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Sample records for breast cancer resistance

  1. Expression of the breast cancer resistance protein in breast cancer

    NARCIS (Netherlands)

    Faneyte, Ian F.; Kristel, Petra M. P.; Maliepaard, Marc; Scheffer, George L.; Scheper, Rik J.; Schellens, Jan H. M.; van de Vijver, Marc J.

    2002-01-01

    PURPOSE: The breast cancer resistance protein (BCRP) is involved in in vitro multidrug resistance and was first identified in the breast cancer cell line MCF7/AdrVp. The aim of this study was to investigate the role of BCRP in resistance of breast cancer to anthracycline treatment. EXPERIMENTAL

  2. Carboplatin treatment of antiestrogen-resistant breast cancer cells

    DEFF Research Database (Denmark)

    Larsen, Mathilde S; Yde, Christina Westmose; Christensen, Ib J

    2012-01-01

    Antiestrogen resistance is a major clinical problem in current breast cancer treatment. Therefore, biomarkers and new treatment options for antiestrogen-resistant breast cancer are needed. In this study, we investigated whether antiestrogen‑resistant breast cancer cell lines have increased...... sensitivity to carboplatin, as it was previously shown with cisplatin, and whether low Bcl-2 expression levels have a potential value as marker for increased carboplatin sensitivity. Breast cancer cells resistant to the pure antiestrogen fulvestrant, and two out of four cell lines resistant...... to the antiestrogen tamoxifen, were more sensitive to carboplatin treatment compared to the parental MCF-7 cell line. This indicates that carboplatin may be an advantageous treatment in antiestrogen‑resistant breast cancer; however, a marker for increased sensitivity would be needed. Low Bcl-2 expression...

  3. ALK and TGF-Beta Resistance in Breast Cancer

    Science.gov (United States)

    2017-10-01

    Award Number: W81XWH‐15‐1‐0650 TITLE: ALK and TGF-Beta Resistance in Breast Cancer PRINCIPAL INVESTIGATOR: Xin-Hua Feng CONTRACTING...and TGF-Beta Resistance in Breast Cancer 5b. GRANT NUMBER W81XWH‐15‐1‐0650 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Xin-Hua Feng...response is a hallmark in human cancer . However, the mechanisms underlying TGF- resistance in breast cancer have not been elucidated. Anaplastic

  4. Functional miRNAs in breast cancer drug resistance

    Directory of Open Access Journals (Sweden)

    Hu WZ

    2018-03-01

    Full Text Available Weizi Hu,1–3,* Chunli Tan,1–3,* Yunjie He,4 Guangqin Zhang,2 Yong Xu,3,5 Jinhai Tang1 1Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 3Nanjing Medical University Affiliated Cancer Hospital, 4The First Clinical School of Nanjing Medical University, 5Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Owing to improved early surveillance and advanced therapy strategies, the current death rate due to breast cancer has decreased; nevertheless, drug resistance and relapse remain obstacles on the path to successful systematic treatment. Multiple mechanisms responsible for drug resistance have been elucidated, and miRNAs seem to play a major part in almost every aspect of cancer progression, including tumorigenesis, metastasis, and drug resistance. In recent years, exosomes have emerged as novel modes of intercellular signaling vehicles, initiating cell–cell communication through their fusion with target cell membranes, delivering functional molecules including miRNAs and proteins. This review particularly focuses on enumerating functional miRNAs involved in breast cancer drug resistance as well as their targets and related mechanisms. Subsequently, we discuss the prospects and challenges of miRNA function in drug resistance and highlight valuable approaches for the investigation of the role of exosomal miRNAs in breast cancer progression and drug resistance. Keywords: microRNA, exosome, breast cancer, drug resistance

  5. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

    OpenAIRE

    Canonici, A; Gijsen, M; Mullooly, M; Bennett, R; Bouguern, N; Pedersen, K; O'Brien, NA; Roxanis, I; Li, J-L; Bridge, E; Finn, R; Siamon, D; McGowan, P; Duffy, MJ; O'Donovan, N

    2013-01-01

    Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. ...

  6. Pristimerin overcomes adriamycin resistance in breast cancer cells through suppressing Akt signaling

    Science.gov (United States)

    XIE, GUI'E; YU, XINPEI; LIANG, HUICHAO; CHEN, JINGSONG; TANG, XUEWEI; WU, SHAOQING; LIAO, CAN

    2016-01-01

    Breast cancer remains a major public health problem worldwide. Chemotherapy serves an important role in the treatment of breast cancer. However, resistance to chemotherapeutic agents, in particular, multi-drug resistance (MDR), is a major cause of treatment failure in cancer. Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. Pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, has been shown to possess antitumor, anti-inflammatory, antioxidant and insecticidal properties. The aim of the present study was to investigate whether pristimerin can override chemoresistance in MCF-7/adriamycin (ADR)-resistant human breast cancer cells. The results demonstrated that pristimerin indeed displayed potent cytocidal effect on multidrug-resistant MCF-7/ADR breast cancer cells, and that these effects occurred through the suppression of Akt signaling, which in turn led to the downregulation of antiapoptotic effectors and increased apoptosis. These findings indicate that use of pristimerin may represent a potentially promising approach for the treatment of ADR-resistant breast cancer. PMID:27123073

  7. Endocrine resistance in breast cancer – an overview and update

    Science.gov (United States)

    Clarke, Robert; Tyson, John J.; Dixon, J. Michael

    2015-01-01

    Tumors that express detectable levels of the product of the ESR1 gene (estrogen receptor-α; ERα) represent the single largest molecular subtype of breast cancer. More women eventually die from ERα+ breast cancer than from either HER2+ disease (almost half of which also express ERα) and/or from triple negative breast cancer (ERα-negative, progesterone receptor-negative, and HER2-negative). Antiestrogens and aromatase inhibitors are largely indistinguishable from each other in their abilities to improve overall survival and almost 50% of ERα+ breast cancers will eventually fail one or more of these endocrine interventions. The precise reasons why these therapies fail in ERα+ breast cancer remain largely unknown. Pharmacogenetic explanations for Tamoxifen resistance are controversial. The role of ERα mutations in endocrine resistance remains unclear. Targeting the growth factors and oncogenes most strongly correlated with endocrine resistance has proven mostly disappointing in their abilities to improve overall survival substantially, particularly in the metastatic setting. Nonetheless, there are new concepts in endocrine resistance that integrate molecular signaling, cellular metabolism, and stress responses including endoplasmic reticulum stress and the unfolded protein response (UPR) that provide novel insights and suggest innovative therapeutic targets. Encouraging evidence that drug combinations with CDK4/CDK6 inhibitors can extend recurrence free survival may yet translate to improvements in overall survival. Whether the improvements seen with immunotherapy in other cancers can be achieved in breast cancer remains to be determined, particularly for ERα+ breast cancers. This review explores the basic mechanisms of resistance to endocrine therapies, concluding with some new insights from systems biology approaches further implicating autophagy and the UPR in detail, and a brief discussion of exciting new avenues and future prospects. PMID:26455641

  8. MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Oudin, Madeleine J; Barbier, Lucie; Schäfer, Claudia; Kosciuk, Tatsiana; Miller, Miles A; Han, Sangyoon; Jonas, Oliver; Lauffenburger, Douglas A; Gertler, Frank B

    2017-01-01

    Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA and particularly its invasive isoform, MENA INV , are established drivers of metastasis. MENA INV expression is significantly correlated with metastasis and poor outcome in human patients with breast cancer. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENA INV confer resistance to the taxane paclitaxel, but not to the widely used DNA-damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MENA INV -driven metastatic lesions. Mechanistically, MENA isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells. MENA expression also increases MAPK signaling in response to paclitaxel treatment. Decreasing ERK phosphorylation by co-treatment with MEK inhibitor restored paclitaxel sensitivity by driving microtubule stabilization in MENA isoform-expressing cells. Our results reveal a novel mechanism of taxane resistance in highly metastatic breast cancer cells and identify a combination therapy to overcome such resistance. Mol Cancer Ther; 16(1); 143-55. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Exosomes in development, metastasis and drug resistance of breast cancer.

    Science.gov (United States)

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-08-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  10. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

    Science.gov (United States)

    Canonici, Alexandra; Gijsen, Merel; Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Siamon, Dennis; McGowan, Patricia; Duffy, Michael J; O'Donovan, Norma; Crown, John; Kong, Anthony

    2013-10-01

    Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.

