015-01-01

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

  20. Women with Disabilities and Breast Cancer Screening

    MedlinePlus

    ... and Reasonable Accommodations (RA) Women with Disabilities and Breast Cancer Screening Recommend on Facebook Tweet Share Compartir Finding Breast Cancer Early Can Save Lives Disabilities & Breast Cancer Screening ...

  1. Global breast cancer seasonality.

    PubMed

    Oh, Eun-Young; Ansell, Christine; Nawaz, Hamayun; Yang, Chul-Ho; Wood, Patricia A; Hrushesky, William J M

    2010-08-01

    Human breast cancer incidence has seasonal patterns that seem to vary among global populations. The aggregate monthly frequency of breast cancer diagnosis was collected and examined for 2,921,714 breast cancer cases diagnosed across 64 global regions over spans from 2 to 53 years. Breast cancer is consistently diagnosed more often in spring and fall, both in the Northern and Southern Hemispheres, regardless of presumable menopausal status (50). This seasonality is increasingly more prominent as population distance from the equator increases and this latitude dependence is most pronounced among women living in rural areas. Moreover, the overall annual incidence (2005-2006), per 100,000 population, of breast cancer increased as the latitude of population residence increased. These data make it clear that human breast cancer discovery occurs non-randomly throughout each year with peaks near both equinoxes and valleys near both solstices. This stable global breast cancer seasonality has implications for better prevention, more accurate screening, earlier diagnosis, and more effective treatment. This complex latitude-dependent breast cancer seasonality is clearly related to predictable local day/night length changes which occur seasonally. Its mechanism may depend upon seasonal sunlight mediation of vitamin D and seasonal mediation of nocturnal melatonin peak level and duration.

  2. BREAST CANCER AND EXERCISE

    ClinicalTrials.gov

    2008-03-19

    Prevent Osteoporosis and Osteoporotic Fractures; Improve Quality of Life; Improve Weight Control, and Muscular and Cardiovascular Fitness; Help the Patients to Return to Working Life; Reduce the Risk of Breast Cancer Recurrence; Prevent Other Diseases and Reduce All-Cause Mortality in Patients With Primary Breast Cancer.

  3. Breast-milk jaundice.

    PubMed

    Brooten, D; Brown, L; Hollingsworth, A; Tanis, J; Bakewell-Sachs, S

    1985-01-01

    The syndrome of breast-milk jaundice, which often results in cessation of breastfeeding, maternal anxiety, and guilt, may be increasing. Research to date on pregnanediol, increased lipase, and free fatty acids as the causes of breast milk jaundice is reviewed. Variations in current treatment are presented and nursing measures supportive of parents and continued breastfeeding are provided.

  4. Types of Breast Pumps

    MedlinePlus

    ... Powered and Electric Pumps A powered breast pump uses batteries or a cord plugged into an electrical outlet ... pumps rely on a power source, women who use powered breast pumps should be prepared for emergency situations when electricity or extra batteries may not be available. If breastfeeding is not ...

  5. 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

  6. Breast Cancer and Bone Loss

    MedlinePlus

    ... Balance › Breast Cancer and Bone Loss Fact Sheet Breast Cancer and Bone Loss July, 2010 Download PDFs English ... JoAnn Pinkerton, MD What is the link between breast cancer and bone loss? Certain treatments for breast cancer ...

  7. Increasing Breast Cancer Surveillance Among African American Breast Cancer Survivors

    DTIC Science & Technology

    2006-07-01

    the Witness model will be tailored for breast cancer survivors and the peer interventionists (breast cancer survivors and lay health advisors) will be...by a lay health advisor; 4) discussion of concerns and myths about breast cancer and screening /surveillance that are prevalent among AAW; 5) review...Breast cancer screening surveillance Breast cancer screening Treatment/Time of Treatment intention /adherence & physician recommendation

  8. Sinomenine inhibits breast cancer cell invasion and migration by suppressing NF-κB activation mediated by IL-4/miR-324-5p/CUEDC2 axis

    SciTech Connect

    Song, Lingqin; Liu, Di; Zhao, Yang; He, Jianjun; Kang, Huafeng; Dai, Zhijun; Wang, Xijing; Zhang, Shuqun; Zan, Ying

    2015-08-28

    Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a vital transcription factor that regulates multiple important biological processes, including the epithelial–mesenchymal transition (EMT) and metastasis of breast cancer. Sinomenine is an isoquinoline well known for its remarkable curative effect on rheumatic and arthritic diseases and can induce apoptosis of several cancer cell types. Recently, sinomenine was reported as a tumor suppressor via inhibiting cell proliferation and inducing apoptosis. However, the role and mechanism of sinomenine in invasion and metastasis of breast cancer are largely unknown. Here, we report that sinomenine suppressed the invasion and migration of MDA-MB-231 and 4T1 breast cancer cells in a dose-dependent manner. We detected binding of NF-κB to the inhibitor of NF-κB (IκB) after the MDA-MB-231 cells were treated with 0.25, 0.5, and 1 mM sinomenine. Co-IP analysis revealed that sinomenine enhanced the binding of NF-κB and IκB in a dose-dependent manner, suggesting that sinomenine had an effect on inactivation of NF-κB. Western blotting and ELISA approaches indicated that the suppression effect was closely associated with the phosphorylation of IκB kinase (IKK) and its negative regulator CUEDC2. Sinomenine treatment decreased miR-324-5p expression, thus increased the level of its target gene CUEDC2, and then blocked the phosphorylation of IKK through altering the upstream axis. Finally, transfection of a miR-324-5p mimic inhibited the suppression of invasion and metastasis of MDA-MB-231 and 4T1 cell by sinomenine, providing evidence that sinomenine treatment suppressed breast cancer cell invasion and metastasis via regulation of the IL4/miR-324-5p/CUEDC2 axis. Our findings reveal a novel mechanism by which sinomenine suppresses cancer cell invasion and metastasis, i.e., blocking NF-κB activation. - Highlights: • Sinomenine reduced invasion and migration of MDA-MB-231 and 4T1 breast cancer cells.

  9. Folate receptor-targeted multimodal polymersomes for delivery of quantum dots and doxorubicin to breast adenocarcinoma: In vitro and in vivo evaluation.

    PubMed

    Alibolandi, Mona; Abnous, Khalil; Sadeghi, Fatemeh; Hosseinkhani, Hossein; Ramezani, Mohammad; Hadizadeh, Farzin

    2016-03-16

    In this study, we report the design and delivery of tumor-targeted, quantum dot (QD) and doxorubicin (DOX)-encapsulated PEG-PLGA nanopolymersomes (NPs) for the imaging and chemotherapy of breast cancer. To achieve active cancer targeting, QD and DOX-encapsulated NPs were conjugated with folate for folate-binding protein receptor-guided delivery, which overexpressed in many cancer cells. Hydrophobic DOX and hydrophilic MSA-capped QD were encapsulated in the bilayer and core of the PEG-PLGA nanopolymersomes, respectively. The data show that the formulated NPs sustained DOX release for a period of 12 days. Fluorescence microscopy and MTT assay demonstrated that the developed folate-targeted DOX-QD NPs had higher cytotoxicity than non-targeted NPs and the free form of the drug; moreover, they preferentially accumulated in 4T1 and MCF-7 cells in vitro. In vivo experiments including whole organ tissue-homogenate analysis and organ fluorescence microscopy imaging of BALB/c mice bearing 4T1 breast adenocarcinoma showed that the folate receptor-targeted QD encapsulated NPs accumulate at tumor sites 6h following intravenous injection. Acute toxicity studies of the prepared targeted QD-loaded NPs showed no evidence of long-term harmful histopathological and physiological effects on the treated animals. The in vivo tumor inhibitory effect of folic acid (FA)-QD-DOX NPs demonstrated an augmented therapeutic efficacy of targeted formulation over the non-targeted and free drug. The data obtained illustrate a high potential of the prepared targeted theranostic nanoplatform in the treatment and imaging of breast cancer. This study may open new directions for preparation of QD-based theranostic polymersomes for clinical application.

  10. Cutaneous manifestations of breast cancer.

    PubMed

    Tan, Antoinette R

    2016-06-01

    Breast cancer may present with cutaneous symptoms. The skin manifestations of breast cancer are varied. Some of the more common clinical presentations of metastatic cutaneous lesions from breast cancer will be described. Paraneoplastic cutaneous dermatoses have been reported as markers of breast malignancy and include erythema gyratum repens, acquired ichthyosis, dermatomyositis, multicentric reticulohistiocytosis, and hypertrichosis lanuginosa acquisita. Mammary Paget's disease, often associated with an underlying breast cancer, and Cowden syndrome, which has an increased risk of breast malignancy, each have specific dermatologic findings. Recognition of these distinct cutaneous signs is important in the investigation of either newly diagnosed or recurrent breast cancer.

  11. Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice

    PubMed Central

    Vila-Leahey, Ava; Oldford, Sharon A.; Marignani, Paola A.; Wang, Jun; Haidl, Ian D.; Marshall, Jean S.

    2016-01-01

    ABSTRACT Histamine receptor 2 (H2) antagonists are widely used clinically for the control of gastrointestinal symptoms, but also impact immune function. They have been reported to reduce tumor growth in established colon and lung cancer models. Histamine has also been reported to modify populations of myeloid-derived suppressor cells (MDSCs). We have examined the impact of the widely used H2 antagonist ranitidine, on both myeloid cell populations and tumor development and spread, in three distinct models of breast cancer that highlight different stages of cancer progression. Oral ranitidine treatment significantly decreased the monocytic MDSC population in the spleen and bone marrow both alone and in the context of an orthotopic breast tumor model. H2 antagonists ranitidine and famotidine, but not H1 or H4 antagonists, significantly inhibited lung metastasis in the 4T1 model. In the E0771 model, ranitidine decreased primary tumor growth while omeprazole treatment had no impact on tumor development. Gemcitabine treatment prevented the tumor growth inhibition associated with ranitidine treatment. In keeping with ranitidine-induced changes in myeloid cell populations in non-tumor-bearing mice, ranitidine also delayed the onset of spontaneous tumor development, and decreased the number of tumors that developed in LKB1−/−/NIC mice. These results indicate that ranitidine alters monocyte populations associated with MDSC activity, and subsequently impacts breast tumor development and outcome. Ranitidine has potential as an adjuvant therapy or preventative agent in breast cancer and provides a novel and safe approach to the long-term reduction of tumor-associated immune suppression. PMID:27622015

  12. Omega-3 Fatty Acid in Treating Patients With Stage I-III Breast Cancer

    ClinicalTrials.gov

    2017-03-13

    Ductal Breast Carcinoma in Situ; Lobular Breast Carcinoma in Situ; Male 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

  13. Intensity Modulated Accelerated Partial Breast Irradiation Before Surgery in Treating Older Patients With Hormone Responsive Stage 0-I Breast Cancer

    ClinicalTrials.gov

    2016-05-04

    Ductal Breast Carcinoma in Situ; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Ductal Breast Carcinoma With Predominant Intraductal Component; Lobular Breast Carcinoma in Situ; Medullary Ductal Breast Carcinoma With Lymphocytic Infiltrate; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Tubular Ductal Breast Carcinoma

  14. Periostin is identified as a putative metastatic marker in breast cancer-derived exosomes

    PubMed Central

    Vardaki, Ioulia; Ceder, Sophia; Rutishauser, Dorothea; Baltatzis, George; Foukakis, Theodoros; Panaretakis, Theocharis

    2016-01-01

    Breast cancer (BrCa) is the most frequent cancer type in women and a leading cause of cancer related deaths in the world. Despite the decrease in mortality due to better diagnostics and palliative care, there is a lack of prognostic markers of metastasis. Recently, the exploitation of liquid biopsies and in particular of the extracellular vesicles has shown promise in the identification of such prognostic markers. In this study we compared the proteomic content of exosomes derived from metastatic and non-metastatic human (MCF7 and MDA-MB-231) and mouse (67NR and 4T1) cell lines. We found significant differences not only in the amount of secreted exosomes but most importantly in the protein content of exosomes secreted from metastatic versus non-metastatic ones. We identified periostin as a protein that is enriched in exosomes secreted by metastatic cells and validated its presence in a pilot cohort of breast cancer patient samples with localized disease or lymph node (LN) metastasis. PMID:27589561

  15. 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

  16. 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

  17. New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate

    PubMed Central

    Cui, Jihong; Hollmén, Maija; Li, Lina; Chen, Yong; Proulx, Steven T.; Reker, Daniel; Schneider, Gisbert; Detmar, Michael

    2017-01-01

    Cancer stem cells (CSCs) play major roles in cancer initiation, metastasis, recurrence and therapeutic resistance. Targeting CSCs represents a promising strategy for cancer treatment. The purpose of this study was to identify selective inhibitors of breast CSCs (BCSCs). We carried out a cell-based phenotypic screening with cell viability as a primary endpoint, using a collection of 2,546 FDA-approved drugs and drug-like molecules in spheres formed by malignant human breast gland-derived cells (HMLER-shEcad cells, representing BCSCs) and control immortalized non-tumorigenic human mammary cells (HMLE cells, representing normal stem cells). 19 compounds were identified from screening. The chemically related molecules benztropine mesylate and deptropine citrate were selected for further validation and both potently inhibited sphere formation and self-renewal of BCSCs in vitro. Benztropine mesylate treatment decreased cell subpopulations with high ALDH activity and with a CD44+/CD24− phenotype. In vivo, benztropine mesylate inhibited tumor-initiating potential in a 4T1 mouse model. Functional studies indicated that benztropine mesylate inhibits functions of CSCs via the acetylcholine receptors, dopamine transporters/receptors, and/or histamine receptors. In summary, our findings identify benztropine mesylate as an inhibitor of BCSCs in vitro and in vivo. This study also provides a screening platform for identification of additional anti-CSC agents. PMID:27894093

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

    PubMed Central

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

    2009-01-01

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

  19. A novel combination immunotherapy for cancer by IL-13Rα2-targeted DNA vaccine and immunotoxin in murine tumor models.

    PubMed

    Nakashima, Hideyuki; Terabe, Masaki; Berzofsky, Jay A; Husain, Syed R; Puri, Raj K

    2011-11-15

    Optimum efficacy of therapeutic cancer vaccines may require combinations that generate effective antitumor immune responses, as well as overcome immune evasion and tolerance mechanisms mediated by progressing tumor. Previous studies showed that IL-13Rα2, a unique tumor-associated Ag, is a promising target for cancer immunotherapy. A targeted cytotoxin composed of IL-13 and mutated Pseudomonas exotoxin induced specific killing of IL-13Rα2(+) tumor cells. When combined with IL-13Rα2 DNA cancer vaccine, surprisingly, it mediated synergistic antitumor effects on tumor growth and metastasis in established murine breast carcinoma and sarcoma tumor models. The mechanism of synergistic activity involved direct killing of tumor cells and cell-mediated immune responses, as well as elimination of myeloid-derived suppressor cells and, consequently, regulatory T cells. These novel results provide a strong rationale for combining immunotoxins with cancer vaccines for the treatment of patients with advanced cancer.

  20. A Radiolabeled Fully Human Antibody to Human Aspartyl (Asparaginyl) β-Hydroxylase Is a Promising Agent for Imaging and Therapy of Metastatic Breast Cancer.

    PubMed

    Revskaya, Ekaterina; Jiang, Zewei; Morgenstern, Alfred; Bruchertseifer, Frank; Sesay, Muctarr; Walker, Susan; Fuller, Steven; Lebowitz, Michael S; Gravekamp, Claudia; Ghanbari, Hossein A; Dadachova, Ekaterina

    2017-03-01

    There is a need for novel effective and safe therapies for metastatic breast cancer based on targeting tumor-specific molecular markers of cancer. Human aspartyl (asparaginyl) β-hydroxylase (HAAH) is a highly conserved enzyme that hydroxylates epidermal growth factor-like domains in transformation-associated proteins and is overexpressed in a variety of cancers, including breast cancer. A fully human monoclonal antibody (mAb) PAN-622 has been developed to HAAH. In this study, they describe the development of PAN-622 mAb as an agent for imaging and radioimmunotherapy of metastatic breast cancer. PAN-622 was conjugated to several ligands such as DOTA, CHXA″, and DTPA to enable subsequent radiolabeling and its immunoreactivity was evaluated by an HAAH-specific enzyme-linked immunosorbent assay and binding to the HAAH-positive cells. As a result, DTPA-PAN-622 was chosen to investigate biodistribution in healthy CD-1 female mice and 4T1 mammary tumor-bearing BALB/c mice. The (111)In-DTPA-pan622 mAb concentrated in the primary tumors and to some degree in lung metastases as shown by SPECT/CT and Cherenkov imaging. A pilot therapy study with (213)Bi-DTPA-PAN-622 demonstrated a significant effect on the primary tumor. The authors concluded that human mAb PAN-622 to HAAH is a promising reagent for development of imaging and possible therapeutic agents for the treatment of metastatic breast cancer.