  11. Increased STAT1 signaling in endocrine-resistant breast cancer.

    Directory of Open Access Journals (Sweden)

    Rui Huang

    Full Text Available Proteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (MCF-7/LCC1 and fully resistant (MCF-7/LCC9 variants was performed to identify modifiers of endocrine sensitivity in breast cancer. Analysis of the expression of 120 paired phosphorylated and non-phosphorylated epitopes in key oncogenic and tumor suppressor pathways revealed that STAT1 and several phosphorylated epitopes (phospho-STAT1(Tyr701 and phospho-STAT3(Ser727 were differentially expressed between endocrine resistant and parental controls, confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG was a more effective inhibitor of the endocrine resistant MCF-7/LCC1 and MCF-7/LCC9 lines than parental MCF-7 cells, while STAT3 inhibitors Stattic and WP1066 were equally effective in endocrine-resistant and parental lines. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Expression of STAT1 and STAT3 were measured by quantitative immunofluorescence in invasive breast cancers and matched lymph nodes. When lymph node expression was compared to its paired primary breast cancer expression, there was greater expression of cytoplasmic STAT1 (∼3.1 fold, phospho-STAT3(Ser727 (∼1.8 fold, and STAT5 (∼1.5 fold and nuclear phospho-STAT3(Ser727 (∼1.5 fold in the nodes. Expression levels of STAT1 and STAT3 transcript were analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532. When treatment with tamoxifen was considered, STAT1 gene expression was nearly predictive of distant metastasis-free survival (DMFS, log-rank p = 0.067, while STAT3 gene expression was predictive of DMFS (log-rank p<0.0001. Analysis of STAT1 and STAT3 protein expression in a series of 546 breast cancers also indicated that high expression of STAT3 protein was associated with improved survival (DMFS, p = 0.006. These results suggest

  12. Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines

    DEFF Research Database (Denmark)

    Jandu, Haatisha; Aluzaite, Kristina; Fogh, Louise

    2016-01-01

    Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this ......Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim...... or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer...... of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan....

  13. Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.

    Science.gov (United States)

    Le, Xiuning; Antony, Rajee; Razavi, Pedram; Treacy, Daniel J; Luo, Flora; Ghandi, Mahmoud; Castel, Pau; Scaltriti, Maurizio; Baselga, Jose; Garraway, Levi A

    2016-10-01

    PIK3CA (which encodes the PI3K alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, Proviral Insertion site in Murine leukemia virus (PIM) kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner. Concurrent pharmacologic inhibition of PIM and PI3K overcame this resistance mechanism. We also observed increased PIM expression and activity in a subset of breast cancer biopsies with clinical resistance to PI3K inhibitors. PIM1 overexpression was mutually exclusive with PIK3CA mutation in treatment-naïve breast cancers, suggesting downstream functional redundancy. Together, these results offer new insights into resistance to PI3K inhibitors and support clinical studies of combined PIM/PI3K inhibition in a subset of PIK3CA-mutant cancers. PIM kinase overexpression confers resistance to small-molecule PI3K inhibitors. Combined inhibition of PIM and PI3K may therefore be warranted in a subset of breast cancers. Cancer Discov; 6(10); 1134-47. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069. ©2016 American Association for Cancer Research.

  14. Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer.

    Science.gov (United States)

    Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

    2016-07-04

    The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.

  15. Chemo Resistance of Breast Cancer Stem Cells

    Science.gov (United States)

    2007-05-01

    165-72. 60. Vestergaard J, Pedersen MW, Pedersen N, Ensinger C, Tumer Z, Tommerup N, et al. Hedgehog signaling in small-cell lung cancer : frequent......NUMBER Chemo Resistance of Breast Cancer Stem Cells 5b. GRANT NUMBER W81XWH-04-1-0471 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d

  16. Taxane resistance in breast cancer: mechanisms, predictive biomarkers and circumvention strategies.

    Science.gov (United States)

    Murray, S; Briasoulis, E; Linardou, H; Bafaloukos, D; Papadimitriou, C

    2012-11-01

    Taxanes are established in the treatment of metastatic breast cancer (MBC) and early breast cancer (EBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancer cytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance in with an outlook of optimizing their clinical use. We searched the PubMed and MEDLINE databases for articles (from inception through to 9th January 2012; last search 10/01/2012) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview. Over-expression of the MDR-1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. In contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/patient heterogeneity. The most

  17. Functional screen for genes responsible for tamoxifen resistance in human breast cancer cells

    NARCIS (Netherlands)

    Meijer, Danielle; van Agthoven, Ton; Bosma, Peter T.; Nooter, Kees; Dorssers, Lambert C. J.

    2006-01-01

    Antiestrogens, such as tamoxifen, are widely used for endocrine treatment of estrogen receptor-positive breast cancer. However, as breast cancer progresses, development of tamoxifen resistance is inevitable. The mechanisms underlying this resistance are not well understood. To identify genes

  18. UCH-L1-containing exosomes mediate chemotherapeutic resistance transfer in breast cancer.

    Science.gov (United States)

    Ning, Kuan; Wang, Teng; Sun, Xu; Zhang, Pengfei; Chen, Yun; Jin, Jian; Hua, Dong

    2017-06-01

    Chemotherapy resistance has become a serious challenge in the treatment of breast cancer. Previous studies showed cells can transfer proteins, including those responsible for drug resistance to adjacent cells via exosomes. The switches of drug resistance via exosomes transfer were assessed by CellTiter-Blue Viability assay, flow cytometry, and immunostaining analysis. Relative protein levels of Ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1), P-glycoprotein (P-gp), extracellular-signal regulated protein kinase1/2 (ERK1/2), and phospho-extracellular-signal regulated protein kinase1/2 (p-ERK1/2) were measured by Western blot. Immunohistochemistry was performed on 93 breast cancer samples to assess the associations of UCH-L1 levels with immunofluorescence value of UCH-L1 in circulating exosomes. The Adriamycin-resistant human breast cancer cells (MCF7/ADM) secreted exosomes carrying UCH-L1 and P-gp proteins into the extracellular microenvironment then integrated into Adriamycin-sensitive human breast cancer cells (MCF7/WT) in a time-dependent manner, transferring the chemoresistance phenotype. Notably, in blood samples from patients with breast cancer, the level of exosomes carrying UCH-L1 before chemotherapy was significantly negatively correlated with prognosis. Our study demonstrated that UCH-L1-containing exosomes can transfer chemoresistance to recipient cells and these exosomes may be useful as non-invasive diagnostic biomarkers for detection of chemoresitance in breast cancer patients, achieving more effective and individualized chemotherapy. © 2017 Wiley Periodicals, Inc.

  19. Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

    International Nuclear Information System (INIS)

    Radde, Brandie N.; Ivanova, Margarita M.; Mai, Huy Xuan; Alizadeh-Rad, Negin; Piell, Kellianne; Van Hoose, Patrick; Cole, Marsha P.; Muluhngwi, Penn; Kalbfleisch, Ted S.; Rouchka, Eric C.; Hill, Bradford G.; Klinge, Carolyn M.

    2016-01-01

    Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. - Highlights: • NRF-1 and TFAM expression are higher in endocrine-resistant breast cancer cells. • Oxygen consumption rate is similar in endocrine-sensitive and resistant cells. • Mitochondrial reserve capacity is lower in endocrine-resistant cells. • Endocrine-resistant breast cancer cells have increased glycolysis. • Bioenergetic responses to E2 and tamoxifen are lower in endocrine-resistant cells.

  20. Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Radde, Brandie N.; Ivanova, Margarita M.; Mai, Huy Xuan; Alizadeh-Rad, Negin; Piell, Kellianne; Van Hoose, Patrick; Cole, Marsha P.; Muluhngwi, Penn; Kalbfleisch, Ted S. [Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Rouchka, Eric C. [Bioinformatics and Biomedical Computing Laboratory, Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY 40292 (United States); Hill, Bradford G. [Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Klinge, Carolyn M., E-mail: carolyn.klinge@louisville.edu [Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States)

    2016-09-10

    Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. - Highlights: • NRF-1 and TFAM expression are higher in endocrine-resistant breast cancer cells. • Oxygen consumption rate is similar in endocrine-sensitive and resistant cells. • Mitochondrial reserve capacity is lower in endocrine-resistant cells. • Endocrine-resistant breast cancer cells have increased glycolysis. • Bioenergetic responses to E2 and tamoxifen are lower in endocrine-resistant cells.

  1. Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

    Science.gov (United States)

    García-Becerra, Rocío; Santos, Nancy; Díaz, Lorenza; Camacho, Javier

    2013-01-01

    Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. PMID:23344024

  2. Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0600 TITLE: Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers PRINCIPAL INVESTIGATOR: Dr...2017 4. TITLE AND SUBTITLE Dissecting the Mechanisms of Drug Resistance in BRCA1/2- Mutant Breast Cancers 5a. CONTRACT NUMBER W81XWH-16-1-0600 5b...therapeutic modality for targeting homologous recombination (HR) deficient tumors such as BRCA1 and BRCA2-mutated triple negative breast cancers

  3. Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer

    International Nuclear Information System (INIS)

    Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

    2016-01-01

    The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns. The online version of this article (doi:10.1186/s12885-016-2452-5) contains supplementary material, which is available to authorized users

  4. CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

    International Nuclear Information System (INIS)

    Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong; Zhou, Xianguang; Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing; Wang, Jiandong; Zhang, Longjiang; Teng, Zhaogang; Lu, Guangming

    2015-01-01

    Graphical abstract: - Highlights: • CD44-engineered mesoporous silica nanoparticles are synthesized. • The mechanism of CD44-engineered mesoporous silica nanoparticles is revealed. • This new delivery system increased the drug accumulation in vitro and in vivo. • This new delivery system offers an effective approach to treat multidrug resistance. - Abstract: Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer

  5. Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells

    International Nuclear Information System (INIS)

    Brown, Iain; Shalli, Kawan; McDonald, Sarah L; Moir, Susan E; Hutcheon, Andrew W; Heys, Steven D; Schofield, Andrew C

    2004-01-01

    Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. However, apoptosis and cell cycle regulation are key mechanisms by which most chemotherapeutic agents exert their cytotoxic effects. We created two docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) and performed cDNA microarray analysis to identify candidate genes associated with docetaxel resistance. Gene expression changes were validated at the RNA and protein levels by reverse transcription PCR and western analysis, respectively. Gene expression cDNA microarray analysis demonstrated reduced p27 expression in docetaxel-resistant breast cancer cells. Although p27 mRNA expression was found to be reduced only in MCF-7 docetaxel-resistant sublines (2.47-fold), reduced expression of p27 protein was noted in both MCF-7 and MDA-MB-231 docetaxel-resistant breast cancer cells (2.83-fold and 3.80-fold, respectively). This study demonstrates that reduced expression of p27 is associated with acquired resistance to docetaxel in breast cancer cells. An understanding of the genes that are involved in resistance to chemotherapy may allow further development in modulating drug resistance, and may permit selection of those patients who are most likely to benefit from such therapies

  6. TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer.

    Science.gov (United States)

    Mercogliano, María F; De Martino, Mara; Venturutti, Leandro; Rivas, Martín A; Proietti, Cecilia J; Inurrigarro, Gloria; Frahm, Isabel; Allemand, Daniel H; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G; Guzmán, Pablo; Roa, Juan C; Elizalde, Patricia V; Schillaci, Roxana

    2017-02-01

    Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab. TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008). We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636-48.

  7. The stepwise evolution of the exome during acquisition of docetaxel resistance in breast cancer cells

    DEFF Research Database (Denmark)

    Hansen, Stine Ninel; Ehlers, Natasja Spring; Zhu, Shida

    2016-01-01

    Background: Resistance to taxane-based therapy in breast cancer patients is a major clinical problem that may be addressed through insight of the genomic alterations leading to taxane resistance in breast cancer cells. In the current study we used whole exome sequencing to discover somatic genomic...... alterations, evolving across evolutionary stages during the acquisition of docetaxel resistance in breast cancer cell lines. Results: Two human breast cancer in vitro models (MCF-7 and MDA-MB-231) of the step-wise acquisition of docetaxel resistance were developed by exposing cells to 18 gradually increasing...... resistance relevant genomic variation appeared to arise midway towards fully resistant cells corresponding to passage 31 (5 nM docetaxel) for MDA-MB-231 and passage 16 (1.2 nM docetaxel) for MCF-7, and where the cells also exhibited a period of reduced growth rate or arrest, respectively. MCF-7 cell acquired...

  8. The application of 99Tcm-MIBI scintimammography to diagnose multidrug resistance of breast cancer

    International Nuclear Information System (INIS)

    Cheng Bing

    2002-01-01

    The author discussed the main mechanism of multidrug resistance of breast cancer tissues, and the correlation between technetium-99m sestamibi ( 99 Tc m -MIBI) breast imaging results, with the expression of drug resistance proteins P-glycoprotein and glutathione-S-transferase-π in human breast cancer. Through not all the results reported before matched each other, as a kind of a noninvasive simple functional test imaging technology in vitro, SPECT can be used to diagnose P-glycoprotein expression in breast cancer, and can be used to predict chemotherapy response

  9. Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

    DEFF Research Database (Denmark)

    Joshi, Tejal; Elias, Daniel; Stenvang, Jan

    2016-01-01

    Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of mi......+ breast cancer patients receiving adjuvant tamoxifen mono-therapy. Our results provide new insight into the molecular mechanisms of tamoxifen resistance and may form the basis for future medical intervention for the large number of women with tamoxifen-resistant ER+ breast cancer.......RNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all Tam...

  10. Aurora kinase B is important for antiestrogen resistant cell growth and a potential biomarker for tamoxifen resistant breast cancer

    DEFF Research Database (Denmark)

    Larsen, Sarah L; Yde, Christina W; Laenkholm, Anne-Vibeke

    2015-01-01

    BACKGROUND: Resistance to antiestrogen therapy is a major clinical challenge in the treatment of estrogen receptor α (ER)-positive breast cancer. The aim of the study was to explore the growth promoting pathways of antiestrogen resistant breast cancer cells to identify biomarkers and novel treatm...

  11. Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1.

    Science.gov (United States)

    Zhu, Yinghua; Liu, Yujie; Zhang, Chao; Chu, Junjun; Wu, Yanqing; Li, Yudong; Liu, Jieqiong; Li, Qian; Li, Shunying; Shi, Qianfeng; Jin, Liang; Zhao, Jianli; Yin, Dong; Efroni, Sol; Su, Fengxi; Yao, Herui; Song, Erwei; Liu, Qiang

    2018-04-23

    Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients.

  12. A targeted enzyme approach to sensitization of tyrosine kinase inhibitor-resistant breast cancer cells.

    Science.gov (United States)

    Giordano, Courtney R; Mueller, Kelly L; Terlecky, Laura J; Krentz, Kendra A; Bollig-Fischer, Aliccia; Terlecky, Stanley R; Boerner, Julie L

    2012-10-01

    Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of potential use in patients with breast cancer. Unfortunately, in clinical studies, gefitinib is often ineffective indicating that resistance to EGFR inhibitors may be a common occurrence in cancer of the breast. EGFR has been shown to be overexpressed in breast cancer, and in particular remains hyperphosphorylated in cell lines such as MDA-MB-468 that are resistant to EGFR inhibitors. Here, we investigate the cause of this sustained phosphorylation and the molecular basis for the ineffectiveness of gefitinib. We show that reactive oxygen species (ROS), known to damage cellular macromolecules and to modulate signaling cascades in a variety of human diseases including cancers, appear to play a critical role in mediating EGFR TKI-resistance. Furthermore, elimination of these ROS through use of a cell-penetrating catalase derivative sensitizes the cells to gefitinib. These results suggest a new approach for the treatment of TKI-resistant breast cancer patients specifically, the targeting of ROS and attendant downstream oxidative stress and their effects on signaling cascades. Copyright © 2012. Published by Elsevier Inc.

  13. Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer

    International Nuclear Information System (INIS)

    Fox, Emily M.; Arteaga, Carlos L.; Miller, Todd W.

    2012-01-01

    Antiestrogen therapies targeting estrogen receptor α (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors.