  1. Implantable micropump technologies for murine intracochlear infusions.

    PubMed

    Johnson, D G; Waldron, M J; Frisina, R D; Borkholder, D A

    2010-01-01

    Due to the very small size of the mouse inner ear, 600 nL volume, developing effective, controlled infusion systems is quite challenging. Key technologies have been created to minimize both size and power for an implantable pump for murine intracochlear infusions. A method for coupling fine capillary tubing to microfluidic channels is presented which provides low volume, biocompatible interconnects withstanding pressures as high as 827 kPa (120 psi) and consuming less than 20 nL of volume exiting in-plane with the pump. Surface micromachined resistive bridges integrated into the flow channel for anemometry based flow rate measurement have been optimized for low power operation in the ultra-low flow rate regime. A process for creation of deformable diaphragms over pump chambers with simultaneous coating of the microfluidic channels has been developed allowing integration of a biocompatible fluid flow path. These advances represent enabling capabilities for a drug delivery system suitable for space constrained applications such as subcutaneous implantation in mice.

  2. Implantable Micropump Technologies for Murine Intracochlear Infusions

    PubMed Central

    Johnson, D. G.; Waldron, M. J.; Frisina, R. D.; Borkholder, D. A.

    2011-01-01

    Due to the very small size of the mouse inner ear, 600 nL volume, developing effective, controlled infusion systems is quite challenging. Key technologies have been created to minimize both size and power for an implantable pump for murine intracochlear infusions. A method for coupling fine capillary tubing to microfluidic channels is presented which provides low volume, biocompatible interconnects withstanding pressures as high as 827 kPa (120 psi) and consuming less than 20 nL of volume exiting in-plane with the pump. Surface micromachined resistive bridges integrated into the flow channel for anemometry based flow rate measurement have been optimized for low power operation in the ultra-low flow rate regime. A process for creation of deformable diaphragms over pump chambers with simultaneous coating of the microfluidic channels has been developed allowing integration of a biocompatible fluid flow path. These advances represent enabling capabilities for a drug delivery system suitable for space constrained applications such as subcutaneous implantation in mice. PMID:21096713

  3. Murine Ileocolic Bowel Resection with Primary Anastomosis

    PubMed Central

    Perry, Troy; Borowiec, Anna; Dicken, Bryan; Fedorak, Richard; Madsen, Karen

    2014-01-01

    Intestinal resections are frequently required for treatment of diseases involving the gastrointestinal tract, with Crohn’s disease and colon cancer being two common examples. Despite the frequency of these procedures, a significant knowledge gap remains in describing the inherent effects of intestinal resection on host physiology and disease pathophysiology. This article provides detailed instructions for an ileocolic resection with primary end-to-end anastomosis in mice, as well as essential aspects of peri-operative care to maximize post-operative success. When followed closely, this procedure yields a 95% long-term survival rate, no failure to thrive, and minimizes post-operative complications of bowel obstruction and anastomotic leak. The technical challenges of performing the procedure in mice are a barrier to its wide spread use in research. The skills described in this article can be acquired without previous surgical experience. Once mastered, the murine ileocolic resection procedure will provide a reproducible tool for studying the effects of intestinal resection in models of human disease. PMID:25406841

  4. ESCRT Requirements for Murine Leukemia Virus Release.

    PubMed

    Bartusch, Christina; Prange, Reinhild

    2016-04-18

    The Murine Leukemia Virus (MLV) is a gammaretrovirus that hijack host components of the endosomal sorting complex required for transport (ESCRT) for budding. To determine the minimal requirements for ESCRT factors in MLV viral and viral-like particles (VLP) release, an siRNA knockdown screen of ESCRT(-associated) proteins was performed in MLV-producing human cells. We found that MLV VLPs and virions primarily engage the ESCRT-I factor Tsg101 and marginally the ESCRT-associated adaptors Nedd4-1 and Alix to enter the ESCRT pathway. Conversely, the inactivation of ESCRT-II had no impact on VLP and virion egress. By analyzing the effects of individual ESCRT-III knockdowns, VLP and virion release was profoundly inhibited in CHMP2A- and CHMP4B-knockdown cells. In contrast, neither the CHMP2B and CHMP4A isoforms nor CHMP3, CHMP5, and CHMP6 were found to be essential. In case of CHMP1, we unexpectedly observed that the CHMP1A isoform was specifically required for virus budding, but dispensable for VLP release. Hence, MLV utilizes only a subset of ESCRT factors, and viral and viral-like particles differ in ESCRT-III factor requirements.

  5. Nuclear Nonhistone Proteins in Murine Melanoma Cells

    PubMed Central

    Wikswo, Muriel A.; Mcguire, Joseph S.; Shansky, Janet E.; Boshes, Roger A.

    1976-01-01

    Nuclear nonhistone proteins (NHP's) have been implicated as regulatory agents involved in controlling genetic expression. Utilizing murine melanoma cells, we describe a method for isolating and fractionating NHP's which greatly increases the yield of these proteins as well as the level of resolution required for detecting small differences in particular NHP's. Mouse melanoma cells were grown in medium labeled with [3H]leucine. Following 48 hr of incubation, the cells were harvested and nuclei isolated. The NHP's were extracted from the nuclei in a series of steps which yielded four major fractions: NHP1, NHP2, NHP3, NHP4. This method solubilized 80-90% of the protein from the nuclear homogenate. The NHP fractions were then separated on DEAE-cellulose columns in a series of salt steps increasing in concentration from 0.05 to 0.50 M NaCl, followed by steps of 2 M NaCl and 4 and 7 M guanidine-hydrochloride. The 40 NHP fractions eluted from these columns were further separated on polyacrylamide-SDS gels and ranged in molecular weight from 9000 to 110,000 daltons. Differences were observed in the electrophoretic pattern of each of these 40 fractions. The high resolution of these fractionation procedures greatly enhances the possibility of observing small changes in proteins which may play a role in gene regulation. ImagesFIG. 2FIG. 5 PMID:997593

  6. Regulation of Murine Natural Killer Cell Development

    PubMed Central

    Goh, Wilford; Huntington, Nicholas D.

    2017-01-01

    Natural killer (NK) cells are effector lymphocytes of the innate immune system that are known for their ability to kill transformed and virus-infected cells. NK cells originate from hematopoietic stem cells in the bone marrow, and studies on mouse models have revealed that NK cell development is a complex, yet tightly regulated process, which is dependent on both intrinsic and extrinsic factors. The development of NK cells can be broadly categorized into two phases: lineage commitment and maturation. Efforts to better define the developmental framework of NK cells have led to the identification of several murine NK progenitor populations and mature NK cell subsets, each defined by a varied set of cell surface markers. Nevertheless, the relationship between some of these NK cell subsets remains to be determined. The classical approach to studying both NK cell development and function is to identify the transcription factors involved and elucidate the mechanistic action of each transcription factor. In this regard, recent studies have provided further insight into the mechanisms by which transcription factors, such as ID2, FOXO1, Kruppel-like factor 2, and GATA-binding protein 3 regulate various aspects of NK cell biology. It is also becoming evident that the biology of NK cells is not only transcriptionally regulated but also determined by epigenetic alterations and posttranscriptional regulation of gene expression by microRNAs. This review summarizes recent progress made in NK development, focusing primarily on transcriptional regulators and their mechanistic actions. PMID:28261203

  7. Murine cytomegalovirus infection of cultured mouse embryos.

    PubMed Central

    Tsutsui, Y.; Naruse, I.

    1987-01-01

    Isolated mouse whole embryos of 7.5 days' gestation were infected with murine cytomegalovirus (MCMV) and cultured in pure rat serum. Although the MCMV infection had little effect on the survival and development of the embryos during 3 days of cultivation, immunohistochemical analysis of their serial sections using monoclonal antibody showed MCMV-infected cells in various portions of the embryos. This monoclonal antibody, when tested with the use of infected cultured mouse fibroblasts, reacted with nuclear antigen within 2 hours after infection and also reacted with nuclear inclusions in the late phase of infection. The viral antigen-positive cells detected by the monoclonal antibody were present in almost all of the ectoplacental cone and the yolk sac and in about 82% of the embryos. In the embryos, antigen-positive cells were frequently observed in the epithelium of the digestive tracts, endothelial cells of the blood vessels, and the mesodermal cells. In some of the embryos, viral antigen-positive cells were clearly observed in a small percentage of the blood cells. These findings indicate that blood cells, in addition to cell migration during embryogenesis, may play an important role in transmission of infectious virus into the embryos. Mouse whole embryo culture infected with MCMV can provide a model for the study of cellular tropism related to congenital infection by cytomegalovirus. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:3034066

  8. Characterization of ozone disinfection of murine norovirus.

    PubMed

    Lim, Mi Young; Kim, Ju-Mi; Lee, Jung Eun; Ko, GwangPyo

    2010-02-01

    Despite the importance of human noroviruses (NoVs) in public health, little information concerning the effectiveness of ozone against NoVs is available. We determined the efficacy of ozone disinfection using murine norovirus (MNV) as a surrogate of human NoV. MNV in ozone demand-free buffer was exposed to a predetermined dose of ozone at two different pHs and temperatures. The virus remaining in the solution was analyzed by plaque assay, real-time TaqMan reverse transcriptase PCR (RT-PCR) (short template), and long-template conventional RT-PCR. Under all conditions, more than 99% of the MNV was inactivated by ozone at 1 mg/liter within 2 min. Both RT-PCR assays significantly underestimated the inactivation of MNV, compared with that measured by plaque assay. Our results indicate that NoV may be more resistant to ozone than has been previously reported. Nevertheless, proper ozone disinfection practices can be used to easily control its transmission in water.

  9. Quantitative Trait Loci for Murine Growth

    PubMed Central

    Cheverud, J. M.; Routman, E. J.; Duarte, FAM.; van-Swinderen, B.; Cothran, K.; Perel, C.

    1996-01-01

    Body size is an archetypal quantitative trait with variation due to the segregation of many gene loci, each of relatively minor effect, and the environment. We examine the effects of quantitative trait loci (QTLs) on age-specific body weights and growth in the F(2) intercross of the LG/J and SM/J strains of inbred mice. Weekly weights (1-10 wk) and 75 microsatellite genotypes were obtained for 535 mice. Interval mapping was used to locate and measure the genotypic effects of QTLs on body weight and growth. QTL effects were detected on 16 of the 19 autosomes with several chromosomes carrying more than one QTL. The number of QTLs for age-specific weights varied from seven at 1 week to 17 at 10 wk. The QTLs were each of relatively minor, subequal effect. QTLs affecting early and late growth were generally distinct, mapping to different chromosomal locations indicating separate genetic and physiological systems for early and later murine growth. PMID:8846907

  10. Expansion of CD11b(+)Ly6G (+)Ly6C (int) cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions.

    PubMed

    Spallanzani, Raúl Germán; Dalotto-Moreno, Tomás; Raffo Iraolagoitia, Ximena Lucía; Ziblat, Andrea; Domaica, Carolina Inés; Avila, Damián Ezequiel; Rossi, Lucas Ezequiel; Fuertes, Mercedes Beatriz; Battistone, María Agustina; Rabinovich, Gabriel Adrián; Salatino, Mariana; Zwirner, Norberto Walter

    2013-12-01

    The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b(+)Gr-1(+), mostly CD11b(+)Ly6G(+)Ly6C(int) and CD11b(+)Ly6G(-)Ly6C(high) cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance. We used the highly metastatic 4T1 breast tumor (which does not express the classical progesterone receptor and expands MDSCs) to challenge BALB/c mice in the absence or in the presence of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice, but with reduced degranulation ability and in vivo cytotoxic activity. Simultaneously, MPA induced a preferential expansion of CD11b(+)Ly6G(+)Ly6C(int) cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro, MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed these cells with the ability to promote a preferential differentiation of bone marrow cells into CD11b(+)Ly6G(+)Ly6C(int) cells that displayed suppressive activity on NK cell degranulation. Sorted CD11b(+)Gr-1(+) cells from MPA-treated tumor-bearing mice exhibited higher suppressive activity on NK cell degranulation than CD11b(+)Gr-1(+) cells from vehicle-treated tumor-bearing mice. Thus, MPA, acting through the GR, endows tumor cells with an enhanced capacity to expand CD11b(+)Ly6G(+)Ly6C(int) cells that subsequently display a stronger suppression of NK cell-mediated anti-tumor immunity. Our results describe an alternative mechanism by which MPA may affect immunosurveillance and have potential implication in breast cancer incidence.

  11. Treatment Options for 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 ...

  12. Treatment Option Overview (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 ...

  13. General Information about 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 ...

  14. G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer

    PubMed Central

    Hollmén, Maija; Karaman, Sinem; Schwager, Simon; Lisibach, Angela; Christiansen, Ailsa J.; Maksimow, Mikael; Varga, Zsuzsanna; Jalkanen, Sirpa; Detmar, Michael

    2016-01-01

    ABSTRACT Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and a strong infiltration by TAMs has been associated with estrogen receptor (ER)-negative tumors and poor prognosis. However, the molecular mechanisms behind these observations are unclear. We investigated macrophage activation in response to co-culture with several breast cancer cell lines (T47D, MCF-7, BT-474, SKBR-3, Cal-51 and MDA-MB-231) and found that high granulocyte colony-stimulating factor (G-CSF) secretion by the triple-negative breast cancer (TNBC) cell line MDA-MB-231 gave rise to immunosuppressive HLA-DRlo macrophages that promoted migration of breast cancer cells via secretion of TGF-α. In human breast cancer samples (n = 548), G-CSF was highly expressed in TNBC (p < 0.001) and associated with CD163+ macrophages (p < 0.0001), poorer overall survival (OS) (p = 0.021) and significantly increased numbers of TGF-α+ cells. While G-CSF blockade in the 4T1 mammary tumor model promoted maturation of MHCIIhi blood monocytes and TAMs and significantly reduced lung metastasis, anti-CSF-1R treatment promoted MHCIIloF4/80hiMRhi anti-inflammatory TAMs and enhanced lung metastasis in the presence of high G-CSF levels. Combined anti-G-CSF and anti-CSF-1R therapy significantly increased lymph node metastases, possibly via depletion of the so-called “gate-keeper” subcapsular sinus macrophages. These results indicate that G-CSF promotes the anti-inflammatory phenotype of tumor-induced macrophages when CSF-1R is inhibited and therefore caution against the use of M-CSF/CSF-1R targeting agents in tumors with high G-CSF expression. PMID:27141367

  15. 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

  16. Breast cancer and depression.

    PubMed

    Somerset, Wendy; Stout, Steven C; Miller, Andrew H; Musselman, Dominique

    2004-07-01

    Major depression and depressive symptoms, although commonly encountered in patients with medical illnesses, are frequently underdiagnosed and undertreated in women with breast cancer. Depression and its associated symptoms diminish quality of life, adversely affect compliance with medical therapies, and reduce survival. Treatment of depression in women with breast cancer improves their dysphoria and other depressive symptoms, enhances quality of life, and may increase longevity. In this review, studies that investigate pathophysiologic alterations in patients with cancer and comorbid depression are discussed, and the few studies on treatment of depression and related symptoms in women with breast cancer are examined.

  17. CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages

    PubMed Central

    Ball, Michael S.; Shipman, Emilie P.; Kim, Hyunjung; Liby, Karen T.; Pioli, Patricia A.

    2016-01-01

    Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer. PMID:26918785

  18. Pertuzumab, Trastuzumab, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With HER2-Positive Advanced Breast Cancer

    ClinicalTrials.gov

    2016-12-23

    HER2-positive Breast Cancer; Recurrent Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Breast Adenocarcinoma; Inflammatory Breast Carcinoma

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

    PubMed

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

    2015-12-22

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

  20. The murine Sry gene encodes a nuclear transcriptional activator

    SciTech Connect

    Dubin, R.A.; Ostrer, H.