  14. MicroRNA‑663b mediates TAM resistance in breast cancer by modulating TP73 expression.

    Science.gov (United States)

    Jiang, Hua; Cheng, Lin; Hu, Pan; Liu, Renbin

    2018-05-23

    Breast cancer is the second leading cause of cancer‑associated mortalities in women. Tamoxifen (TAM) is an endocrine therapy commonly used in the treatment of patients with breast cancer expressing estrogen receptor α. However, treatment often ends in failure due to the emergence of drug resistance. MicroRNAs (miRNAs), a family of small non‑coding RNAs, serve critical roles in the regulation of gene expression and cell events. To date, whether miRNA‑663b could mediate TAM resistance in breast cancer remains unknown. Therefore, the aim of the present study was to investigate the role of miRNA‑663b in TAM resistance in breast cancer. The results demonstrated that miRNA‑663b was upregulated in breast cancer with TAM resistance. Tumor protein 73 (TP73) was a direct target of miRNA‑663b, and was negatively regulated by miRNA‑663b in MCF‑7 cells. Furthermore, it was identified that downregulation of miRNA‑663b inhibited cell proliferation ability and promoted cell apoptosis, resulting in enhanced TAM sensitivity. In addition, these findings suggested that TP73 silencing may have eliminated the effects of miRNA‑663b inhibitor on breast cancer cells. In conclusion, the present study verified a novel molecular link between miRNA‑663b and TP73, and indicated that miRNA‑663b may be a critical therapeutic target in breast cancer.

  15. Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

    International Nuclear Information System (INIS)

    Lui, Asona; New, Jacob; Ogony, Joshua; Thomas, Sufi; Lewis-Wambi, Joan

    2016-01-01

    mTOR inhibition of aromatase inhibitor (AI)-resistant breast cancer is currently under evaluation in the clinic. Everolimus/RAD001 (Afinitor®) has had limited efficacy as a solo agent but is projected to become part of combination therapy for AI-resistant breast cancer. This study was conducted to investigate the anti-proliferative and resistance mechanisms of everolimus in AI-resistant breast cancer cells. In this study we utilized two AI-resistant breast cancer cell lines, MCF-7:5C and MCF-7:2A, which were clonally derived from estrogen receptor positive (ER+) MCF-7 breast cancer cells following long-term estrogen deprivation. Cell viability assay, colony formation assay, cell cycle analysis and soft agar anchorage-independent growth assay were used to determine the efficacy of everolimus in inhibiting the proliferation and tumor forming potential of MCF-7, MCF-7:5C, MCF-7:2A and MCF10A cells. Confocal microscopy and transmission electron microscopy were used to evaluate LC3-II production and autophagosome formation, while ERE-luciferase reporter, Western blot, and RT-PCR analyses were used to assess ER expression and transcriptional activity. Everolimus inhibited the proliferation of MCF-7:5C and MCF-7:2A cells with relatively equal efficiency to parental MCF-7 breast cancer cells. The inhibitory effect of everolimus was due to G1 arrest as a result of downregulation of cyclin D1 and p21. Everolimus also dramatically reduced estrogen receptor (ER) expression (mRNA and protein) and transcriptional activity in addition to the ER chaperone, heat shock protein 90 protein (HSP90). Everolimus restored 4-hydroxy-tamoxifen (4OHT) sensitivity in MCF-7:5C cells and enhanced 4OHT sensitivity in MCF-7 and MCF-7:2A cells. Notably, we found that autophagy is one method of everolimus insensitivity in MCF-7 breast cancer cell lines. This study provides additional insight into the mechanism(s) of action of everolimus that can be used to enhance the utility of mTOR inhibitors as

  16. ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

    Science.gov (United States)

    Feldinger, Katharina; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Ng, Tzi Bun; Wong, Jack Ho; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Li, Ji-Liang; Bridges, Esther; Turley, Helen; Leek, Russell; Roxanis, Ioannis; Capala, Jacek; Murphy, Gillian; Harris, Adrian L.; Kong, Anthony

    2014-01-01

    Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p≤0.001 in BT474; p≤0.01 in SKBR3) and in vivo (p≤0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p≤0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p≤0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p≤0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients. PMID:24952873

  17. microRNAs in High and Low Responders to Resistance Training in Breast Cancer Survivors.

    Science.gov (United States)

    Hagstrom, Amanda D; Denham, Joshua

    2018-04-26

    Accounting for one in three cancer diagnoses, breast cancer is the second most commonly diagnosed cancer in women. Exercise has a well-accepted role in the multi-disciplinary approach to rehabilitating breast cancer survivors. Despite the many known benefits of resistance training on women recovering from breast cancer, the molecular mechanisms are poorly understood. MicroRNAs are small non-coding RNAs that have crucial roles in growth and development. Here, we analysed the abundance of 9 miRNAs, with known roles in muscle physiology and some linked to cancer, in serum samples from 24 breast cancer survivors before and after a 16-week resistance training or usual care intervention. The resistance training group completed supervised thrice-weekly training. miRNA abundance was assessed before and after the intervention period using qPCR. There were no statistically significant changes in any of the miRNAs between groups after the intervention period (all p>0.05). After assessing miRNA abundance in context with high and low responders to resistance training, we observed that relative to low responders, high responders exhibited increased miR-133a-3p and a borderline statistically significant increase in miR-370-3p. Findings from our controlled study indicate the diverse interindividual miRNA responses to resistance training and reveal a discordant regulation between high and low responders. © Georg Thieme Verlag KG Stuttgart · New York.

  18. VAV3 mediates resistance to breast cancer endocrine therapy

    NARCIS (Netherlands)

    H. Aguilar (Helena); A. Urruticoechea (Ander); P. Halonen (Pasi); K. Kiyotani (Kazuma); T. Mushiroda (Taisei); X. Barril (Xavier); J. Serra-Musach (Jordi); A.B.M.M.K. Islam (Abul); L. Caizzi (Livia); L. Di Croce (Luciano); E. Nevedomskaya (Ekaterina); W. Zwart (Wilbert); J. Bostner (Josefine); E. Karlsson (Elin); G. Pérez Tenorio (Gizeh); T. Fornander (Tommy); D.C. Sgroi (Dennis); R. Garcia-Mata (Rafael); M.P.H.M. Jansen (Maurice); N. García (Nadia); N. Bonifaci (Núria); F. Climent (Fina); E. Soler (Eric); A. Rodríguez-Vida (Alejo); M. Gil (Miguel); J. Brunet (Joan); G. Martrat (Griselda); L. Gómez-Baldó (Laia); A.I. Extremera (Ana); J. Figueras; J. Balart (Josep); R. Clarke (Robert); K.L. Burnstein (Kerry); K.E. Carlson (Kathryn); J.A. Katzenellenbogen (John); M. Vizoso (Miguel); M. Esteller (Manel); A. Villanueva (Alberto); A.B. Rodríguez-Peña (Ana); X.R. Bustelo (Xosé); Y. Nakamura (Yusuke); H. Zembutsu (Hitoshi); O. Stål (Olle); R.L. Beijersbergen (Roderick); M.A. Pujana (Miguel)

    2014-01-01

    textabstractIntroduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through

  19. Embryonic transcription factor SOX9 drives breast cancer endocrine resistance.

    Science.gov (United States)

    Jeselsohn, Rinath; Cornwell, MacIntosh; Pun, Matthew; Buchwalter, Gilles; Nguyen, Mai; Bango, Clyde; Huang, Ying; Kuang, Yanan; Paweletz, Cloud; Fu, Xiaoyong; Nardone, Agostina; De Angelis, Carmine; Detre, Simone; Dodson, Andrew; Mohammed, Hisham; Carroll, Jason S; Bowden, Michaela; Rao, Prakash; Long, Henry W; Li, Fugen; Dowsett, Mitchell; Schiff, Rachel; Brown, Myles

    2017-05-30

    The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2-ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

  20. The lipid content of cisplatin- and doxorubicin-resistant MCF-7 human breast cancer cells.

    Science.gov (United States)

    Todor, I N; Lukyanova, N Yu; Chekhun, V F

    2012-07-01

    To perform the comparative study both of qualitative and quantitative content of lipids in parental and drug resistant breast cancer cells. Parental (MCF-7/S) and resistant to cisplatin (MCF-7/CP) and doxorubicin (MCF-7/Dox) human breast cancer cells were used in the study. Cholesterol, total lipids and phospholipids content were determined by means of thin-layer chromatography. It was found that cholesterol as well as cholesterol ethers content are significantly higher but diacylglycerols, triacyl-glycerols content are significantly lower in resistant cell strains than in parental (sensitive) cells. Moreover the analysis of individual phospholipids showed the increase of sphingomyelin, phosphatidylserine, cardiolipin, phosphatidic acid and the decrease of phosphatidy-lethanolamine, phosphatidylcholine in MCF-7/CP and MCF-7/Dox cells. Obtained results allow to suggest that the lipid profile changes can mediate the modulation of membrane fluidity in drug resistant MCF-7 breast cancer cells.