    1994-09-01

    The Sry gene functions as a genetic switch in gonadal ridge initiating testis determination. The murine Sry and human SRY open reading frames (ORF) share a conserved 79 amino acid motif, the HMG-box, that binds DNA. Outside this region the two genes share no additional homology. These studies were undertaken to determine whether the Sry/SRY genes encode nuclear transcriptional regulators. As judged by the accumulation of lacZ-SRY hybrid proteins in the nucleus, both the human and murine SRY ORFs contain a nuclear localization signal. The murine Sry HMG-box selectively binds the sequence NACAAT in vitro when presented with a random pool of oligonucleotides and binds AACAAT with the highest affinity. The murine Sry ORF, when expressed in HeLa cells, activates transcription of a reporter gene containing multiple copies of the AACAAT binding site. Activation was observed for a GAL4-responsive gene when the murine Sry ORF was linked to the DNA-binding domain of GAL4. Using this system, the activation function was mapped to a C-terminal glutamine/histidine-rich domain. In addition, LexA-Sry fusion genes activated a LexA-responsive gene in yeast. In contrast, a GAL4-human SRY fusion gene did not cause transcriptional activation. These studies suggest that both the human and mouse SRY ORFs encode nuclear, DNA-binding proteins, and that the mouse Sry ORF can function as a transcriptional activator with separable DNA-binding and activator domains.

  1. Analysis of cardiomyocyte movement in the developing murine heart

    SciTech Connect

    Hashimoto, Hisayuki; Yuasa, Shinsuke; Tabata, Hidenori; Tohyama, Shugo; Seki, Tomohisa; Egashira, Toru; Hayashiji, Nozomi; Hattori, Fumiyuki; Kusumoto, Dai; Kunitomi, Akira; Takei, Makoto; Kashimura, Shin; Yozu, Gakuto; Shimojima, Masaya; Motoda, Chikaaki; Muraoka, Naoto; Nakajima, Kazunori; Sakaue-Sawano, Asako; Miyawaki, Atsushi; Fukuda, Keiichi

    2015-09-04

    The precise assemblage of several types of cardiac precursors controls heart organogenesis. The cardiac precursors show dynamic movement during early development and then form the complicated heart structure. However, cardiomyocyte movements inside the newly organized mammalian heart remain unclear. We previously established the method of ex vivo time-lapse imaging of the murine heart to study cardiomyocyte behavior by using the Fucci (fluorescent ubiquitination-based cell cycle indicator) system, which can effectively label individual G1, S/G2/M, and G1/S-transition phase nuclei in living cardiomyocytes as red, green, and yellow, respectively. Global analysis of gene expression in Fucci green positive ventricular cardiomyocytes confirmed that cell cycle regulatory genes expressed in G1/S, S, G2/M, and M phase transitions were upregulated. Interestingly, pathway analysis revealed that many genes related to the cell cycle were significantly upregulated in the Fucci green positive ventricular cardiomyocytes, while only a small number of genes related to cell motility were upregulated. Time-lapse imaging showed that murine proliferating cardiomyocytes did not exhibit dynamic movement inside the heart, but stayed on site after entering the cell cycle. - Highlights: • We directly visualized cardiomyocyte movement inside the developing murine heart. • Cell cycle related genes were upregulated in the proliferating cardiomyocytes. • Time-lapse imaging revealed that proliferating murine cardiomyocytes stayed in place. • Murine ventricular cardiomyocytes proliferate on site during development.

  2. Murine bladder wall biomechanics following partial bladder obstruction.

    PubMed

    Chen, Joseph; Drzewiecki, Beth A; Merryman, W David; Pope, John C

    2013-10-18

    Evaluation of bladder wall mechanical behavior is important in understanding the functional changes that occur in response to pathologic processes such as partial bladder outlet obstruction (pBOO). In the murine model, the traditional approach of cystometry to describe bladder compliance can prove difficult secondary to small bladder capacity and surgical exposure of the bladder. Here, we explore an alternative technique to characterize murine mechanical properties by applying biaxial mechanical stretch to murine bladders that had undergone pBOO. 5-6 week old female C57/Bl6 mice were ovariectomized and subjected to pBOO via an open surgical urethral ligation and sacrificed after 4 weeks (n=12). Age matched controls (n=6) were also analyzed. Bladders were separated based on phenotype of fibrotic (n=6) or distended (n=6) at the time of harvest. Biaxial testing was performed in modified Kreb's solution at 37°C. Tissue was preconditioned to 10 cycles and mechanical response was evaluated by comparing axial strain at 50kPa. The normal murine bladders exhibited anisotropy and were stiffer in the longitudinal direction. All mice showed a loss of anisotropy after 4 weeks of pBOO. The two phenotypes observed after pBOO, fibrotic and distended, exhibited less and more extensibility, respectively. These proof-of-principle data demonstrate that pBOO creates quantifiable changes in the mechanics of the murine bladder that can be effectively quantified with biaxial testing.

  3. Optimized flow cytometry isolation of murine spermatocytes

    PubMed Central

    Gaysinskaya, Valeriya; Soh, Ina Y.; van der Heijden, Godfried W.; Bortvin, Alex

    2014-01-01

    Meiotic prophase I (MPI), is an initial stage of meiosis characterized by intricate homologous chromosome interactions, synapsis and DNA recombination. These processes depend on the complex, but poorly understood early MPI events of homologous chromosome search, alignment and pairing. Detailed molecular investigation of these early events requires isolation of individual MPI substages. Enrichment for Pachytene (P) and Diplotene (D) substages of late MPI was previously accomplished using flow cytometry. However, separation of early MPI spermatocytes, specifically, of Leptotene (L) and Zygotene (Z) substages, has been a challenge due to these cells’ similar characteristics. In this report, we describe an optimized Hoechst-33342 (Hoechst)-based flow cytometry approach for isolating individual MPI populations from adult murine testis. We get significant enrichment for individual L and Z spermatocytes, previously inseparable from each other, and optimize the isolation of other MPI substages. Our flow cytometry approach is a combination of three optimized strategies. The first is optimization of testis dissociation protocol that yields more consistent and reproducible testicular single cell suspension. The second involves optimization of flow cytometric gating protocol where a critical addition to the standard protocol for cell discrimination based on Hoechst fluorescence, involves a back-gating technique based on light scattering parameters. This step specifies selection of individual MPI substages. The third, is an addition of DNA content restriction to the gating protocol to minimize contamination from non-meiotic cells. Finally, we confirm significant enrichment of high-purity Preleptotene (PreL), L, Z, P and D MPI spermatocytes using stage-specific marker distribution. The technique will facilitate understanding of the molecular events underlying meiotic prophase I. PMID:24664803

  4. Neuropharmacological properties of farnesol in Murine model

    PubMed Central

    Shahnouri, M.; Abouhosseini Tabari, M.; Araghi, A.

    2016-01-01

    Research on new compounds of therapeutic value for behavioral disorders has progressed recently. Several studies have reported neuropharmacological activities of plant derived terpenes. Farnesol is a sesquiterpene whose most popular source is fruits but the anxiolytic activity for farnesol is still unknown. The present study was conducted on 32 male Swiss Albino mice (8 in each group) to evaluate the neuropharmacological properties of farnesol and its effects on plasma cortisol levels. Farnesol was administered intraperitoneally at single doses of 50 and 100 mg/kg, while diazepam 2 mg/kg was used as standard anxiolytic. Thirty minutes after injections, open field test (OFT), elevated plus maze (EPM), a forced swimming test (FST), and a hot plate test (HPT) were performed for evaluation of anxiety-like behavior, depression and nociception. In OFT, farnesol at the dose of 100 mg/kg led to significant decrease in locomotor activity (P<0.01). In EPM, only farnesol 100 mg/kg led to significant increase in the number of entries to the open arms and the time spent in open arms (P<0.01). Increase in immobility time in FST was seen in farnesol 50 and 100 mg/kg (P<0.001). Farnesol 100 mg/kg exerts significant prolongation in the latency of responses to noxious heat stimuli in HPT. Like diazepam, farnesol decreased plasma levels of cortisol. Results revealed that farnesol had anxiolytic, anti-nociceptive and depressant effects in murine models. The present study provides pharmacological evidence supporting the use of farnesol as a sedative for anxiety disorders. PMID:28224010

  5. Remodeling of alveolar septa after murine pneumonectomy

    PubMed Central

    Ysasi, Alexandra B.; Wagner, Willi L.; Bennett, Robert D.; Ackermann, Maximilian; Valenzuela, Cristian D.; Belle, Janeil; Tsuda, Akira; Konerding, Moritz A.

    2015-01-01

    In most mammals, removing one lung (pneumonectomy) results in the compensatory growth of the remaining lung. In mice, stereological observations have demonstrated an increase in the number of mature alveoli; however, anatomic evidence of the early phases of alveolar growth has remained elusive. To identify changes in the lung microstructure associated with neoalveolarization, we used tissue histology, electron microscopy, and synchrotron imaging to examine the configuration of the alveolar duct after murine pneumonectomy. Systematic histological examination of the cardiac lobe demonstrated no change in the relative frequency of dihedral angle components (Ends, Bends, and Junctions) (P > 0.05), but a significant decrease in the length of a subset of septal ends (“E”). Septal retraction, observed in 20–30% of the alveolar ducts, was maximal on day 3 after pneumonectomy (P < 0.01) and returned to baseline levels within 3 wk. Consistent with septal retraction, the postpneumonectomy alveolar duct diameter ratio (Dout:Din) was significantly lower 3 days after pneumonectomy compared to all controls except for the detergent-treated lung (P < 0.001). To identify clumped capillaries predicted by septal retraction, vascular casting, analyzed by both scanning electron microscopy and synchrotron imaging, demonstrated matted capillaries that were most prominent 3 days after pneumonectomy. Numerical simulations suggested that septal retraction could reflect increased surface tension within the alveolar duct, resulting in a new equilibrium at a higher total energy and lower surface area. The spatial and temporal association of these microstructural changes with postpneumonectomy lung growth suggests that these changes represent an early phase of alveolar duct remodeling. PMID:26078396

  6. Breast Cancer: Treatment Options

    MedlinePlus

    ... when lymph nodes are not involved, called node-negative breast cancer. These shorter schedules are becoming more ... patients with a smaller, less-aggressive, and node-negative tumor. Intensity-modulated radiation therapy. Intensity-modulated radiation ...

  7. Recurrent Breast Cancer

    MedlinePlus

    ... when examined under a microscope, that's considered a negative margin. If any part of the border has ... or treatments directed at the HER2 gene (triple negative breast cancer), you may have an increased risk ...

  8. The breast cancer conundrum.

    PubMed

    Adams, Patrick

    2013-09-01

    For decades, rates of breast cancer have been going up faster in rich countries than in poor ones. Scientists are beginning to understand more about its causes but unanswered questions remain. Patrick Adams reports.

  9. Breast Reconstruction Options

    MedlinePlus

    ... surgery to allow for better healing. You need radiation therapy. Many doctors recommend that women not have immediate ... al. Ischemic complications in pedicle, free, and muscle sparing transverse rectus abdominis myocutaneous flaps for breast reconstruction. ...

  10. MRI of the Breast

    MedlinePlus

    ... of the breast uses a powerful magnetic field, radio waves and a computer to produce detailed pictures of ... scans, MRI does not utilize ionizing radiation. Instead, radio waves redirect alignment of hydrogen atoms that naturally exist ...

  11. Fibrocystic breast disease

    MedlinePlus

    ... Gynecol Clin North Am. 2008;35:285-300. Katz VL, Dotters D. Breast diseases: diagnosis and treatment ... disease. In: Lentz GM, Lobo RA, Gershenson DM, Katz VL, eds. Comprehensive Gynecology . 6th ed. Philadelphia, PA: ...

  12. Breast biopsy - ultrasound

    MedlinePlus

    ... Interventional . 1st ed. Philadelphia, PA: Elsevier Saunders; 2010. Katz VL, Dotters D. Breast diseases: diagnosis and treatment ... disease. In: Lentz GM, Lobo RA, Gershenson DM, Katz VL, eds. Comprehensive Gynecology . 6th ed. Philadelphia, PA: ...

  13. Breast biopsy -- stereotactic

    MedlinePlus

    ... Therapy . 11th ed. Philadelphia, PA: Elsevier Saunders; 2014. Katz VL, Dotters D. Breast diseases: diagnosis and treatment ... disease. In: Lentz GM, Lobo RA, Gershenson DM, Katz VL, eds. Comprehensive Gynecology . 6th ed. Philadelphia, PA: ...

  14. Breast MRI scan

    MedlinePlus

    ... an imaging test that uses powerful magnets and radio waves to create pictures of the breast and ... No side effects from the magnetic fields and radio waves have been reported. The most common type ...

  15. Breast carcinoma metastases.

    PubMed

    Bodzin, G A; Staren, E D; Faber, L P

    1998-02-01

    With careful selection of patients, complete resection of pulmonary metastases from breast carcinoma may be a useful therapeutic option. Such a treatment appears to offer a significant survival benefit when compared with medical treatment alone, or with incomplete resection.

  16. Using a Breast Pump

    MedlinePlus

    ... 15 seconds, then rinse with plenty of warm water. After washing, dry your hands thoroughly with a clean paper towel. You do not need to wash your breasts before you pump unless you have been using a cream, ointment, ...

  17. Obesity and Breast Cancer.

    PubMed

    Fortner, Renée T; Katzke, Verena; Kühn, Tilman; Kaaks, Rudolf

    2016-01-01

    The relationship between adiposity and breast cancer risk and prognosis is complex, with associations that differ depending on when body size is assessed (e.g., pre- vs. postmenopausal obesity) and when breast cancer is diagnosed (i.e., pre- vs. postmenopausal disease). Further, the impact of obesity on risk differs by tumor hormone receptor status (e.g., estrogen (ER) and progesterone (PR) receptor) and, among postmenopausal women, use of exogenous hormones (i.e., hormone replacement therapy (HRT)). In the context of these complexities, this review focuses on associations between childhood and adolescent adiposity, general adiposity, weight changes (i.e., loss and gain), abdominal adiposity, and breast cancer risk and survival. Finally, we discuss potential mechanisms linking adiposity to breast cancer.

  18. Premenstrual breast changes

    MedlinePlus

    ... occurs during the second half of the menstrual cycle. ... Hormone changes during the menstrual cycle likely lead to breast swelling. More estrogen is made early in the cycle and it peaks just before mid-cycle. This ...

  19. Hormones and Breast Cancer.

    DTIC Science & Technology

    1997-10-01

    criteria were: having ever been treated with chemotherapy, or been diagnosed with systemic lupus erythematosus or liver cirrhosis ; having smoked the previous...concentrations of total and non- protein -bound oestradiol in patients with breast cancer and in normal controls. Int J Cancer 1982;29:17-21. 33. Reed MJ...and prolactin in postmenopausal breast cancer patients. Br J Cancer 1983;47:269-75. 36. Bruning PF, Bonfrer JMG, Hart, AAM. Non- protein bound

  20. Identifying Breast Cancer Oncogenes

    DTIC Science & Technology

    2011-10-01

    which is a study of 3131 human tumor samples and cancer cell lines including 243 breast samples. Tumorscape showed that PAK1 is located in an...chromosome 11q of human tumor samples and cancer cell lines that exhibit highest level of PAK1 amplification divided according to cancer type...breast, non-small cell (NSC) lung, ovarian (Ov), small cell lung (SCL), melanoma (Mel) and esophageal squamous (Esq). PAK1 and CCND1 1oci are marked . B

  1. Identifying Breast Cancer Oncogenes

    DTIC Science & Technology

    2010-10-01

    utilizing mouse intestinal cells and rat fibroblasts suggest that PTK6 may be required for cell death triggered by specific stimuli such as DNA damage [41...Parallel data of 12 normal breast organoids RNA samples and 7 bulk normal breast tissue specimens were used as normal control. Array probe data were...JJ, Tyner AL (2009) Induction of protein tyrosine kinase 6 in mouse intestinal crypt epithelial cells promotes DNA damage-induced apoptosis

  2. 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.

  3. ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program.

    PubMed

    Charafe-Jauffret, Emmanuelle; Ginestier, Christophe; Bertucci, François; Cabaud, Olivier; Wicinski, Julien; Finetti, Pascal; Josselin, Emmanuelle; Adelaide, José; Nguyen, Tien-Tuan; Monville, Florence; Jacquemier, Jocelyne; Thomassin-Piana, Jeanne; Pinna, Guillaume; Jalaguier, Aurélie; Lambaudie, Eric; Houvenaeghel, Gilles; Xerri, Luc; Harel-Bellan, Annick; Chaffanet, Max; Viens, Patrice; Birnbaum, Daniel

    2013-12-15

    Cancer stem-like cells (CSC) have been widely studied, but their clinical relevance has yet to be established in breast cancer. Here, we report the establishment of primary breast tumor-derived xenografts (PDX) that encompass the main diversity of human breast cancer and retain the major clinicopathologic features of primary tumors. Successful engraftment was correlated with the presence of ALDH1-positive CSCs, which predicted prognosis in patients. The xenografts we developed showed a hierarchical cell organization of breast cancer with the ALDH1-positive CSCs constituting the tumorigenic cell population. Analysis of gene expression from functionally validated CSCs yielded a breast CSC signature and identified a core transcriptional program of 19 genes shared with murine embryonic, hematopoietic, and neural stem cells. This generalized stem cell program allowed the identification of potential CSC regulators, which were related mainly to metabolic processes. Using an siRNA genetic screen designed to target the 19 genes, we validated the functional role of this stem cell program in the regulation of breast CSC biology. Our work offers a proof of the functional importance of CSCs in breast cancer, and it establishes the reliability of PDXs for use in developing personalized CSC therapies for patients with breast cancer.

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

    PubMed

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

    2014-04-01

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

  5. Insulin-like growth factor binding protein-3 links obesity and breast cancer progression

    PubMed Central

    Scully, Tiffany; Firth, Sue M.; Scott, Carolyn D.; de Silva, Hasanthi C.; Pintar, John E.; Chan-Ling, Tailoi; Twigg, Stephen M.; Baxter, Robert C.

    2016-01-01

    Obesity is associated epidemiologically with poor breast cancer prognosis, but the mechanisms remain unclear. Since IGF binding protein-3 (IGFBP-3) influences both breast cancer growth and adipocyte maturation, it may impact on how obesity promotes breast oncogenesis. This study investigated the role of endogenous IGFBP-3 on the development of obesity and subsequently on breast tumor growth. Wild-type (WT) C57BL/6 or IGFBP-3-null (BP3KO) mice were fed a high-fat diet (HFD) or control chow-diet for 15 weeks before orthotopic injection with syngeneic EO771 murine breast cancer cells. When the largest tumor reached 1000 mm3, tissues and tumors were excised for analysis. Compared to WT, BP3KO mice showed significantly reduced weight gain and mammary fat pad mass (contralateral to tumor) in response to HFD, despite similar food intake. EO771 tumor weight and volume were increased by HFD and decreased by BP3KO. Despite differences in tumor size, tumors in BP3KO mice showed no differences from WT in the number of mitotically active (Ki67+) and apoptotic (cleaved caspase-3+) cells, but had greater infiltration of CD3+ T-cells. These data suggest that endogenous (circulating and/or stromal) IGFBP-3 is stimulatory to adipose tissue expansion and enhances mammary tumor growth in immune-competent mice, potentially by suppressing T-cell infiltration into tumors. PMID:27448965

  6. Targeting reverse tetracycline-dependent transactivator to murine mammary epithelial cells that express the progesterone receptor.

    PubMed

    Mukherjee, Atish; Soyal, Selma M; Fernandez-Valdivia, Rodrigo; DeMayo, Francesco J; Lydon, John P

    2007-10-01

    Through an established gene-targeting strategy, reverse tetracycline-dependent transactivator (rtTA) was targeted downstream of the murine progesterone receptor (PR) promoter. Mice were generated in which one (PR(+/rtTA)) or both (PR(rtTA/rtTA)) PR alleles harbor the rtTA insertion. The PR(+/rtTA) and PR(rtTA/rtTA) knockins exhibit phenotypes identical to the normal and the progesterone receptor knockout mouse, respectively. Crossed with the TZA reporter, which carries the TetO-LacZ responder transgene, the PR(+/rtTA)/TZA and PR(rtTA/rtTA)/TZA bigenics exhibit doxycycline-induced beta-galactosidase activity specifically in progesterone responsive target tissues such as the mammary gland, uterus, ovary, and pituitary gland. In the case of the PR(+/rtTA)/TZA mammary epithelium, dual immunofluorescence demonstrated that PR expression and doxycycline-induced beta-galactosidase activity colocalized; beta-galactosidase was not detected in the absence of doxycycline. Although both the PR(+/rtTA) and PR(rtTA/rtTA) knockins represent innovative animal models with which to further query progesterone's mechanism of action in vivo, the PR(rtTA/rtTA) mouse in particular promises to provide unique insight into the paracrine mechanism of action, which underpins progesterone's involvement in mammary morphogenesis with obvious implications for extending our understanding of this steroid's role in breast cancer progression.

  7. Increasing Breast Cancer Surveillance Among African American Breast Cancer Survivors

    DTIC Science & Technology

    2010-01-01

    one or both breasts were affected. Family Member (e.g. grandmother, aunt) Paternal or Maternal Type or Location of Cancer (e.g. breast...breast cancer who previously participated in an ongoing parent project and are at least 3 months post-treatment. Participants were to be assigned to... parent study also awaiting approval (“Behavior, Estrogen Metabolism, and Breast Cancer Risk: A Molecular Epidemiologic Study” HSRRB Log Number A

  8. Magnetic resonance imaging and spectroscopy of the murine cardiovascular system.

    PubMed

    Akki, Ashwin; Gupta, Ashish; Weiss, Robert G

    2013-03-01

    Magnetic resonance imaging (MRI) has emerged as a powerful and reliable tool to noninvasively study the cardiovascular system in clinical practice. Because transgenic mouse models have assumed a critical role in cardiovascular research, technological advances in MRI have been extended to mice over the last decade. These have provided critical insights into cardiac and vascular morphology, function, and physiology/pathophysiology in many murine models of heart disease. Furthermore, magnetic resonance spectroscopy (MRS) has allowed the nondestructive study of myocardial metabolism in both isolated hearts and in intact mice. This article reviews the current techniques and important pathophysiological insights from the application of MRI/MRS technology to murine models of cardiovascular disease.

  9. The Role of Oncoplastic Breast Surgery in Breast Cancer Treatment

    PubMed Central

    Emiroğlu, Mustafa; Sert, İsmail; İnal, Abdullah

    2015-01-01

    The aim of this study is to discuss indications, advantages, disadvantages, oncologic and aesthetic results of Oncoplastic Surgery (OBS). Pubmed and Medline database were searched for articles published between 1998 and 2014 for keywords: oncoplastic breast surgery, therapeutic mammoplasty, oncoplastic breast reduction, synchrenous reconstructions. Role of OBS in breast cancer surgery, its aspects to be considered, its value and results have been interpreted. This technique has advantages by providing more extensive tumourectomy, yielding better aesthetic results compared with breast conserving surgery, allowing oncoplastic reduction in breast cancer patients with macromastia, with higher patient satisfaction and quality of life and by being inexpensive due to single session practice. As for its disadvantages are: re-excision is more difficult, risk for mastectomy is higher, it is depent on the Surgeron’s experience, it has a risk for delay in adjuvant therapies and its requirement for additional imaging studies during management. Main indications are patients with small tumour/breast volume, macromastia, multifocality, procedures which can disrupt breast cosmesis such as surgeries for upper inner breas tquadrient tumours. Contraindications are positive margin problems after wide excision, diffuse malign microcalsifications, inflammatory breast cancer, history of radiotherapy and patients’ preferences. Despite low evidence level, Oncoplastic Breast Surgery seems to be both reliable and acceptable in terms of oncologic and aesthetic aspects. Oncoplastic Breast Surgery increase the application rate of breast conserving surgery by obviating practical limitations and improve the results of breast conserving surgery. Correct patient and technique choice in OBS is vital for optimization of post surgical

  10. Breast milk - pumping and storing

    MedlinePlus

    ... to 9 hours. DO NOT refreeze. DO NOT microwave breast milk. Overheating destroys nutrients, and "hot spots" ... burn your baby. Bottles may explode when you microwave them for too long. When leaving breast milk ...

  11. Breast Reconstruction with Flap Surgery

    MedlinePlus

    ... that restores shape to your breast after a mastectomy — surgery that removes your breast tissue to treat ... can be accomplished at the time of your mastectomy (immediate reconstruction), though sometimes it can be done ...

  12. Understanding your breast cancer risk

    MedlinePlus

    ... ency/patientinstructions/000830.htm Understanding your breast cancer risk To use the sharing features on this page, ... you can do to help prevent breast cancer. Risk Factors You Cannot Control Risk factors you cannot ...

  13. Risks of Breast Cancer Screening

    MedlinePlus

    ... trials is available from the NCI website . Three tests are used by health care providers to screen for breast cancer: Mammogram Mammography is the most common screening test for breast cancer . A mammogram is an x- ...

  14. Causes of breast lumps (image)

    MedlinePlus

    ... breast lumps are benign (non-cancerous), as in fibroadenoma, a condition that mostly affects women under age ... with the menstrual cycle, whereas a lump from fibroadenoma does not. While most breast lumps are benign, ...

  15. Treatment Option Overview (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 ...

  16. General Information about 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 ...

  17. Preparing for Breast Reconstruction Surgery

    MedlinePlus

    ... Cancer Breast Reconstruction Surgery Preparing for Breast Reconstruction Surgery Your surgeon can help you know what to ... The plan for follow-up Costs Understanding your surgery costs Health insurance policies often cover most or ...

  18. Ultrasound-Guided Breast Biopsy

    MedlinePlus

    ... Breast Biopsy An ultrasound-guided breast biopsy uses sound waves to help locate a lump or abnormality ... exam. The transducer sends out inaudible, high—frequency sound waves into the body and then listens for ...

  19. Computerized Cognitive Retraining in Improving Cognitive Function in Breast Cancer Survivors

    ClinicalTrials.gov

    2017-03-02

    Cancer Survivor; Stage 0 Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  20. Virtual Weight Loss Program in Maintaining Weight in African American Breast Cancer Survivors

    ClinicalTrials.gov

    2017-01-19

    Cancer Survivor; Invasive Breast Carcinoma; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  1. Cardiac Rehabilitation Program in Improving Cardiorespiratory Fitness in Stage 0-III Breast Cancer Survivors

    ClinicalTrials.gov

    2017-01-30

    Cancer Survivor; Stage 0 Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  2. Multiparametric Breast MRI of Breast Cancer

    PubMed Central

    Rahbar, Habib; Partridge, Savannah C.

    2015-01-01

    Synopsis Breast MRI has increased in popularity over the past two decades due to evidence for its high sensitivity for cancer detection. Current clinical MRI approaches rely on the use of a dynamic contrast enhanced (DCE-MRI) acquisition that facilitates morphologic and semi-quantitative kinetic assessments of breast lesions. The use of more functional and quantitative parameters, such as pharmacokinetic features from high temporal resolution DCE-MRI, apparent diffusion coefficient (ADC) and intravoxel incoherent motion (IVIM) on diffusion weighted MRI, and choline concentrations on MR spectroscopy, hold promise to broaden the utility of MRI and improve its specificity. However, due to wide variations in approach among centers for measuring these parameters and the considerable technical challenges, robust multicenter data supporting their routine use is not yet available, limiting current applications of many of these tools to research purposes. PMID:26613883

  3. Redefining Myeloid Cell Subsets in Murine Spleen.

    PubMed

    Hey, Ying-Ying; Tan, Jonathan K H; O'Neill, Helen C

    2015-01-01

    Spleen is known to contain multiple dendritic and myeloid cell subsets, distinguishable on the basis of phenotype, function and anatomical location. As a result of recent intensive flow cytometric analyses, splenic dendritic cell (DC) subsets are now better characterized than other myeloid subsets. In order to identify and fully characterize a novel splenic subset termed "L-DC" in relation to other myeloid cells, it was necessary to investigate myeloid subsets in more detail. In terms of cell surface phenotype, L-DC were initially characterized as a CD11b(hi)CD11c(lo)MHCII(-)Ly6C(-)Ly6G(-) subset in murine spleen. Their expression of CD43, lack of MHCII, and a low level of CD11c was shown to best differentiate L-DC by phenotype from conventional DC subsets. A complete analysis of all subsets in spleen led to the classification of CD11b(hi)CD11c(lo)MHCII(-)Ly6C(lo)Ly6G(-) cells as monocytes expressing CX3CR1, CD43 and CD115. Siglec-F expression was used to identify a specific eosinophil population, distinguishable from both Ly6C(lo) and Ly6C(hi) monocytes, and other DC subsets. L-DC were characterized as a clear subset of CD11b(hi)CD11c(lo)MHCII(-)Ly6C(-)Ly6G(-) cells, which are CD43(+), Siglec-F(-) and CD115(-). Changes in the prevalence of L-DC compared to other subsets in spleens of mutant mice confirmed the phenotypic distinction between L-DC, cDC and monocyte subsets. L-DC development in vivo was shown to occur independently of the BATF3 transcription factor that regulates cDC development, and also independently of the FLT3L and GM-CSF growth factors which drive cDC and monocyte development, so distinguishing L-DC from these commonly defined cell types.

  4. Organization of the murine Cd22 locus

    SciTech Connect

    Law, Che-Leung; Torres, R.M.; Sundeberg, H.A.; Clark, E.A ); Parkhouse, R.M.E. ); Brannan, C.I.; Copeland, N.G.; Jenkins, N.A. )

    1993-07-01

    Murine CD22 (mCD22) is a B cell-associated adhesion protein with seven extracellular Ig-like domains that has 62% amino acid identify to its human homologue. Southern analysis on genomic DNA isolated from tissues and cell lines from several mouse strains using mCD22 cDNA demonstrated that the Cd22 locus encoding mCD22 is a single copy gene of [le]30 kb. Digestion of genomic DNA preparations with four restriction endonucleases revealed the presence of restriction fragment length polymorphisms (RFLP) in BALB/c, C57BL/6, and C3H strains vs DBA/2j, NZB, and NZC strains, suggesting the presence of two or more Cd22 alleles. Using a mCD22 cDNA clone derived from the BALB/c strain, the authors isolated genomic clones from a DBA/2 genomic library that contained all the exons necessary to encode the full length mCD22 cDNA. Fifteen exons, including exon 3 that encodes the translation start codon, were identified. Each extracellular Ig-like domain of mCD22 is encoded by a single exon. A comparison between the nucleotide sequences of the BALB/c CD22 cDNA and the exons of the DBA/2j CD22 genomic clones revealed an 18-nucleotide deletion in exon 4 (encoding the most distal Ig-like domain 1 of mCD22) of the DBA/2j genomic sequence in addition to a number of substitutions, insertions, and deletions in other exons. These nucleotide differences were also present in a cDNA clone isolated from total RNA of LPS-activated DBA/2j splenocytes mosome 7, a region sytenic to human chromosome 19q, close to the previously reported loci, Lyb-8 and Mag (a homologue of Cd22). An antibody (CY34) against the Lyb-8.2 B cell marker reacted with a BHK transfectant expressing the full length mCd22 cDNA, thus demonstrating that Lyb-8 and Cd22 loci are identical. Furthermore, a rat anti-mCD22 mAb, NIM-R6, bound to slgM[sup +] DBA/2j B cells, confirming the expression of a CD22 protein by the Cd22[sup a]/lyb-8[sup a] allele. 63 refs., 7 figs., 1 tab.

  5. Nanoelectroablation therapy for murine basal cell carcinoma

    SciTech Connect

    Nuccitelli, Richard; Tran, Kevin; Athos, Brian; Kreis, Mark; Nuccitelli, Pamela; Chang, Kris S.; Epstein, Ervin H.; Tang, Jean Y.

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer Nanoelectroablation is a new, non-thermal therapy that triggers apoptosis in tumors. Black-Right-Pointing-Pointer Low energy, ultrashort, high voltage pulses ablate the tumor with little or no scar. Black-Right-Pointing-Pointer Nanoelectroablation eliminates 99.8% of the BCC but may leave a few remnants behind. Black-Right-Pointing-Pointer Pilot clinical trials on human BCCs are ongoing and leave no remnants in most cases. -- Abstract: When skin tumors are exposed to non-thermal, low energy, nanosecond pulsed electric fields (nsPEF), apoptosis is initiated both in vitro and in vivo. This nanoelectroablation therapy has already been proven effective in treating subdermal murine allograft tumors. We wanted to determine if this therapy would be equally effective in the treatment of autochthonous BCC tumors in Ptch1{sup +/-}K14-Cre-ER p53 fl/fl mice. These tumors are similar to human BCCs in histology and in response to drug therapy . We have treated 27 BCCs across 8 mice with either 300 pulses of 300 ns duration or 2700 pulses of 100 ns duration, all at 30 kV/cm and 5-7 pulses per second. Every nsPEF-treated BCC began to shrink within a day after treatment and their initial mean volume of 36 {+-} 5 (SEM) mm{sup 3} shrunk by 76 {+-} 3% over the ensuing two weeks. After four weeks, they were 99.8% ablated if the size of the treatment electrode matched the tumor size. If the tumor was larger than the 4 mm wide electrode, multiple treatments were needed for complete ablation. Treated tumors were harvested for histological analysis at various times after treatment and exhibited apoptosis markers. Specifically, pyknosis of nuclei was evident as soon as 2 days after nsPEF treatment, and DNA fragmentation as detected via TUNEL staining was also evident post treatment. Nanoelectroablation is effective in triggering apoptosis and remission of radiation-induced BCCs with a single 6 min-long treatment of 2700 pulses.