  1. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.

    LENUS (Irish Health Repository)

    Mohd Sharial, M S N

    2012-12-01

    Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.

  2. Breast cancer resistance protein is localized at the plasma membrane in mitoxantrone- and topotecan-resistant cell lines

    NARCIS (Netherlands)

    Scheffer, GL; Maliepaard, M; Pijnenborg, ACLM; van Gastelen, MA; Schroeijers, AB; Allen, JD; Ross, DD; van der Valk, P; Dalton, WS; Schellens, JHM; Scheper, RJ; de Jong, MC

    2000-01-01

    Tumor cells may display a multidrug resistant phenotype by overexpression of ATP-binding cassette transporters such as multidrug resistance (,MDR1) P-glycoprotein, multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). The presence of BCRP has thus far been reported

  3. Differential effect of EGFR inhibitors on tamoxifen-resistant breast cancer cells.

    Science.gov (United States)

    Kim, Sangmin; Lee, Jeongmin; Oh, Soo Jin; Nam, Seok Jin; Lee, Jeong Eon

    2015-09-01

    Although tamoxifen is the most common and effective therapy for treatment of estrogen receptor-α (ER-α) breast cancer patients, resistance of endocrine therapy occurs, either de novo or acquired during therapy. Here, we investigated the clinical value of epidermal growth factor receptor (EGFR) in tamoxifen-resistant (TamR) patients and the differential effect of EGFR inhibitors, neratinib and gefitinib, on TamR breast cancer cell model. The morphology of TamR MCF7 cells showed mesenchymal phenotypes and did not induce cell death by tamoxifen treatment compared with tamoxifen‑sensitive (TamS) MCF7 cells. In addition, mesenchymal marker proteins, including N-cadherin (N-cad), fibronectin (FN), and Slug, significantly increased in TamR cells. In contrast, ER-α and E-cadherin (E-cad) were greatly decreased. We also found that the levels of EGFR and HER2 expression were increased in TamR cells. Furthermore, we observed that EGFR expression was directly involved with poor prognosis of tamoxifen-treated breast cancer patients using the GSE1378 date set. Thus, we treated TamR and TamS cells with EGFR inhibitors, neratinib and gefitinib, respectively. Interestingly, neratinib induced apoptotic cell death of TamR but not gefitinib. Cleaved PARP-1 expression was also increased by neratinib treatment in TamR cells. Therefore, we suggest that neratinib may be a potential therapeutic drug for treating TamR breast cancer.

  4. Effect of 8 Weeks Resistance Training on Some Antioxidant/Oxidative Indexes in Postmenopausal Women with Breast Cancer

    Directory of Open Access Journals (Sweden)

    F. Fathollahi Shoorabeh

    2017-04-01

    Full Text Available Aims: Breast cancer is the most common cancer among women that usually begins with abnormal growth and division of different breast cells. There is some evidence that there is an inverse relationship between levels of antioxidants and the risk of breast cancer. The purpose of this study was to investigate the effect of 8 weeks resistance training on some antioxidant/oxidative indexes in postmenopausal women with breast cancer. Materials & Methods: In this semi-experimental study, in 2014, 30 postmenopausal women with breast cancer in Khorramabad city were selected by available sampling method and randomly divided into 2 groups: experimental group (n=16 and control group (n=14. The experimental group performed resistance training for 8 weeks, which started from 30% 1RM (one repetition maximum and reached 45-50% 1RM at the end of the eighth week. Blood samples were taken from subjects for the measurement of superoxide dismutase (SOD, glutathione peroxidase (GPX and malondialdehyde (MDA serum levels, 48 hours before and after the training protocol. Data were analyzed by SPSS 19 software using independent t-test and dependent t-test. Findings: After performing 8 weeks of resistance training, serum levels of SOD and GPX significantly increased and MDA levels decreased significantly (p0.05. Conclusion: Resistance training for 8 weeks increases antioxidant indexes and decreases oxidative indexes in postmenopausal women with breast cancer.

  5. Effect of 8 Weeks Resistance Training on Some Antioxidant/Oxidative Indexes in Postmenopausal Women with Breast Cancer

    Directory of Open Access Journals (Sweden)

    Fathollahi Shoorabeh F.

    2017-12-01

    Full Text Available Aims Breast cancer is the most common cancer among women that usually begins with abnormal growth and division of different breast cells. There is some evidence that there is an inverse relationship between levels of antioxidants and the risk of breast cancer. The purpose of this study was to investigate the effect of 8 weeks resistance training on some antioxidant/oxidative indexes in postmenopausal women with breast cancer. Materials & Methods In this semi-experimental study, in 2014, 30 postmenopausal women with breast cancer in Khorramabad city were selected by available sampling method and randomly divided into 2 groups: experimental group (n=16 and control group (n=14. The experimental group performed resistance training for 8 weeks, which started from 30% 1RM (one repetition maximum and reached 45-50% 1RM at the end of the eighth week. Blood samples were taken from subjects for the measurement of superoxide dismutase (SOD, glutathione peroxidase (GPX and malondialdehyde (MDA serum levels, 48 hours before and after the training protocol. Data were analyzed by SPSS 19 software using independent t-test and dependent t-test. Findings After performing 8 weeks of resistance training, serum levels of SOD and GPX significantly increased and MDA levels decreased significantly (p0.05. Conclusion Resistance training for 8 weeks increases antioxidant indexes and decreases oxidative indexes in postmenopausal women with breast cancer.

  6. A review of obesity, insulin resistance, and the role of exercise in breast cancer patients.

    Science.gov (United States)

    Ghose, Abhimanyu; Kundu, Ria; Toumeh, Anis; Hornbeck, Catherine; Mohamed, Iman

    2015-01-01

    Breast cancer, the most common female malignancy in the world, has a strong association with obesity and insulin resistance. The importance of these risk factors goes up significantly in patients already affected by this cancer as they negatively affect the prognosis, recurrence rate, and survival by various mechanisms. The literature on the role of physical activity and aerobic exercise on modifying the above risks is debatable with data both for and against it. In this article, we have reviewed the risks of obesity and insulin resistance in breast cancer patients and the controversy associated with the impact of exercise. Ultimately, we have concluded that a randomized control trial is necessary with an individualized aerobic exercise program for a minimum duration of 20 wk on breast cancer patients, who are undergoing or recently completed chemotherapy, to study its effects on insulin resistance, weight, and clinical outcome.

  7. Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.

    Science.gov (United States)

    Thewes, Verena; Simon, Ronald; Schroeter, Petra; Schlotter, Magdalena; Anzeneder, Tobias; Büttner, Reinhard; Benes, Vladimir; Sauter, Guido; Burwinkel, Barbara; Nicholson, Robert I; Sinn, Hans-Peter; Schneeweiss, Andreas; Deuschle, Ulrich; Zapatka, Marc; Heck, Stefanie; Lichter, Peter

    2015-02-15

    Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer. ©2015 American Association for Cancer Research.

  8. Inflammatory Markers and Breast Cancer Risk

    Science.gov (United States)

    2011-07-01

    breast cancer [26, 27] or cytologic atypia [28], while another observed elevated IL-6 levels among breast cancer cases with insulin resistance [29...Relation between insulin resistance and serum concentrations of IL-6 and TNF- alpha in overweight or obese women with early stage breast cancer...without oophorectomy, hysterectomy with uni- or bilateral oophorectomy), prior breast biopsy (no, yes), ever been pregnant (no, yes), and

  9. APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation.

    Science.gov (United States)

    VanKlompenberg, Monica K; Leyden, Emily; Arnason, Anne H; Zhang, Jian-Ting; Stefanski, Casey D; Prosperi, Jenifer R

    2017-11-28

    Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of Adenomatous Polyposis Coli (APC) in the Mouse Mammary Tumor Virus - Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance. Our data demonstrate that MMTV-PyMT; Apc Min/+ cells have increased signal transducer and activator of transcription 3 (STAT3) activation. STAT3 can be constitutively activated in breast cancer, maintains the tumor initiating cell (TIC) population, and upregulates multidrug resistance protein 1 (MDR1). The activation of STAT3 in the MMTV-PyMT; Apc Min/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT; Apc Min/+ cells may be responsible for the increased STAT3 activation. Inhibiting STAT3 with a small molecule inhibitor A69 in combination with doxorubicin, but not cisplatin, restores drug sensitivity. A69 also decreases doxorubicin enhanced MDR1 gene expression and the TIC population enhanced by loss of APC. In summary, these results have revealed the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance.

  10. Up-regulation of HOXB cluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells.

    Science.gov (United States)

    Yang, Seoyeon; Lee, Ji-Yeon; Hur, Ho; Oh, Ji Hoon; Kim, Myoung Hee

    2018-05-28

    Tamoxifen (TAM) is commonly used to treat estrogen receptor (ER)-positive breast cancer. Despite the remarkable benefits, resistance to TAM presents a serious therapeutic challenge. Since several HOX transcription factors have been proposed as strong candidates in the development of resistance to TAM therapy in breast cancer, we generated an in vitro model of acquired TAM resistance using ER-positive MCF7 breast cancer cells (MCF7-TAMR), and analyzed the expression pattern and epigenetic states of HOX genes. HOXB cluster genes were uniquely up-regulated in MCF7-TAMR cells. Survival analysis of in slico data showed the correlation of high expression of HOXB genes with poor response to TAM in ER-positive breast cancer patients treated with TAM. Gain- and loss-of-function experiments showed that the overexpression of multi HOXB genes in MCF7 renders cancer cells more resistant to TAM, whereas the knockdown restores TAM sensitivity. Furthermore, activation of HOXB genes in MCF7-TAMR was associated with histone modifications, particularly the gain of H3K9ac. These findings imply that the activation of HOXB genes mediate the development of TAM resistance, and represent a target for development of new strategies to prevent or reverse TAM resistance.

  11. Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Hee-Jin [Department of Biomedical Science, College of Life Science, CHA University, Seoul (Korea, Republic of); Kim, Gwangil [Department of Pathology, CHA Bundang Medical Center, CHA University, Seoul (Korea, Republic of); Park, Kyung-Soon, E-mail: kspark@cha.ac.kr [Department of Biomedical Science, College of Life Science, CHA University, Seoul (Korea, Republic of)

    2013-08-09

    Highlights: •Ell3 enhances proliferation and drug resistance of breast cancer cell lines. •Ell3 is related to the cancer stem cell characteristics of breast cancer cell lines. •Ell3 enhances oncogenicity of breast cancer through the ERK1/2 signaling pathway. -- Abstract: Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven−nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK−extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway.

  12. Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

    International Nuclear Information System (INIS)

    Ahn, Hee-Jin; Kim, Gwangil; Park, Kyung-Soon

    2013-01-01

    Highlights: •Ell3 enhances proliferation and drug resistance of breast cancer cell lines. •Ell3 is related to the cancer stem cell characteristics of breast cancer cell lines. •Ell3 enhances oncogenicity of breast cancer through the ERK1/2 signaling pathway. -- Abstract: Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven−nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK−extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway

  13. Distinct apoptotic blocks mediate resistance to panHER inhibitors in HER2+ breast cancer cells.

    Science.gov (United States)

    Karakas, Bahriye; Ozmay, Yeliz; Basaga, Huveyda; Gul, Ozgur; Kutuk, Ozgur

    2018-05-04

    Despite the development of novel targeted therapies, de novo or acquired chemoresistance remains a significant factor for treatment failure in breast cancer therapeutics. Neratinib and dacomitinib are irreversible panHER inhibitors, which block their autophosphorylation and downstream signaling. Moreover, neratinib and dacomitinib have been shown to activate cell death in HER2-overexpressing cell lines. Here we showed that increased MCL1 and decreased BIM and PUMA mediated resistance to neratinib in ZR-75-30 and SKBR3 cells while increased BCL-XL and BCL-2 and decreased BIM and PUMA promoted neratinib resistance in BT474 cells. Cells were also cross-resistant to dacomitinib. BH3 profiles of HER2+ breast cancer cells efficiently predicted antiapoptotic protein dependence and development of resistance to panHER inhibitors. Reactivation of ERK1/2 was primarily responsible for acquired resistance in SKBR3 and ZR-75-30 cells. Adding specific ERK1/2 inhibitor SCH772984 to neratinib or dacomitinib led to increased apoptotic response in neratinib-resistant SKBR3 and ZR-75-30 cells, but we did not detect a similar response in neratinib-resistant BT474 cells. Accordingly, suppression of BCL-2/BCL-XL by ABT-737 was required in addition to ERK1/2 inhibition for neratinib- or dacomitinib-induced apoptosis in neratinib-resistant BT474 cells. Our results showed that different mitochondrial apoptotic blocks mediated acquired panHER inhibitor resistance in HER2+ breast cancer cell lines as well as highlighted the potential of BH3 profiling assay in prediction of panHER inhibitor resistance in breast cancer cells. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Claire Jackson

    2013-01-01

    Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

  15. Multidrug Resistance in Breast Cancer: From In Vitro Models to Clinical Studies

    International Nuclear Information System (INIS)

    Wind, N.S.; Holen, I.

    2011-01-01

    The development of multidrug resistance (MDR) and subsequent relapse on therapy is a widespread problem in breast cancer, but our understanding of the underlying molecular mechanisms is incomplete. Numerous studies have aimed to establish the role of drug transporter pumps in MDR and to link their expression to response to chemotherapy. The ATP-binding cassette (ABC) transporters are central to breast cancer MDR, and increases in ABC expression levels have been shown to correlate with decreases in response to various chemotherapy drugs and a reduction in overall survival. But as there is a large degree of redundancy between different ABC transporters, this correlation has not been seen in all studies. This paper provides an introduction to the key molecules associated with breast cancer MDR and summarises evidence of their potential roles reported from model systems and clinical studies. We provide possible explanations for why despite several decades of research, the precise role of ABC transporters in breast cancer MDR remains elusive

  16. Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

    Science.gov (United States)

    Nafi, Siti Norasikin Mohd; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Haider, Syed; Li, Ji-Liang; Bridges, Esther; Capala, Jacek; Ioannis, Roxanis; Harris, Adrian L; Kong, Anthony

    2014-01-01

    The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. PMID:25153719

  17. Global characterization of signalling networks associated with tamoxifen resistance in breast cancer

    DEFF Research Database (Denmark)

    Browne, Brigid C.; Hochgräfe, Falko; Wu, Jianmin

    2013-01-01

    R cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin‐binding protein myristoylated alanine‐rich C‐kinase substrate (MARCKS) were increased two‐ and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in Tam......Acquired resistance to the anti‐estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen‐resistant MCF7 breast cancer cells (Tam...... was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell–cell and cell matrix‐initiated signalling. Consistent with known roles for Ras/MAPK and PI3‐kinase signalling in tamoxifen resistance, tyrosine‐phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in Tam...

  18. Surface TRAIL decoy receptor-4 expression is correlated with TRAIL resistance in MCF7 breast cancer cells

    International Nuclear Information System (INIS)

    Sanlioglu, Ahter D; Dirice, Ercument; Aydin, Cigdem; Erin, Nuray; Koksoy, Sadi; Sanlioglu, Salih

    2005-01-01

    Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) selectively induces apoptosis in cancer cells but not in normal cells. Despite this promising feature, TRAIL resistance observed in cancer cells seriously challenged the use of TRAIL as a death ligand in gene therapy. The current dispute concerns whether or not TRAIL receptor expression pattern is the primary determinant of TRAIL sensitivity in cancer cells. This study investigates TRAIL receptor expression pattern and its connection to TRAIL resistance in breast cancer cells. In addition, a DcR2 siRNA approach and a complementary gene therapy modality involving IKK inhibition (AdIKKβKA) were also tested to verify if these approaches could sensitize MCF7 breast cancer cells to adenovirus delivery of TRAIL (Ad5hTRAIL). TRAIL sensitivity assays were conducted using Molecular Probe's Live/Dead Cellular Viability/Cytotoxicity Kit following the infection of breast cancer cells with Ad5hTRAIL. The molecular mechanism of TRAIL induced cell death under the setting of IKK inhibition was revealed by Annexin V binding. Novel quantitative Real Time RT-PCR and flow cytometry analysis were performed to disclose TRAIL receptor composition in breast cancer cells. MCF7 but not MDA-MB-231 breast cancer cells displayed strong resistance to adenovirus delivery of TRAIL. Only the combinatorial use of Ad5hTRAIL and AdIKKβKA infection sensitized MCF7 breast cancer cells to TRAIL induced cell death. Moreover, novel quantitative Real Time RT-PCR assays suggested that while the level of TRAIL Decoy Receptor-4 (TRAIL-R4) expression was the highest in MCF7 cells, it was the lowest TRAIL receptor expressed in MDA-MB-231 cells. In addition, conventional flow cytometry analysis demonstrated that TRAIL resistant MCF7 cells exhibited substantial levels of TRAIL-R4 expression but not TRAIL decoy receptor-3 (TRAIL-R3) on surface. On the contrary, TRAIL sensitive MDA-MB-231 cells displayed very low levels of surface TRAIL-R4

  19. "US-detonated nano bombs" facilitate targeting treatment of resistant breast cancer.