  6. Oral contraceptives and breast cancer.

    PubMed

    Johnson, K H; Millard, P S

    1996-10-01

    The Collaborative Group on Hormonal Factors in Breast Cancer conducted a meta-analysis of data from 10 cohort and 44 case-control studies of the association between combined oral contraceptive (OC) use and breast cancer. 53,297 women with breast cancer and 100,239 women with no breast cancer from 25 countries worldwide were studied. Current OC users faced a 24% increased risk of developing breast cancer (confidence interval = 1.15-1.33). This risk fell steadily after cessation and reached 0 at 10 years and thereafter. Use of OCs with higher doses were associated with a greater risk of breast cancer than medium or low-dose OCs. The number of excess cancers in women while using OCs and up to 10 years after OC cessation stood at 0.5/10,000 women 16-19 years old, 1.5/10,000 women 20-24 years old, and 4.7/10,000 women 25-29 years old. The elevated risk of developing breast cancer did not differ by country of origin, ethnic background, reproductive history, or family history of breast cancer. OC users had less clinically advanced breast cancer than never-users who had breast cancer. This finding plus the moderate reduced risk of breast cancer more than 10 years after OC cessation suggest that OCs may effect earlier diagnosis of existing breast cancer instead of causing new breast cancers. The findings of this meta-analysis along with a plausible biologic mechanism (estrogen stimulates breast cancer cells) suggest a causal relationship between OC use and breast cancer. They also indicate that the risk is small, decreases with time, and is lower among low-dose OC users. It is reassuring that the breast cancers found among OC users is less clinically advanced than those found in never-users.

  7. Early detection of breast cancer.

    PubMed

    Nettles-Carlson, B

    1989-01-01

    Timely, comprehensive screening for breast cancer is a major, though often overlooked, component of primary health care for women. This article reviews the scientific rationale for screening and outlines the current recommendations of the American Cancer Society and the U.S. Preventive Services Task Force regarding the use of mammography, clinical breast examination (CBE), and breast self-examination (BSE). Nursing interventions to decrease barriers to effective screening are discussed, and an expanded role of nurses in breast cancer screening is proposed.

  8. Protective effects of dendrosomal curcumin on an animal metastatic breast tumor.

    PubMed

    Farhangi, Baharak; Alizadeh, Ali Mohammad; Khodayari, Hamid; Khodayari, Saeed; Dehghan, Mohammad Javad; Khori, Vahid; Heidarzadeh, Alemeh; Khaniki, Mahmood; Sadeghiezadeh, Majid; Najafi, Farhood

    2015-07-05

    Curcumin has been shown to inhibit migration and invasion of cancer angiogenesis via interacting with key regulatory molecules like NF-κB. Rapidly metabolized and conjugated in the liver, curcumin has the limited systemic bioavailability. Previous results have shown a new light of potential biocompatibility, biodegradability, as well as anti-cancer effects of dendrosomal curcumin (DNC) in biological systems. The present study aims to deliberate the protective effects of DNC on metastatic breast tumor in vitro and in vivo. After the dosing procedure, twenty-seven female mice were divided into 40 and 80mg/kg groups of DNC, along with a control group to investigate the anti-metastatic effects of DNC on mammary tumor-bearing mice. In vitro results showed that the different concentrations of DNC reduced the migration and the adhesion of 4T1 cells after 24h (P<0.05). Under the dosing procedure, DNC was safe at 80mg/kg and lower doses. The treated DNC animals had a higher survival rate and lower metastatic signs (14%) compared to control (100%) (P<0.05). The metastatic tumors were more common in control mice than the treated groups in the lung, the liver and the sternum tissues. Animals treated with DNC had smaller tumor volume in comparison with control group (P<0.05). Final mean tumor volume reached to approximately 1.11, 0.31 and 0.27cm(3) in the control, and 40 and 80mg/kg DNC groups, respectively (P<0.05). Furthermore, suppression of NF-κB expression by DNC led to down-regulation of VEGF, COX-2, and MMP-9 expressions in the breast tumor, the lung, the brain, the spleen and the liver tissues (P<0.05). These outcomes indicate that dendrosomal curcumin has a chemoprotective effect on the breast cancer metastasis through suppression of NF-κB and its regulated gene products.

  9. Surveying Breast Cancer's Genomic Landscape.

    PubMed

    2016-07-01

    An in-depth analysis has produced the most comprehensive portrait to date of the myriad genomic alterations involved in breast cancer. In sequencing the whole genomes of 560 breast cancers and combining this information with published data from another 772 breast tumors, the research team uncovered several new genes and mutational signatures that potentially influence this disease.

  10. Regulation of Survival by IKK(epsilon) in Inflammatory Breast Cancer Involves EpCAM

    DTIC Science & Technology

    2013-12-01

    responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms . Blood 115, 5232-5240 (2010). 28. J. S. Duncan, M. C. Whittle, K...H. Chen, D. Morosini, K. Bell, M. Alimzhanov, S. Ioannidis, P. McCoon, Z. A. Cao, H. Yu, R. Jove, M. Zinda, The JAK2 inhibitor AZD1480 potently...Frank, K. Polyak, The JAK2 /STAT3 signaling pathway is required for growth of CD44CD24 stem cell-like breast cancer cells in human tumors. The Journal

  11. Myosin 1e promotes breast cancer malignancy by enhancing tumor cell proliferation and stimulating tumor cell de-differentiation

    PubMed Central

    Ouderkirk-Pecone, Jessica L.; Goreczny, Gregory J.; Chase, Sharon E.; Tatum, Arthur H.; Turner, Christopher E.; Krendel, Mira

    2016-01-01

    Despite advancing therapies, thousands of women die every year of breast cancer. Myosins, actin-dependent molecular motors, are likely to contribute to tumor formation and metastasis via their effects on cell adhesion and migration and may provide promising new targets for cancer therapies. Using the MMTV-PyMT murine model of breast cancer, we identified Myosin 1e (MYO1E) as a novel tumor promoter. Tumor latency in mice lacking MYO1E was significantly increased, and tumors formed in the absence of MYO1E displayed unusual papillary morphology, with well-differentiated layers of epithelial cells covering fibrovascular cores, rather than solid sheets of tumor cells typically observed in this cancer model. These tumors were reminiscent of papillary breast cancer in humans that is typically non-invasive and often cured by tumor excision. MYO1E-null tumors exhibited decreased expression of the markers of cell proliferation, which was recapitulated in primary tumor cells derived from MYO1E-null mice. In agreement with our findings, meta-analysis of patient survival data indicated that MYO1E expression level was associated with reduced recurrence-free survival in basal-like breast cancer. Overall, our data suggests that MYO1E contributes to breast tumor malignancy and regulates the differentiation and proliferation state of breast tumor cells. PMID:27329840

  12. Pregnancy associated breast cancer and pregnancy after breast cancer treatment.

    PubMed

    Doğer, Emek; Calışkan, Eray; Mallmann, Peter

    2011-01-01

    Breast cancer is one of the most common cancers diagnosed during pregnancy and its frequency is increasing as more women postpone their pregnancies to their thirties and forties. Breast cancer diagnosis during pregnancy and lactation is difficult and complex both for the patient and doctors. Delay in diagnosis is frequent and treatment modalities are difficult to accept for the pregnant women. The common treatment approach is surgery after diagnosis, chemotherapy after the first trimester and radiotherapy after delivery. Even though early stage breast cancers have similar prognosis, advanced stage breast cancers diagnosed during pregnancy and lactation have poorer prognosis than similar stage breast cancers diagnosed in non-pregnant women. Women who desire to become pregnant after treatment of breast cancer will have many conflicts. Although the most common concern is recurrence of breast cancer due to pregnancy, the studies conducted showed that pregnancy has no negative effect on breast cancer prognosis. In this review we search for the frequency of breast cancer during pregnancy, the histopathological findings, risk factor, diagnostic and treatment modalities. We reviewed the literature for evidence based findings to help consult the patients on the outcome of breast cancer diagnosed during pregnancy and lactation, and also inform the patients who desire to become pregnant after breast cancer according to current evidences.

  13. Murine Sirt3 protein isoforms have variable half-lives

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sirt3 is a NAD+-dependent protein deacetylase mainly localized in mitochondria. Recent studies indicate that the murine Sirt3 gene expresses different transcript variants resulting in three possible Sirt3 protein isoforms with variable lengths at the N-terminus: M1 (aa 1-334), M2 (aa 15-334), and M3...

  14. Expression of biologically active murine interleukin-18 in Lactococcus lactis.

    PubMed

    Feizollahzadeh, Sadegh; Khanahmad, Hossein; Rahimmanesh, Ilnaz; Ganjalikhani-Hakemi, Mazdak; Andalib, Alireza; Sanei, Mohammad Hossein; Rezaei, Abbas

    2016-11-01

    The food-grade bacterium Lactococcus lactis is increasingly used for heterologous protein expression in therapeutic and industrial applications. The ability of L. lactis to secrete biologically active cytokines may be used for the generation of therapeutic cytokines. Interleukin (IL)-18 enhances the immune response, especially on mucosal surfaces, emphasizing its therapeutic potential. However, it is produced as an inactive precursor and has to be enzymatically cleaved for maturation. We genetically manipulated L. lactis to secrete murine IL-18. The mature murine IL-18 gene was inserted downstream of a nisin promoter in pNZ8149 plasmid and the construct was used to transform L. lactis NZ3900. The transformants were selected on Elliker agar and confirmed by restriction enzyme digestion and sequencing. The expression and secretion of IL-18 protein was verified by SDS-PAGE, western blotting and ELISA. The biological activity of recombinant IL-18 was determined by its ability to induce interferon (IFN)-γ production in L. lactis co-cultured with murine splenic T cells. The amounts of IL-18 in bacterial lysates and supernatants were 3-4 μg mL(-1) and 0.6-0.7 ng mL(-1), respectively. The successfully generated L. lactis strain that expressed biologically active murine IL-18 can be used to evaluate the possible therapeutic effects of IL-18 on mucosal surfaces.

  15. Biochemical characterization of murine glycosylation-inhibiting factor

    SciTech Connect

    Tagaya, Yutaka; Mori, Akio; Ishizaka, Kimishige )

    1991-10-15

    The glycosylation-inhibiting factor (GIF) was isolated from serum-free culture supernatants of the murine T-cell hybridoma, 231F1 cells, by using an immunosorbent coupled with the monoclonal anti-lipomodulin antibody. The isolated lymphokine is a 14-kDa protein with a pI of 5.5, as determined by SDS/PAGE and two-dimensional gel electrophoresis. Fractionation of a mixture of radiolabeled GIF with culture supernatant of the 231F1 cells on ion-exchange and revere-phase columns and by gel filtration demonstrated homogeneity of the 14-kDa GIF and confirmed that the bioactivity of GIF and the antigenic determinant recognized by the monoclonal anti-GIF antibody are associated with the 14-kDa protein. The {sup 125}II-labeled 14-kDa protein binds to the murine T-cell hybridoma 12H5 cells, which have been used for bioassay of GIF, and the murine B-cell line A20.3 cells, but the binding of the protein to resting murine splenic lymphocytes was barely detectable. Under the same experimental conditions, binding of the {sup 125}I-labeled recombinant human lipocortin I to the 12H5 cells was not detectable. In contrast, the {sup 125}I labeled lipocortin, but not the 14-kDa GIF, bound to phosphatidylserine vesicles. The results indicate that GIF does not belong to the anexin family.

  16. Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery

    ClinicalTrials.gov

    2017-03-06

    Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  17. Mindfulness Meditation or Survivorship Education in Improving Behavioral Symptoms in Younger Stage 0-III Breast Cancer Survivors (Pathways to Wellness)

    ClinicalTrials.gov

    2017-03-21

    Cancer Survivor; Early-Stage Breast Carcinoma; Stage 0 Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  18. Azacitidine in Treating Patients With Triple Negative Stage I-IV Invasive Breast Cancer That Can Be Removed By Surgery

    ClinicalTrials.gov

    2014-02-05

    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; Triple-negative Breast Cancer

  19. 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

  20. Diet and breast cancer.

    PubMed

    Bradlow, H Leon; Sepkovic, Daniel W

    2002-06-01

    The preponderance of evidence suggests a role for fat and alcohol as risk factors for breast cancer. The role of milk is more controversial with some studies suggesting that milk is a risk factor and others that consumption of milk is protective against breast cancer. No other major nutrient appears to play a significant role in increasing breast cancer risk. On the other hand, there is increasing evidence that a variety of micronutrients and hormones appear to have significant anticancer activity. These range from steroids such as dehydroepiandrosterone (DHEA) and its analysis to indoles, isothiocyanates, and isoflavone derivatives. These compounds act directly by interfering with cyclins and promoting apoptosis as well as indirectly by altering estrogen metabolism in a favorable direction. These effects are not merely theoretical actions in cell culture and tissue explants; they have been demonstrated in human patients as a range of studies have demonstrated.

  1. Current Translational Research and Murine Models For Duchenne Muscular Dystrophy

    PubMed Central

    Rodrigues, Merryl; Echigoya, Yusuke; Fukada, So-ichiro; Yokota, Toshifumi

    2016-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscle degeneration. Mutations in the DMD gene result in the absence of dystrophin, a protein required for muscle strength and stability. Currently, there is no cure for DMD. Since murine models are relatively easy to genetically manipulate, cost effective, and easily reproducible due to their short generation time, they have helped to elucidate the pathobiology of dystrophin deficiency and to assess therapies for treating DMD. Recently, several murine models have been developed by our group and others to be more representative of the human DMD mutation types and phenotypes. For instance, mdx mice on a DBA/2 genetic background, developed by Fukada et al., have lower regenerative capacity and exhibit very severe phenotype. Cmah-deficient mdx mice display an accelerated disease onset and severe cardiac phenotype due to differences in glycosylation between humans and mice. Other novel murine models include mdx52, which harbors a deletion mutation in exon 52, a hot spot region in humans, and dystrophin/utrophin double-deficient (dko), which displays a severe dystrophic phenotype due the absence of utrophin, a dystrophin homolog. This paper reviews the pathological manifestations and recent therapeutic developments in murine models of DMD such as standard mdx (C57BL/10), mdx on C57BL/6 background (C57BL/6-mdx), mdx52, dystrophin/utrophin double-deficient (dko), mdxβgeo, Dmd-null, humanized DMD (hDMD), mdx on DBA/2 background (DBA/2-mdx), Cmah-mdx, and mdx/mTRKO murine models. PMID:27854202

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

    PubMed

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

    2012-11-13

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

  3. Synergistic inhibition of migration and invasion of breast cancer cells by dual docetaxel/quercetin-loaded nanoparticles via Akt/MMP-9 pathway.

    PubMed

    Li, Jing; Zhang, Jun; Wang, Yiyue; Liang, Xiao; Wusiman, Zaitongguli; Yin, Yunzhi; Shen, Qi

    2017-03-21

    Metastasis impedes the successful chemotherapy for breast cancer. In this study, an Akt inhibitor (quercetin, Qu) was co-delivered with a chemotherapeutic agent (docetaxel, DTX) by using hyaluronic acid (HA)-modified nanoparticles (NPs) as vectors to block metastasis. Dual DTX/Qu-loaded HA/polylactic-co-glycolic acid-polyethyleneimine NPs (PP-HA/NPs) were prepared through a modified emulsion solvent evaporation technique. The particle size of PP-HA/NPs with narrow polydispersity was 209.8±10.8nm. Wound healing assay revealed that Qu co-delivery and HA modification elicited synergistic inhibitory effects on cell motility. The downregulation of p-Akt and matrix metalloproteinase-9 (MMP-9) expression contributed to the significant inhibition of cell migration and invasion with inhibition rates of 95.6% and 99.3%, respectively. Further studies indicated that PP-HA/NPs could be efficiently uptaken by 4T1 breast cancer cells and could further induce cytotoxicity, decrease colony formation and promote cell apoptosis. Biodistribution assay demonstrated PP-HA/NPs also enhanced drug accumulation in the tumor and lungs and predicted that PP-HA/NPs could be employed as an effective therapy for primary tumor and pulmonary metastasis. Therefore, PP-HA/NPs could be a promising delivery system to treat metastatic breast cancer effectively.

  4. Development of the Human Breast

    PubMed Central

    Javed, Asma; Lteif, Aida

    2013-01-01

    Mammalia are so named based on the presence of the mammary gland in the breast. The mammary gland is an epidermal appendage, derived from the apocrine glands. The human breast consists of the parenchyma and stroma, originating from ectodermal and mesodermal elements, respectively. Development of the human breast is distinctive for several reasons. The human breast houses the mammary gland that produces and delivers milk through development of an extensive tree-like network of branched ducts. It is also characterized by cellular plasticity, with extensive remodeling in adulthood, a factor that increases its susceptibility to carcinogenesis. Also, breast development occurs in distinct stages via complex epithelial–mesenchymal interactions, orchestrated by signaling pathways under the regulation of systemic hormones. Congenital and acquired disorders of the breast often have a basis in development, making its study essential to understanding breast pathology. PMID:24872732

  5. Breast-feeding after transplantation.

    PubMed

    Constantinescu, Serban; Pai, Akshta; Coscia, Lisa A; Davison, John M; Moritz, Michael J; Armenti, Vincent T

    2014-11-01

    Transplantation affords recipients the potential for a full life and, for some, parenthood. Female transplant recipients must continue to take immunosuppression during pregnancy and breast-feeding. This article reviews case and series reports regarding breast-feeding in those taking transplant medications. Avoidance of breast-feeding has been the customary advice because of the potential adverse effects of immunosuppressive exposure on the infant. Subsequent studies have demonstrated that not all medication exposure translates to risk for the infant, that the exposure in utero is greater than via breast milk and that no lingering effects due to breast-feeding have been found to date in infants who were breast-fed while their mothers were taking prednisone, azathioprine, cyclosporine, and/or tacrolimus. Thus, except for those medications where clinical information is inadequate (mycophenolic acid products, sirolimus, everolimus, and belatacept), the recommendation for transplant recipients regarding breast-feeding has evolved into one that is cautiously optimistic.

  6. Breast cancer screening and biomarkers.

    PubMed

    Brooks, Mai

    2009-01-01

    Annual screening mammograms have been shown to be cost-effective and are credited for the decline in mortality of breast cancer. New technologies including breast magnetic resonance imaging (MRI) may further improve early breast cancer detection in asymptomatic women. Serum tumor markers such as CA 15-3, carcinoembyonic antigen (CEA), and CA 27-29 are ordered in the clinic mainly for disease surveillance, and not useful for detection of localized cancer. This review will discuss blood-based markers and breast-based markers, such as nipple/ductal fluid, with an emphasis on biomarkers for early detection of breast cancer. In the future, it is likely that a combination approach to simultaneously measure multiple markers would be most successful in detecting early breast cancer. Ideally, such a biomarker panel should be able to detect breast cancer in asymptomatic patients, even in the setting of normal mammogram and physical examination results.

  7. Drugs in breast milk.

    PubMed

    1974-03-15

    Data on the pharmacology of drugs in breast milk are incomplete. The concentration in milk of drugs present in maternal blood depends on the lipid solubility of the drug and its degree of ionization. The immature renal and hepatic functions in the nursing infant can delay excretion of drugs. There has been no documented harm to nursing infants due to maternal use of oral contraceptives although long-term studies are unavailalbe. Breast feeding is contraindicated if the mother uses therapeutic doses of radioactive iodine, is a severe chronic alcoholic, or takes corticosteroids, phenobarbitone, and anticancer drugs. During lactation, drugs should be avoided as much as possible.

  8. Breast cancer epidemiology.

    PubMed

    Kelsey, J L; Berkowitz, G S

    1988-10-15

    The various risk factors for breast cancer have been recognized for many years. A table lists these established breast cancer risk factors together with the approximate magnitude of the increase in risk associated with them. Breast cancer incidence rates increase with age throughout the life span in Western countries, although the rate of increase is greater up to age 50 years than after 50 years. Breast cancer is more common among women in upper rather than lower social classes, among women who never have been married, among women living in urban areas, among women living in the northern US than in the southern US, and among whites than blacks, at least among those over age 50. Women in North American and Northern European countries have the highest risk for breast cancer, women in Southern European and Latin American countries are at intermediate risk, and women in Africa and Asian countries have the lowest risk. Yet, rapid rates of increase in incident rates have been noted in recent years in many Asian, Central European, and some South American countries. The later the age at which a woman has her 1st full-term pregnancy, the higher her risk for breast cancer; the earlier the age at menarche and the later the age at menopause the higher the risk; and among women who have a premenopausal oophorectomy, the earlier the age at which this occurs the lower the risk. Among postmenopausal women, obesity is associated with an increase in risk. Lactation is negatively associated with subsequent breast cancer risk. Some current research is considering potential risk factors that have not been well studied in the past, including alcohol consumption, cigarette smoking, caffeine consumption, exposure to diethylstilbestrol (DES), emotional stress, exposure to electric power, and lack of physical activity. Other areas of current research reviewed here include radiation, mammographic parenchymal patterns, a high-fat diet, use of oral contraceptives (OCs), use of estrogen

  9. [Occult multicentric breast cancer].

    PubMed

    Vtorushin, S V; Zab'ialova, M V; Glushchenko, S A; Perel'muter, V M; Slonimskaia, E M

    2009-01-01

    The study included 92 patients with invasive ductal breast cancer (T2-4N0-2M0-1). In 38 cases, tumor growth was unicentric while histologically identifiable ones as multicentric in 44. Multicentricity mostly occurred in cases of macroscopically-identifiable nodes located in the central segments of the breast. Clinically-identifiable nodes of multicentric tumor growth measured more than 3 cm. Multicentric tumors were mostly grade III, featured lower expression of sex hormone receptors and positive Her2 status.

  10. Characterization of the murine plasminogen/urokinase-type plasminogen-activator system.

    PubMed

    Lijnen, H R; Van Hoef, B; Collen, D

    1996-11-01

    The murine plasminogen/urokinase-type plasminogen-activator (u-PA) system was studied using purified proteins, plasma and endothelioma cells. Recombinant murine u-PA was obtained as a single-chain molecule of 45 kDa which was converted to two-chain u-PA with plasmin by cleavage of the Lys159-Ile160 peptide bond. Murine plasminogen, purified from plasma as a single-chain protein of 95 kDa, was resistant to quantitative activation with murine recombinant two-chain u-PA: only 15% activation within 1 h at 37 degrees C was obtained in mixtures of 1 microM plasminogen and 5 nM recombinant two-chain u-PA, whereas quantitative activation was observed in the autologous human system. Addition of 6-aminohexanoic acid to native murine plasminogen resulted in quantitative activation within 1 h. In murine plasma in vitro, plasminogen was also resistant to quantitative activation with u-PA (50% activation within 1 h at 37 degrees C with 50 nM recombinant two-chain u-PA, whereas in the human system nearly quantitative activation was obtained). Murine plasma clots submerged in murine plasma were resistant to lysis with u-PA; < or = 2% clot lysis in 2 h was obtained with 80 nM recombinant two-chain u-PA in the autologous murine system whereas 50% clot lysis in 2 h required only 15 nM recombinant two-chain u-PA in the autologous human system. Saturable binding of murine recombinant two-chain u-PA was observed to murine endothelioma cells that are genetically deficient in u-PA (u-PA-/- End cells). Binding was characterized by a Kd of 5.5 nM and 800000 binding sites/cell. However, u-PA-/- End cells did not significantly stimulate the activation rate of murine plasminogen by murine recombinant two-chain u-PA and did not enhance the plasmin-mediated conversion rate of murine recombinant single-chain u-PA to its two-chain derivative. Murine recombinant two-chain u-PA bound to murine endothelioma cells was quantitatively inhibited by murine plasminogen-activator inhibitor-1 (PAI-1). Thus

  11. Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases.

    PubMed

    Gil, Margaret; Seshadri, Mukund; Komorowski, Marcin P; Abrams, Scott I; Kozbor, Danuta

    2013-04-02

    Oncolytic viruses hold promise for the treatment of cancer, but their interaction with the tumor microenvironment needs to be elucidated for optimal tumor cell killing. Because the CXCR4 receptor for the stromal cell-derived factor-1 (SDF-1/CXCL12) chemokine is one of the key stimuli involved in signaling interactions between tumor cells and their stromal microenvironment, we used oncolytic virotherapy with a CXCR4 antagonist to target the CXCL12/CXCR4 signaling axis in a triple-negative 4T1 breast carcinoma in syngeneic mice. We show here that CXCR4 antagonist expression from an oncolytic vaccinia virus delivered intravenously to mice with orthotopic tumors attains higher intratumoral concentration than its soluble counterpart and exhibits increased efficacy over that mediated by oncolysis alone. A systemic delivery of the armed virus after resection of the primary tumor was efficacious in inhibiting the development of spontaneous metastasis and increased overall tumor-free survival. Inhibition of tumor growth with the armed virus was associated with destruction of tumor vasculature, reductions in expression of CXCL12 and VEGF, and decrease in intratumoral numbers of bone marrow-derived endothelial and myeloid cells. These changes led to induction of antitumor antibody responses and resistance to tumor rechallenge. Engineering an oncolytic virus armed with a CXCR4 antagonist represents an innovative strategy that targets multiple elements within the tumor microenvironment. As such, this approach could have a significant therapeutic impact against primary and metastatic breast cancer.

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

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

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

  13. Biodegradable polymeric micelles coencapsulating paclitaxel and honokiol: a strategy for breast cancer therapy in vitro and in vivo

    PubMed Central

    Wang, Ning; Wang, Zhihan; Nie, Shihong; Song, Linjiang; He, Tao; Yang, Suleixin; Yang, Xi; Yi, Cheng; Wu, Qinjie; Gong, Changyang

    2017-01-01

    The combination of chemotherapy drugs attracts more attention in clinical cancer trials. However, the poor water solubility of chemotherapeutic drugs restricts their anticancer application. In order to improve antitumor efficiency and reduce side effects of free drugs, we prepared paclitaxel (PTX) and honokiol (HK) combination methoxy poly(ethylene glycol)–poly(caprolactone) micelles (P–H/M) by solid dispersion method against breast cancer. The particle size of P–H/M was 28.7±2.5 nm, and transmission electron microscope image confirmed that P–H/M were spherical in shape with small particle size. After being encapsulated in micelles, the release of PTX or HK showed a sustained behavior in vitro. In addition, both the cytotoxicity and the cellular uptake of P–H/M were increased in 4T1 cells, and P–H/M induced more apoptosis than PTX-loaded micelles or HK-loaded micelles, as analyzed by flow cytometry assay and Western blot. Furthermore, the antitumor effect of P–H/M was significantly improved compared with PTX-loaded micelles or HK-loaded micelles in vivo. P–H/M were more effective in inhibiting tumor proliferation, inducing tumor apoptosis, and decreasing the density of microvasculature. Moreover, bioimaging analysis showed that drug-loaded polymeric micelles could accumulate more in tumor tissues compared with the free drug. Our results suggested that P–H/M may have potential applications in breast cancer therapy. PMID:28260895

  14. Transfer of Maternal Immune Cells by Breastfeeding: Maternal Cytotoxic T Lymphocytes Present in Breast Milk Localize in the Peyer’s Patches of the Nursed Infant

    PubMed Central

    Tang, May; Zumba, Osvaldo; Mehta, Hetali; Toma, Annmarie; Sant’Angelo, Derek; Laouar, Yasmina

    2016-01-01

    Despite our knowledge of the protective role of antibodies passed to infants through breast milk, our understanding of immunity transfer via maternal leukocytes is still limited. To emulate the immunological interface between the mother and her infant while breast-feeding, we used murine pups fostered after birth onto MHC-matched and MHC-mismatched dams. Overall, data revealed that: 1) Survival of breast milk leukocytes in suckling infants is possible, but not significant after the foster-nursing ceases; 2) Most breast milk lymphocytes establish themselves in specific areas of the intestine termed Peyer’s patches (PPs); 3) While most leukocytes in the milk bolus were myeloid cells, the majority of breast milk leukocytes localized to PPs were T lymphocytes, and cytotoxic T cells (CTLs) in particular; 4) These CTLs exhibit high levels of the gut-homing molecules α4β7 and CCR9, but a reduced expression of the systemic homing marker CD62L; 5) Under the same activation conditions, transferred CD8 T cells through breast milk have a superior capacity to produce potent cytolytic and inflammatory mediators when compared to those generated by the breastfed infant. It is therefore possible that maternal CTLs found in breast milk are directed to the PPs to compensate for the immature adaptive immune system of the infant in order to protect it against constant oral infectious risks during the postnatal phase. PMID:27285085

  15. What's New in Breast Cancer Research and Treatment?

    MedlinePlus

    ... Cancer Research? Breast Cancer About Breast Cancer What’s New in Breast Cancer Research? Researchers around the world ... cancer causes Reducing breast cancer risk Managing DCIS New lab tests for breast cancer New imaging tests ...

  16. What Happens After Treatment for Breast Cancer in Men?

    MedlinePlus

    ... Men After Treatment What Happens After Treatment for Breast Cancer in Men? For many men with breast cancer, ... Breast Cancer in Men Stops Working More In Breast Cancer In Men About Breast Cancer in Men Causes, ...

  17. Breast Cancer Research Program

    DTIC Science & Technology

    2010-09-01

    tion of tumor cells with red indicating the highest density of tumor cells at the primary tumor (4th mammary fat pad ) and purple/blue showing the...Idea Award Elaine Hardman and Philippe Georgel “ Maternal Consumption of Omega 3 Fatty Acids to Reduce Breast Cancer Risk in Offspring” FY09

  18. Male breast cancer.

    PubMed

    Reis, Leonardo Oliveira; Dias, Fernando Gf; Castro, Marcos As; Ferreira, Ubirajara

    2011-06-01

    Male breast cancer (MBC) is a rare disease. However, as global populace ages, there is a trend to MBC increasing. Although aetiology is still unclear, constitutional, environmental, hormonal (abnormalities in estrogen/androgen balance) and genetic (positive family history, Klinefelter syndrome, mutations in BRCA1 and specially BRCA2) risk factors are already known. Clinic manifestation is painless hard and fixed nodule in the subareolar region in 75% of cases, with nipple commitment earlier than in women. Breast cancer has similar prognostic factors in males and females, among which axillary adenopathy (present in 40-55% cases) is the most important one. Although mammography, ultrasonography and scintigraphy can be useful tools in diagnosis; clinical assessment, along with a confirmatory biopsy, remains the main step in the evaluation of men with breast lesions. Infiltrating ductal carcinoma is the most frequent histological type. The established standard of care is modified radical mastectomy followed by tamoxifen for endocrine-responsive positive disease, although other options are being explored. While similarities between breast cancer in males and females exist, it is not appropriate to extrapolate data from female disease to the treatment of male. There is a need for specific multi-institutional trials to better understanding of clinicopathologic features and establishment of optimal therapy for this disease.

  19. [Breast carcinoma in men].

    PubMed

    Zigić, B; Balvanović, D; Rac, S; Bilbija, S

    1989-01-01

    The authors describe 8 cases of carcinoma of the male breast treated at the Clinic of Surgery, Clinical Medical Center Banja Luka in the period 1968-1988. In their discussion, the authors review contemporary findings concerning the genesis, evolution and treatment of this carcinoma.

  20. Breast Reconstruction and Prosthesis

    MedlinePlus

    ... For more information, visit komen.org or call Susan G. Komen’s breast care helpline at 1-877 ... buy bras and mastectomy bathing suits online. Resources Susan G. Komen ® 1-877 GO KOMEN (1-877- ...

  1. Breast reduction (mammoplasty) - slideshow

    MedlinePlus

    ... Indications URL of this page: //medlineplus.gov/ency/presentations/100189.htm Breast reduction (mammoplasty) - series—Indications To use the sharing features on this page, please enable JavaScript. Go to slide 1 out of 4 Go to slide 2 ...

  2. Breast lift (mastopexy) - slideshow

    MedlinePlus

    ... Incisions URL of this page: //medlineplus.gov/ency/presentations/100188.htm Breast lift (mastopexy) - series—Incisions To use the sharing features on this page, please enable JavaScript. Go to slide 1 out of 3 Go to slide 2 ...