    Science.gov (United States)

    Shi, Jinjin; Liu, Wei; Fu, Yu; Yin, Na; Zhang, Hongling; Chang, Junbiao; Zhang, Zhenzhong

    2018-03-28

    Reversal of drug resistance and targeted therapy are the keys but remain challenging in resistant breast cancer treatment. Herein, low frequency ultrasound detonated "nano bombs" were rationally designed and used for treatment of resistant breast cancer. For the 'nano bombs', the ammunition (Doxorubicin, DOX) was loaded into the ammunition depot (hollow mesoporous TiO 2 , MTNs), and the safety device (dsDNA) was wrapped on the surface of MTNs to avoid the unexpected DOX release. We found the "US-detonated explosive" abilities of "nano bomb" MTNs (NBMTNs), including explosive generation of ROS, explosive release of DOX, US-triggered lysosome escape and mitochondrial targeting in the in vitro and in vivo studies. More importantly, the drug resistance of MCF-7/ADR cells could be reversed via the inhibition of mitochondrial energy supply approach caused by the "explosion" of NBMTNs. Furthermore, NBMTNs combined the superior chemotherapy efficacy of DOX and potent SDT efficacy in one single platform and significantly enhanced the anticancer efficacy. Our results demonstrate an approach for reversing resistance and specific targeting of tumors using 'US-detonated nano bombs'. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles for minimizing drug resistance in breast cancer.

    Science.gov (United States)

    Lv, Li; Liu, Chunxia; Chen, Chuxiong; Yu, Xiaoxia; Chen, Guanghui; Shi, Yonghui; Qin, Fengchao; Ou, Jiebin; Qiu, Kaifeng; Li, Guocheng

    2016-05-31

    The combination of a chemotherapeutic drug with a chemosensitizer has emerged as a promising strategy for cancers showing multidrug resistance (MDR). Herein we describe the simultaneous targeted delivery of two drugs to tumor cells by using biotin-decorated poly(ethylene glycol)-b-poly(ε-caprolactone) nanoparticles encapsulating the chemotherapeutic drug doxorubicin and the chemosensitizer quercetin (BNDQ). Next, the potential ability of BNDQ to reverse MDR in vitro and in vivo was investigated. Studies demonstrated that BNDQ was more effectively taken up with less efflux by doxorubicin-resistant MCF-7 breast cancer cells (MCF-7/ADR cells) than by the cells treated with the free drugs, single-drug-loaded nanoparticles, or non-biotin-decorated nanoparticles. BNDQ exhibited clear inhibition of both the activity and expression of P-glycoprotein in MCF-7/ADR cells. More importantly, it caused a significant reduction in doxorubicin resistance in MCF-7/ADR breast cancer cells both in vitro and in vivo, among all the groups. Overall, this study suggests that BNDQ has a potential role in the treatment of drug-resistant breast cancer.

  1. Predictive role of GSTP1-containing exosomes in chemotherapy-resistant breast cancer.

    Science.gov (United States)

    Yang, Su-Jin; Wang, Dan-Dan; Li, Jian; Xu, Han-Zi; Shen, Hong-Yu; Chen, Xiu; Zhou, Si-Ying; Zhong, Shan-Liang; Zhao, Jian-Hua; Tang, Jin-Hai

    2017-08-05

    Anthracycline/taxane-based chemotherapy regimens are usually used as neoadjuvant chemotherapies to decrease tumour size and prevent metastasis of advanced breast cancer. However, patients have a high risk of developing chemo-resistance during treatment through still unknown mechanisms. Glutathione S-transferase P1 (GSTP1), which belongs to the family of phase II metabolic enzymes, has been reported to function in detoxifying several anti-cancer drugs by conjugating them with glutathione. Previous studies have identified GSTP1 as a predictor of prognosis and chemo-resistance in breast cancer patients, but the mechanisms governing GSTP1-dependent drug resistance are still unclear. We have found that GSTP1 expression is much higher in adriamycin-resistant cells and their corresponding exosomes. The role of GSTP1-containing exosomes in conferring drug resistance was analysed through cell apoptosis and immunofluorescence staining assays. Furthermore, we analysed 42 cases of paired breast cancer tissues collected before and after anthracycline/taxane-based neoadjuvant chemotherapy by immunohistochemistry. Higher GSTP1 expression was shown in the progressive disease (PD)/stable disease (SD) group than in the partial response (PR)/complete response (CR) group both in the samples collected before and after the chemotherapy treatment. Interestingly, GSTP1 partly re-localized from the cell nucleus to the cytoplasm upon treatment, and similar results were obtained for the exosomal marker Tumour susceptibility gene 101 protein (TSG101), which also increased in the cytoplasm after chemotherapy. After analysing the serum exosomes of 30 patients treated with anthracycline/taxane-based neoadjuvant chemotherapy, we discovered that the levels of GSTP1 in exosomes from patients in the PD/SD group were significantly higher than those in the PR/CR group. Here, for the first time, we investigated a novel role for GSTP1-containing exosomes and their capability to transfer drug resistance

  2. Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells.

    Science.gov (United States)

    Li, Guangmin; Guo, Jun; Shen, Ben-Quan; Bumbaca Yadav, Daniela; Sliwkowski, Mark X; Crocker, Lisa M; Lacap, Jennifer A; Lewis Phillips, Gail D

    2018-04-25

    The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla®, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the anti-mitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and up-regulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1 resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1 resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. Copyright ©2018, American Association for Cancer Research.

  3. Involvement of miR-30c in resistance to doxorubicin by regulating YWHAZ in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Y. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Shen, H. [Department of Oncology, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Cao, Y. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Li, H. [Department of Central Laboratory, The Fourth Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Qin, R. [Department of Oncology, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Chen, Q. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Long, L. [Department of Oncology, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Zhu, X.L. [Department of Central Laboratory, The Fourth Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Xie, C.J. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Xu, W.L. [Department of Central Laboratory, The Fourth Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China)

    2014-01-10

    MicroRNAs (miRNAs) are small RNA molecules that modulate gene expression implicated in cancer, which play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. The aim of this study was to investigate whether miR-30c mediated the resistance of breast cancer cells to the chemotherapeutic agent doxorubicin (ADR) by targeting tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ). miR-30c was downregulated in the doxorubicin-resistant human breast cancer cell lines MCF-7/ADR and MDA-MB-231/ADR compared with their parental MCF-7 and MDA-MB-231 cell lines, respectively. Furthermore, we observed that transfection of an miR-30c mimic significantly suppressed the ability of MCF-7/ADR to resist doxorubicin. Moreover, the anti-apoptotic gene YWHAZ was confirmed as a target of miR-30c by luciferase reporter assay, and further studies indicated that the mechanism for miR-30c on the sensitivity of breast cancer cells involved YWHAZ and its downstream p38 mitogen-activated protein kinase (p38MAPK) pathway. Together, our findings provided evidence that miR-30c was one of the important miRNAs in doxorubicin resistance by regulating YWHAZ in the breast cancer cell line MCF-7/ADR.