  3. Breast-milk jaundice.

    PubMed

    Poland, R L

    1981-07-01

    The inhibiting agent of UDP-glucuronyl transferase (UDPGT), inhibition of which is associated with breast milk jaundice syndrome in infants, was thought to be 3(alpha),20(beta)-pregnandiol. European researchers have begun in vitro investigations to discover the inhibiting substance, and all studies have confirmed it is a nonesterified fatty acid. The strong association between breast milk jaundice, elevated values of nonesterified fatty acids, and unstimulated lipase in UDPGT-inhibitory milk was confirmed by electrophoretic technique. The mechanisms responsible for production of prolonged unconjugated hyperbilirubeinemia in infants, however, is not understood. 2 theories have been offered: 1) that milk triglyceride digestion before the milk reaches the duodenum leads to early absorption of most of the liberated glycerol that might otherwise be used by intestinal epithelium to resynthesize triglycerides; or 2) inhibitory human milk may facilitate the enterohepatic recirculation of bilirubin (reabsorption of bilirubin from intestinal lumen). Breast-feeding per se does not result in an increased incidence of neonatal hyperbilirubinemia; it is rather those infants who receive insufficient amounts of breast milk who develop the condition.

  4. The pill and the breast.

    PubMed

    Drife, J O

    1984-12-01

    Discussion focused on the role of the ovarian steriods, estrogen and progesterone, in the development of breast cancer, the effects of natural and synethic hormones on breast tissue, and recent epidemiological studies concerning breast cancer and the use of oral contraceptives (OCs). Apparently, ovarian hormones play a role in the development of breast cancer. Late menarche, early menopause, and the removal of the ovaries provides some protection against breast cancer. Women who experience a full term pregnancy also have a reduced risk, and the level of protection is increased if the pregnancy occurs early in the reproductive life span. Little is known about how these protective effects operate. It is known that estrogen proliferates endometrial cells and that progesterone checks this growth. Unchecked proliferation can produce malignant cells. Perhpas during pregnancy, breast epithelium becomes more responsive to progesterone, or perhaps the increased progesterone levels which prepare the breast for lactation alter the growth of breast epithelium. Changes in breast tissue during the course of the menstrual cycle, which could be attributed to the altering levels of ovarian hormones during the cycle, appear to be minimal; however, recent investigations report that DNA synthesis and mitotic counts in breast tissue increase during the 2nd half of the menstrual cycle. These findings indicate that progesterone might stimulate breast activity. The effect is the opposite of that observed for endometrial proliferation which occurs during the 1st half of the cycle in response to estrogen. One would expect that breast activity would also be increased for women who use OCs, but preliminary studies indicate that OCs do not overstimulate breast epithelium. Perhaps breast tissue is less responsive to synthetic hormone or perhaps OCs inhibit progesterone receptor synthesis. It is difficult to assess the epidemiological evidence concerning a link between breast cancer and OC use

  5. Breast cancer in systemic lupus.

    PubMed

    Bernatsky, S; Ramsey-Goldman, R; Petri, M; Urowitz, M B; Gladman, D D; Fortin, P F; Ginzler, E; Romero-Diaz, J; Peschken, C; Jacobsen, S; Hanly, J G; Gordon, C; Nived, O; Yelin, E H; Isenberg, D; Rahman, A; Bae, S-C; Joseph, L; Witte, T; Ruiz-Irastorza, G; Aranow, C; Kamen, D; Sturfeldt, G; Foulkes, W D; Hansen, J E; St Pierre, Y; Raymer, P Chrétien; Tessier-Cloutier, B; Clarke, A E

    2017-03-01

    Objective There is a decreased breast cancer risk in systemic lupus erythematosus (SLE) versus the general population. We assessed a large sample of SLE patients, evaluating demographic and clinical characteristics and breast cancer risk. Methods We performed case-cohort analyses within a multi-center international SLE sample. We calculated the breast cancer hazard ratio (HR) in female SLE patients, relative to demographics, reproductive history, family history of breast cancer, and time-dependent measures of anti-dsDNA positivity, cumulative disease activity, and drugs, adjusted for SLE duration. Results There were 86 SLE breast cancers and 4498 female SLE cancer-free controls. Patients were followed on average for 7.6 years. Versus controls, SLE breast cancer cases tended to be white and older. Breast cancer cases were similar to controls regarding anti-dsDNA positivity, disease activity, and most drug exposures over time. In univariate and multivariate models, the principal factor associated with breast cancers was older age at cohort entry. Conclusions There was little evidence that breast cancer risk in this SLE sample was strongly driven by any of the clinical factors that we studied. Further search for factors that determine the lower risk of breast cancer in SLE may be warranted.

  6. Breast feeding in organic acidaemias.

    PubMed

    Gokcay, G; Baykal, T; Gokdemir, Y; Demirkol, M

    2006-01-01

    Breast feeding has been recommended for the dietary treatment of infants with organic acidaemias, but studies documenting clinical experience are still very few. Nine infants, diagnosed with methylmalonic acidaemia (n = 4), propionic acidaemia (n = 1), isovaleric acidaemia (n = 2) and glutaric acidaemia type I (n = 2) were breast fed after diagnosis. The age of the patients was 28.9+/- 13.4 months (mean +/- SD) (range 10-57 months). Eight patients were diagnosed with clinical symptoms and one because of an affected sibling. After the control of acute metabolic problems, an initial period with a measured volume of expressed breast milk was continued with on-demand breast feeding with the addition of a special essential amino acid mixture and energy supplements. Breast feeding was well tolerated in seven infants with good growth, metabolic control and neurological outcome. The duration of breast feeding was 12.3+/- 7.4 months (mean +/- SD) (range 4-24 months) in these patients. Breast feeding was terminated in the patient with propionic acidaemia because of two acute metabolic episodes requiring hospitalization, and could not be continued in one of the patients with isovaleric acidaemia owing to shortage of breast milk. A decrease in the frequency of infections, acute metabolic episodes and hospital admissions was observed in breast-fed infants. Breast feeding of infants with organic acidaemias is feasible with close monitoring of clinical parameters such as growth, development and biochemistry, including amino acids, organic acids and ammonia.

  7. Eigenbreasts for statistical breast phantoms

    NASA Astrophysics Data System (ADS)

    Sturgeon, Gregory M.; Tward, Daniel J.; Ketcha, M.; Ratnanather, J. T.; Miller, M. I.; Park, Subok; Segars, W. P.; Lo, Joseph Y.

    2016-03-01

    To facilitate rigorous virtual clinical trials using model observers for breast imaging optimization and evaluation, we demonstrated a method of defining statistical models, based on 177 sets of breast CT patient data, in order to generate tens of thousands of unique digital breast phantoms. In order to separate anatomical texture from variation in breast shape, each training set of breast phantoms were deformed to a consistent atlas compressed geometry. Principal component analysis (PCA) was then performed on the shape-matched breast CT volumes to capture the variation of patient breast textures. PCA decomposes the training set of N breast CT volumes into an N-1-dimensional space of eigenvectors, which we call eigenbreasts. By summing weighted combinations of eigenbreasts, a large ensemble of different breast phantoms can be newly created. Different training sets can be used in eigenbreast analysis for designing basis models to target sub-populations defined by breast characteristics, such as size or density. In this work, we plan to generate ensembles of 30,000 new phantoms based on glandularity for an upcoming virtual trial of lesion detectability in digital breast tomosynthesis. Our method extends our series of digital and physical breast phantoms based on human subject anatomy, providing the capability to generate new, unique ensembles consisting of tens of thousands or more virtual subjects. This work represents an important step towards conducting future virtual trials for tasks-based assessment of breast imaging, where it is vital to have a large ensemble of realistic phantoms for statistical power as well as clinical relevance.

  8. Breast-Feeding Twins: Making Feedings Manageable

    MedlinePlus

    ... breast-feed more than one baby? Here's help breast-feeding twins or other multiples, from getting positioned and ensuring an adequate milk supply to combining breast-feeding and formula-feeding. By Mayo Clinic Staff If ...

  9. Abortion, Miscarriage, and Breast Cancer Risk

    MedlinePlus

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Abortion, Miscarriage, and Breast Cancer Risk: 2003 Workshop In ... cancer risk, including studies of induced and spontaneous abortions. They concluded that having an abortion or miscarriage ...

  10. You, Your Teenage Daughter and Breast Cancer.

    ERIC Educational Resources Information Center

    Brateman, Libby

    1991-01-01

    Discusses breast cancer and teenagers, focusing on how parents can introduce the subject and encourage breast self-examination. The article provides information on breast cancer statistics, mammography, and American Cancer Society services. (SM)

  11. Why Are My Breasts Sore? (For Teens)

    MedlinePlus

    ... mammals have breasts and humans are no exception. Breasts, which are milk-producing glands, begin to enlarge in females around the onset of puberty. Breasts are made of fat and other tissue that ...

  12. Association between CLN3 (Neuronal Ceroid Lipofuscinosis, CLN3 Type) Gene Expression and Clinical Characteristics of Breast Cancer Patients.

    PubMed

    Makoukji, Joelle; Raad, Mohamad; Genadry, Katia; El-Sitt, Sally; Makhoul, Nadine J; Saad Aldin, Ehab; Nohra, Eden; Jabbour, Mark; Sangaralingam, Ajanthah; Chelala, Claude; Habib, Robert H; Boulos, Fouad; Tfayli, Arafat; Boustany, Rose-Mary

    2015-01-01

    Breast cancer is the most common cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. CLN3 protein (CLN3p), deficient in neurodegenerative CLN3 disease is anti-apoptotic, and defects in the CLN3 gene cause accelerated apoptosis of neurons in CLN3 disease and up-regulation of ceramide. Dysregulated apoptotic pathways are often implicated in the development of the oncogenic phenotype. Predictably, CLN3 mRNA expression and CLN3 protein were up-regulated in a number of human and murine breast cancer-cell lines. Here, we determine CLN3 expression in non-tumor vs. tumor samples from fresh and formalin-fixed/paraffin-embedded (FFPE) breast tissue and analyze the association between CLN3 overexpression and different clinicopathological characteristics of breast cancer patients. Additionally, gene expression of 28 enzymes involved in sphingolipid metabolism was determined. CLN3 mRNA is overexpressed in tumor vs. non-tumor breast tissue from FFPE and fresh samples, as well as in mouse MCF7 breast cancer compared to MCF10A normal cells. Of the clinicopathological characteristics of tumor grade, age, menopause status, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), only absence of HER2 expression correlated with CLN3 overexpression. Sphingolipid genes for ceramide synthases 2 and 6 (CerS2; CerS6), delta(4)-desaturase sphingolipid 2 (DEGS2), and acidic sphingomyelinase (SMPD1) displayed higher expression levels in breast cancer vs. control tissue, whereas ceramide galactosyltransferase (UGT8) was underexpressed in breast cancer samples. CLN3 may be a novel molecular target for cancer drug discovery with the goal of modulation of ceramide pathways.

  13. Association between CLN3 (Neuronal Ceroid Lipofuscinosis, CLN3 Type) Gene Expression and Clinical Characteristics of Breast Cancer Patients

    PubMed Central

    Makoukji, Joelle; Raad, Mohamad; Genadry, Katia; El-Sitt, Sally; Makhoul, Nadine J.; Saad Aldin, Ehab; Nohra, Eden; Jabbour, Mark; Sangaralingam, Ajanthah; Chelala, Claude; Habib, Robert H.; Boulos, Fouad; Tfayli, Arafat; Boustany, Rose-Mary

    2015-01-01

    Breast cancer is the most common cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. CLN3 protein (CLN3p), deficient in neurodegenerative CLN3 disease is anti-apoptotic, and defects in the CLN3 gene cause accelerated apoptosis of neurons in CLN3 disease and up-regulation of ceramide. Dysregulated apoptotic pathways are often implicated in the development of the oncogenic phenotype. Predictably, CLN3 mRNA expression and CLN3 protein were up-regulated in a number of human and murine breast cancer-cell lines. Here, we determine CLN3 expression in non-tumor vs. tumor samples from fresh and formalin-fixed/paraffin-embedded (FFPE) breast tissue and analyze the association between CLN3 overexpression and different clinicopathological characteristics of breast cancer patients. Additionally, gene expression of 28 enzymes involved in sphingolipid metabolism was determined. CLN3 mRNA is overexpressed in tumor vs. non-tumor breast tissue from FFPE and fresh samples, as well as in mouse MCF7 breast cancer compared to MCF10A normal cells. Of the clinicopathological characteristics of tumor grade, age, menopause status, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), only absence of HER2 expression correlated with CLN3 overexpression. Sphingolipid genes for ceramide synthases 2 and 6 (CerS2; CerS6), delta(4)-desaturase sphingolipid 2 (DEGS2), and acidic sphingomyelinase (SMPD1) displayed higher expression levels in breast cancer vs. control tissue, whereas ceramide galactosyltransferase (UGT8) was underexpressed in breast cancer samples. CLN3 may be a novel molecular target for cancer drug discovery with the goal of modulation of ceramide pathways. PMID:26528430

  14. The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer.

    PubMed

    Hait, N C; Avni, D; Yamada, A; Nagahashi, M; Aoyagi, T; Aoki, H; Dumur, C I; Zelenko, Z; Gallagher, E J; Leroith, D; Milstien, S; Takabe, K; Spiegel, S

    2015-06-08

    Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERα could sensitize ERα-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERα-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERα and increased therapeutic sensitivity of ERα-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer.

  15. The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer

    PubMed Central

    Hait, N C; Avni, D; Yamada, A; Nagahashi, M; Aoyagi, T; Aoki, H; Dumur, C I; Zelenko, Z; Gallagher, E J; Leroith, D; Milstien, S; Takabe, K; Spiegel, S

    2015-01-01

    Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERα could sensitize ERα-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERα-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERα and increased therapeutic sensitivity of ERα-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer. PMID:26053034

  16. Schisandrin B Attenuates Cancer Invasion and Metastasis Via Inhibiting Epithelial-Mesenchymal Transition

    PubMed Central

    Liu, Kun; Ding, Zonghui; Hu, Xun

    2012-01-01

    Background Metastasis is the major cause of cancer related death and targeting the process of metastasis has been proposed as a strategy to combat cancer. Therefore, to develop candidate drugs that target the process of metastasis is very important. In the preliminary studies, we found that schisandrin B (Sch B), a naturally-occurring dibenzocyclooctadiene lignan with very low toxicity, could suppress cancer metastasis. Methodology BALB/c mice were inoculated subcutaneously or injected via tail vein with murine breast cancer 4T1 cells. Mice were divided into Sch B-treated and control groups. The primary tumor growth, local invasion, lung and bone metastasis, and survival time were monitored. Tumor biopsies were examined immuno- and histo-pathologically. The inhibitory activity of Sch B on TGF-β induced epithelial-mesenchymal transition (EMT) of 4T1 and primary human breast cancer cells was assayed. Principal Findings Sch B significantly suppressed the spontaneous lung and bone metastasis of 4T1 cells inoculated s.c. without significant effect on primary tumor growth and significantly extended the survival time of these mice. Sch B did not inhibit lung metastasis of 4T1 cells that were injected via tail vein. Delayed start of treatment with Sch B in mice with pre-existing tumors did not reduce lung metastasis. These results suggested that Sch B acted at the step of local invasion. Histopathological evidences demonstrated that the primary tumors in Sch B group were significantly less locally invasive than control tumors. In vitro assays demonstrated that Sch B could inhibit TGF-β induced EMT of 4T1 cells and of primary human breast cancer cells. Conclusions Sch B significantly suppresses the lung and bone metastasis of 4T1 cells via inhibiting EMT, suggesting its potential application in targeting the process of cancer metastasis. PMID:22848381

  17. Increasing Breast Cancer Surveillance among African American Breast Cancer Survivors

    DTIC Science & Technology

    2007-07-01

    predictors of surveillance and follow-up care is Baldwin’s Afrocentric model for describing AA women’s participation in breast and cervical cancer screening...African American women’s participation in breast and cervical cancer early detection and screening. Adv Nurs Sci. 1996;19(2):27Y42. 28. Marin G. Subjective...AD_________________ Award Number: DAMD17-03-1-0454 TITLE: Increasing Breast Cancer Surveillance

  18. Genetic epidemiology of breast cancer.

    PubMed

    Thompson, W D

    1994-07-01

    It has been recognized for some time that a family history of breast cancer is associated rather strongly with a woman's own risk of developing the disease. Recent segregation analyses of population-based data on familial patterns provide evidence for a rare autosomal dominant allele that increases a carrier's susceptibility to breast cancer. The estimated proportion of breast cancer patients who carry this allele declines sharply with age at diagnosis. Empirical estimates of the risk associated with particular patterns of family history of breast cancer indicate the following: (1) having any first-degree relative with breast cancer increases a woman's risk of breast cancer 1.5-3-fold, depending on age, (2) having multiple first degree relatives affected is associated with particularly elevated risks, (3) having a second-degree relative affected increases the risk by approximately 50%, (4) affected family members on the maternal side and the paternal side contribute similarly to the risk, (5) a family history of breast cancer is associated with bilateral disease, and (6) breast cancer in males is associated with breast cancer in female relatives in much the same way as is breast cancer in women. Ovarian cancer clearly has been shown to be associated with breast cancer in families, and genetic linkage has provided strong evidence for a breast-ovarian cancer gene located somewhere on chromosome 17q. At the population level, having a first degree relative with ovarian cancer may be at least as predictive of a woman's risk for developing breast cancer as is having a second-degree relative with breast cancer. Considerably weaker evidence points to a possible familial relationship between breast and endometrial cancer and between breast cancer in women and prostatic cancer in males. The clinical applications of the genetic epidemiology of breast cancer are complicated by uncertainty as to the efficacy of mammographic screening in women under the age of 50. For the vast

  19. Breast-feeding after breast cancer: if you wish, madam.

    PubMed

    Azim, Hatem A; Bellettini, Giulia; Gelber, Shari; Peccatori, Fedro A

    2009-03-01

    Breast cancer is the most common malignant tumor-affecting women during the child bearing period. With the rising trend in delaying pregnancy later in life, the issue of subsequent pregnancy and lactation following breast cancer diagnosis has been more frequently encountered. In this context, data is scarce particularly those addressing the issue of lactation. In this review, we discussed different endocrinal, clinical and biological aspects dealing with breast-feeding after breast cancer in an attempt to determine how safe and feasible this approach is.

  20. Transcriptional targets of Foxd3 in murine ES cells.

    PubMed

    Plank, Jennifer L; Suflita, Michael T; Galindo, Cristi L; Labosky, Patricia A

    2014-01-01

    Understanding gene regulatory networks controlling properties of pluripotent stem cells will facilitate development of stem cell-based therapies. The transcription factor Foxd3 is critical for maintenance of self-renewal, survival, and pluripotency in murine embryonic stem cells (ESCs). Using a conditional deletion of Foxd3 followed by gene expression analyses, we demonstrate that genes required for several developmental processes including embryonic organ development, epithelium development, and epithelial differentiation were misregulated in the absence of Foxd3. Additionally, we identified 6 novel targets of Foxd3 (Sox4, Safb, Sox15, Fosb, Pmaip1 and Smarcd3). Finally, we present data suggesting that Foxd3 functions upstream of genes required for skeletal muscle development. Together, this work provides further evidence that Foxd3 is a critical regulator of murine development through the regulation of lineage specific differentiation.

  1. Effects of the murine skull in optoacoustic brain microscopy.

    PubMed

    Kneipp, Moritz; Turner, Jake; Estrada, Héctor; Rebling, Johannes; Shoham, Shy; Razansky, Daniel

    2016-01-01

    Despite the great promise behind the recent introduction of optoacoustic technology into the arsenal of small-animal neuroimaging methods, a variety of acoustic and light-related effects introduced by adult murine skull severely compromise the performance of optoacoustics in transcranial imaging. As a result, high-resolution noninvasive optoacoustic microscopy studies are still limited to a thin layer of pial microvasculature, which can be effectively resolved by tight focusing of the excitation light. We examined a range of distortions introduced by an adult murine skull in transcranial optoacoustic imaging under both acoustically- and optically-determined resolution scenarios. It is shown that strong low-pass filtering characteristics of the skull may significantly deteriorate the achievable spatial resolution in deep brain imaging where no light focusing is possible. While only brain vasculature with a diameter larger than 60 µm was effectively resolved via transcranial measurements with acoustic resolution, significant improvements are seen through cranial windows and thinned skull experiments.

  2. Practical Murine Hematopathology: A Comparative Review and Implications for Research

    PubMed Central

    O'Connell, Karyn E; Mikkola, Amy M; Stepanek, Aaron M; Vernet, Andyna; Hall, Christopher D; Sun, Chia C; Yildirim, Eda; Staropoli, John F; Lee, Jeannie T; Brown, Diane E

    2015-01-01

    Hematologic parameters are important markers of disease in human and veterinary medicine. Biomedical research has benefited from mouse models that recapitulate such disease, thus expanding knowledge of pathogenetic mechanisms and investigative therapies that translate across species. Mice in health have many notable hematologic differences from humans and other veterinary species, including smaller erythrocytes, higher percentage of circulating reticulocytes or polychromasia, lower peripheral blood neutrophil and higher peripheral blood and bone marrow lymphocyte percentages, variable leukocyte morphologies, physiologic splenic hematopoiesis and iron storage, and more numerous and shorter-lived erythrocytes and platelets. For accurate and complete hematologic analyses of disease and response to investigative therapeutic interventions, these differences and the unique features of murine hematopathology must be understood. Here we review murine hematology and hematopathology for practical application to translational investigation. PMID:25926395

  3. Increased photosensitivity to near-ultraviolet light in murine SLE

    SciTech Connect

    Golan, D.T.; Borel, Y.

    1984-02-01

    The authors investigated whether there is increased susceptibility to near-UVL in murine SLE. Cultured spleen cells from either strain of mice with lupus disease or conventional strains of mice were exposed to different UVL fractions in vitro. The effect of DNA synthesis, release, and repair was examined. DNA synthesis and release was measured as percent of (/sup 3/H)thymidine (dT) uptake into either total acid-precipitable radioactive material of cell sediment plus supernatant, or that of the medium alone, whereas hydroxyurea-resistant dT incorporation represented DNA repair. The data indicate that all SLE strains, in contrast to all non-SLE strains, show increased DNA synthesis and release after UV-A exposure. In addition, all murine SLE strains demonstrate increased susceptibility to induction of DNA damage by UV-A. The significance of these observations in relation to the clinical activity of SLE after sunlight exposure is discussed.

  4. Generation of murine tumor cell lines deficient in MHC molecule surface expression using the CRISPR/Cas9 system

    PubMed Central

    Lenkl, Clarissa; Goyal, Ashish; Diederichs, Sven; Dickes, Elke; Osen, Wolfram

    2017-01-01

    In this study, the CRISPR/Cas9 technology was used to establish murine tumor cell lines, devoid of MHC I or MHC II surface expression, respectively. The melanoma cell line B16F10 and the murine breast cancer cell line EO-771, the latter stably expressing the tumor antigen NY-BR-1 (EO-NY), were transfected with an expression plasmid encoding a β2m-specific single guide (sg)RNA and Cas9. The resulting MHC I negative cells were sorted by flow cytometry to obtain single cell clones, and loss of susceptibility of peptide pulsed MHC I negative clones to peptide-specific CTL recognition was determined by IFNγ ELISpot assay. The β2m knockout (KO) clones did not give rise to tumors in syngeneic mice (C57BL/6N), unless NK cells were depleted, suggesting that outgrowth of the β2m KO cell lines was controlled by NK cells. Using sgRNAs targeting the β-chain encoding locus of the IAb molecule we also generated several B16F10 MHC II KO clones. Peptide loaded B16F10 MHC II KO cells were insusceptible to recognition by OT-II cells and tumor growth was unaltered compared to parental B16F10 cells. Thus, in our hands the CRISPR/Cas9 system has proven to be an efficient straight forward strategy for the generation of MHC knockout cell lines. Such cell lines could serve as parental cells for co-transfection of compatible HLA alleles together with human tumor antigens of interest, thereby facilitating the generation of HLA matched transplantable tumor models, e.g. in HLAtg mouse strains of the newer generation, lacking cell surface expression of endogenous H2 molecules. In addition, our tumor cell lines established might offer a useful tool to investigate tumor reactive T cell responses that function independently from MHC molecule surface expression by the tumor. PMID:28301575

  5. Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Older Patients With Locally Advanced or Metastatic Breast Cancer

    ClinicalTrials.gov

    2016-10-14

    Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  6. Caloric Restriction in Treating Patients With Stage 0-I Breast Cancer Undergoing Surgery and Radiation Therapy

    ClinicalTrials.gov

    2016-10-19

    Ductal Breast Carcinoma in Situ; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Lobular Breast Carcinoma in Situ; Recurrent Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer

  7. Biomarkers in Tissue Samples From Patients With Newly Diagnosed Breast Cancer Treated With Zoledronic Acid

    ClinicalTrials.gov

    2016-07-12

    Estrogen Receptor-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer

  8. Soy Isoflavones Supplementation in Treating Women at High Risk For or With Breast Cancer

    ClinicalTrials.gov

    2017-04-08

    BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Ductal Breast Carcinoma in Situ; Lobular Breast Carcinoma in Situ; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer

  9. Onalespib and Paclitaxel in Treating Patients With Advanced Triple Negative Breast Cancer

    ClinicalTrials.gov

    2017-02-02

    Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  10. Vascular and Cognitive Assessments in Patients With Breast Cancer Undergoing Chemotherapy After Surgery

    ClinicalTrials.gov

    2017-02-20

    Cognitive/Functional Effects; 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

  11. Rosuvastatin in Treating Women With Cardiovascular Complications Who Are Undergoing Chemotherapy For Breast Cancer

    ClinicalTrials.gov

    2017-02-20

    Cardiovascular Complications; Recurrent Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  12. Neo-adjuvant Therapy With Anastrozole Plus Pazopanib in Stage II and III ER+ Breast Cancer

    ClinicalTrials.gov

    2016-05-24

    Estrogen Receptor-positive Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Male Breast Cancer; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer

  13. Digital Mammography and Digital Breast Tomosynthesis.

    PubMed

    Moseley, Tanya W

    2016-06-01

    Breast imaging technology has advanced significantly from the 1930s until the present. American women have a 1 in 8 chance of developing breast cancer. Mammography has been proven in multiple clinical trials to reduce breast cancer mortality. Although a mainstay of breast imaging and improved from film-screen mammography, digital mammography is not a perfect examination. Overlapping obscuring breast tissue limits mammographic interpretation. Breast digital tomosynthesis reduces and/or eliminates overlapping obscuring breast tissue. Although there are some disadvantages with digital breast tomosynthesis, this relatively lost-cost technology may be used effectively in the screening and diagnostic settings.

  14. Murine immunization by cesium-137 irradiation attenuated Schistosoma mansoni cercariae

    SciTech Connect

    Stek, M. Jr.; Minard, P.; Cruess, D.F.

    1984-06-01

    Cesium-137, becoming a more readily available ionizing gamma radiation source for laboratory use, was shown to effectively attenuate Schistosoma mansoni cercariae for vaccine production. In parallel comparison studies with the murine model, cesium-137 attenuated cercariae consistently afforded better protection than did the cobalt-60 prepared vaccine. Dose-response data indicated that the optimal total irradiation with cesium-137 was between 45 and 50 Krad.

  15. Osteopontin Is Upregulated in Human and Murine Acute Schistosomiasis Mansoni

    PubMed Central

    Pereira, Thiago Almeida; Syn, Wing-Kin; Amâncio, Frederico Figueiredo; Cunha, Pedro Henrique Diniz; Caporali, Julia Fonseca Morais; Trindade, Guilherme Vaz de Melo; Santos, Elisângela Trindade; Souza, Márcia Maria; Andrade, Zilton Araújo; Witek, Rafal P; Secor, William Evan; Pereira, Fausto Edmundo Lima; Lambertucci, José Roberto; Diehl, Anna Mae

    2016-01-01

    Background Symptomatic acute schistosomiasis mansoni is a systemic hypersensitivity reaction against the migrating schistosomula and mature eggs after a primary infection. The mechanisms involved in the pathogenesis of acute schistosomiasis are not fully elucidated. Osteopontin has been implicated in granulomatous reactions and in acute hepatic injury. Our aims were to evaluate if osteopontin plays a role in acute Schistosoma mansoni infection in both human and experimentally infected mice and if circulating OPN levels could be a novel biomarker of this infection. Methodology/Principal Findings Serum/plasma osteopontin levels were measured by ELISA in patients with acute (n = 28), hepatointestinal (n = 26), hepatosplenic (n = 39) schistosomiasis and in uninfected controls (n = 21). Liver osteopontin was assessed by immunohistochemistry in needle biopsies of 5 patients. Sera and hepatic osteopontin were quantified in the murine model of schistosomiasis mansoni during acute (7 and 8 weeks post infection, n = 10) and chronic (30 weeks post infection, n = 8) phase. Circulating osteopontin levels are increased in patients with acute schistosomiasis (p = 0.0001). The highest levels of OPN were observed during the peak of clinical symptoms (7–11 weeks post infection), returning to baseline level once the granulomas were modulated (>12 weeks post infection). The plasma levels in acute schistosomiasis were even higher than in hepatosplenic patients. The murine model mirrored the human disease. Macrophages were the major source of OPN in human and murine acute schistosomiasis, while the ductular reaction maintains OPN production in hepatosplenic disease. Soluble egg antigens from S. mansoni induced OPN expression in primary human kupffer cells. Conclusions/Significance S. mansoni egg antigens induce the production of OPN by macrophages in the necrotic-exudative granulomas characteristic of acute schistosomiasis mansoni. Circulating OPN levels are upregulated in human and

  16. A Case of Laboratory-Acquired Murine Typhus

    PubMed Central

    Woo, Jun Hee; Cho, Joo Young; Kim, Young Sun; Choi, Doo Hong; Lee, Nam Min; Choe, Kang Won; Chang, Woo Hyun

    1990-01-01

    We encountered a 32-year-old Korean woman who developed murine typhus in a laboratory. She worked as a technician in a laboratory for rickettsial disease. Immunofluorescence test with rickettsial antigen (R. typhi) was positive at 1 : 320 on admission and 1 : 1280 after 4 weeks. A dose of 200 mg of doxycycline for 7 days proved to be effective for her condition. PMID:2098096

  17. Miniature Microwave Applicator for Murine Bladder Hyperthermia Studies

    PubMed Central

    Salahi, Sara; Maccarini, Paolo F.; Rodrigues, Dario B.; Etienne, Wiguins; Landon, Chelsea D.; Inman, Brant A.; Dewhirst, Mark W.; Stauffer, Paul R.

    2012-01-01

    Purpose Novel combinations of heat with chemotherapeutic agents are often studied in murine tumor models. Currently, no device exists to selectively heat small tumors at depth in mice. In this project, we modelled, built and tested a miniature microwave heat applicator, the physical dimensions of which can be scaled to adjust the volume and depth of heating to focus on the tumor volume. Of particular interest is a device that can selectively heat murine bladder. Materials and Methods Using Avizo® segmentation software, we created a numerical mouse model based on micro-MRI scan data. The model was imported into HFSS™ simulation software and parametric studies were performed to optimize the dimensions of a water-loaded circular waveguide for selective power deposition inside a 0.15ml bladder. A working prototype was constructed operating at 2.45GHz. Heating performance was characterized by mapping fiber-optic temperature sensors along catheters inserted at depths of 0-1mm (subcutaneous), 2-3mm (vaginal), and 4-5mm (rectal) below the abdominal wall, with the mid-depth catheter adjacent to the bladder. Core temperature was monitored orally. Results Thermal measurements confirm the simulations which demonstrate that this applicator can provide local heating at depth in small animals. Measured temperatures in murine pelvis show well-localized bladder heating to 42-43°C while maintaining normothermic skin and core temperatures. Conclusions Simulation techniques facilitate the design optimization of microwave antennas for use in pre-clinical applications such as localized tumor heating in small animals. Laboratory measurements demonstrate the effectiveness of a new miniature water-coupled microwave applicator for localized heating of murine bladder. PMID:22690856

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

    PubMed Central

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

    2009-01-01

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

  19. Macrophage mediated biomimetic delivery system for the treatment of lung metastasis of breast cancer.

    PubMed

    Fu, Jijun; Wang, Dan; Mei, Dong; Zhang, Haoran; Wang, Zhaoyang; He, Bing; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Zhang, Qiang

    2015-04-28

    The biomimetic delivery system (BDS) based on special types of endogenous cells like macrophages and T cells, has been emerging as a novel strategy for cancer therapy, due to its tumor homing property and biocompatibility. However, its development is impeded by complicated construction, low drug loading or negative effect on the cell bioactivity. The present report constructed a BDS by loading doxorubicin (DOX) into a mouse macrophage-like cell line (RAW264.7). It was found that therapeutically meaningful amount of DOX could be loaded into the RAW264.7 cells by simply incubation, without significantly affecting the viability of the cells. Drug could release from the BDS and maintain its activity. RAW264.7 cells exhibited obvious tumor-tropic capacity towards 4T1 mouse breast cancer cells both in vitro and in vivo, and drug loading did not alter this tendency. Importantly, the DOX loaded macrophage system showed promising anti-cancer efficacy in terms of tumor suppression, life span prolongation and metastasis inhibition, with reduced toxicity. In conclusion, it is demonstrated that the BDS developed here seems to overcome some of the main issues related to a BDS. The DOX loaded macrophages might be a potential BDS for targeted cancer therapy.

  20. 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.