  4. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan

    NARCIS (Netherlands)

    Jonker, JW; Smit, JW; Brinkhuis, RF; Maliepaard, M; Beijnen, JH; Schellens, JHM; Schinkel, AH

    2000-01-01

    Background and Methods: Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin,

  5. Proteome analysis of multidrug-resistant, breast cancer–derived microparticles

    Directory of Open Access Journals (Sweden)

    Deep Pokharel

    2014-08-01

    Full Text Available Cancer multidrug resistance (MDR occurs when cancer cells evade the cytotoxic actions of chemotherapeutics through the active efflux of drugs from within the cells. Our group have previously demonstrated that multidrug-resistant breast cancer cells spontaneously shed microparticles (MPs and that these MPs can transfer resistance to drug-responsive cells and confer MDR on those cells in as little as 4 h. Furthermore, we also showed that, unlike MPs derived from leukaemia cells, breast cancer–derived MPs display a tissue selectivity in the transfer of P-glycoprotein (P-gp, transferring the resistance protein only to malignant breast cells. This study aims to define the proteome of breast cancer–derived MPs in order to understand the differences in protein profiles between those shed from drug-resistant versus drug-sensitive breast cancer cells. In doing so, we detail the protein cargo required for the intercellular transfer of MDR to drug-sensitive recipient cells and the factors governing the transfer selectivity to malignant breast cells. We describe the first proteomic analysis of MPs derived from human breast cancer cells using SDS PAGE and liquid chromatography–tandem mass spectrometry (LC/MS/MS, in which we identify 120 unique proteins found only in drug-resistant, breast cancer–derived MPs. Our results demonstrate that the MP-mediated transfer of P-gp to recipient cells occurs alongside CD44; the Ezrin, Radixin and Moesin protein family (ERM; and cytoskeleton motor proteins within the MP cargo.

  6. GP88 (PC-Cell Derived Growth Factor, progranulin stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

    Directory of Open Access Journals (Sweden)

    Sabnis Gauri

    2011-06-01

    Full Text Available Abstract Background Aromatase inhibitors (AI that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+ breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88, also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+ breast cancer cells Methods We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined. Results GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole. Conclusion Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+ breast cancer.

  7. Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222.

    Science.gov (United States)

    Yu, Dan-Dan; Wu, Ying; Zhang, Xiao-Hui; Lv, Meng-Meng; Chen, Wei-Xian; Chen, Xiu; Yang, Su-Jin; Shen, Hongyu; Zhong, Shan-Liang; Tang, Jin-Hai; Zhao, Jian-Hua

    2016-03-01

    Breast cancer (BCa) is one of the major deadly cancers in women. However, treatment of BCa is still hindered by the acquired-drug resistance. It is increasingly reported that exosomes take part in the development, metastasis, and drug resistance of BCa. However, the specific role of exosomes in drug resistance of BCa is poorly understood. In this study, we investigate whether exosomes transmit drug resistance through delivering miR-222. We established an adriamycin-resistant variant of Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line (MCF-7/Adr) from a drug-sensitive variant (MCF-7/S). Exosomes were isolated from cell supernatant by ultracentrifugation. Cell viability was assessed by MTT assay and apoptosis assay. Individual miR-222 molecules in BCa cells were detected by fluorescence in situ hybridization (FISH). Then, FISH was combined with locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH). Individual miR-222 could be detected as bright photostable fluorescent spots and then the quantity of miR-222 per cell could be counted. Stained exosomes were taken in by the receipt cells. MCF-7/S acquired drug resistance after co-culture with exosomes from MCF-7/Adr (A/exo) but did not after co-culture with exosomes from MCF-7/S (S/exo). The quantity of miR-222 in A/exo-treated MCF-7/S was significantly greater than in S/exo-treated MCF-7/S. MCF-7/S transfected with miR-222 mimics acquired adriamycin resistance while MCF-7/S transfected with miR-222 inhibitors lost resistance. In conclusion, exosomes are effective in transmitting drug resistance and the delivery of miR-222 via exosomes may be a mechanism.

  8. PI3K inhibition to overcome endocrine resistance in breast cancer.

    Science.gov (United States)

    Keegan, Niamh M; Gleeson, Jack P; Hennessy, Bryan T; Morris, Patrick G

    2018-01-01

    Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.

  9. A Novel Approach to Detect Therapeutic Resistance in Breast Cancer

    Science.gov (United States)

    2008-09-01

    Resistance in Breast Cancer PRINCIPAL INVESTIGATOR: Kamila Czene, Ph.D. CONTRACTING ORGANIZATION: Karolinska Institutet ...ORGANIZATION REPORT NUMBER Karolinska Institutet Stockholm, Sweden 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10...analysis. The digital image analysis algorithms and software that have been developed at Karolinska Institutet consists of an optimized combination of

  10. BMI-1 Promotes Self-Renewal of Radio- and Temozolomide (TMZ)-Resistant Breast Cancer Cells.

    Science.gov (United States)

    Yan, Yanfang; Wang, Ying; Zhao, Pengxin; Ma, Weiyuan; Hu, Zhigang; Zhang, Kaili

    2017-12-01

    Breast cancer is a hormone-dependent malignancy and is the most prevalent cause of cancer-related mortality among females. Radiation therapy and chemotherapy are common treatments of breast cancer. However, tumor relapse and metastasis following therapy are major clinical challenges. The importance of B-lymphoma Moloney murine leukemia virus insertion region-1 (BMI-1) was implicated in cell proliferation, stem cell maintenance, and tumor initiation. We established radio- and temozolomide (TMZ)-resistant (IRC-R) MCF-7 and MDA-MB-231 cell lines to investigate the mechanism involved in therapeutic resistance. Cell proliferation and sphere number were dramatically elevated, and BMI-1 was remarkably upregulated, in IRC-R cells compared to parental cells. Silencing BMI-1 by RNA interference only affected the cell proliferation of IRC-R but not parental cells, suggesting the critical role of BMI-1 in radio- and TMZ resistance. We used a xenograft mice model to elucidate that BMI-1 was necessary in tumor development by assessing tumor volume and Ki67 expression. We found that Hedgehog (Hhg) signaling exerted synergized functions together with BMI-1, implicating the importance of BMI-1 in Hhg signaling. Downregulation of BMI-1 could be an effective strategy to suppress tumor growth, which supports the potential clinical use of targeting BMI-1 in breast cancer treatment.

  11. miR-193b Modulates Resistance to Doxorubicin in Human Breast Cancer Cells by Downregulating MCL-1

    Directory of Open Access Journals (Sweden)

    Jingpei Long

    2015-01-01

    Full Text Available MicroRNAs (miRNAs family, which is involved in cancer development, proliferation, apoptosis, and drug resistance, is a group of noncoding RNAs that modulate the expression of oncogenes and antioncogenes. Doxorubicin is an active cytotoxic agent for breast cancer treatment, but the acquisition of doxorubicin resistance is a common and critical limitation to cancer therapy. The aim of this study was to investigate whether miR-193b mediated the resistance of breast cancer cells to doxorubicin by targeting myeloid cell leukemia-1 (MCL-1. In this study, we found that miR-193b levels were significantly lower in doxorubicin-resistant MCF-7 (MCF-7/DOXR cells than in the parental MCF-7 cells. We observed that exogenous miR-193b significantly suppressed the ability of MCF-7/DOXR cells to resist doxorubicin. It demonstrated that miR-193b directly targeted MCL-1 3′-UTR (3′-Untranslated Regions. Further studies indicated that miR-193b sensitized MCF-7/DOXR cells to doxorubicin through a mechanism involving the downregulation of MCL-1. Together, our findings provide evidence that the modulation of miR-193b may represent a novel therapeutic target for the treatment of breast cancer.

  12. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer.

    Science.gov (United States)

    Malorni, Luca; Piazza, Silvano; Ciani, Yari; Guarducci, Cristina; Bonechi, Martina; Biagioni, Chiara; Hart, Christopher D; Verardo, Roberto; Di Leo, Angelo; Migliaccio, Ilenia

    2016-09-13

    Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 - 3.2] p = 1.87e-08 and HR = 2.62 [1.9- 3.5] p = 8.6e-11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted.

  13. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease.

    Science.gov (United States)

    Wardell, Suzanne E; Nelson, Erik R; Chao, Christina A; McDonnell, Donald P

    2013-05-01

    There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-α) antagonists, or that downregulate the expression of ER-α, would have clinical use in the treatment of advanced tamoxifen- and aromatase-resistant breast cancer. Although such compounds are currently in development, we reasoned, based on our understanding of ER-α pharmacology, that there may already exist among the most recently developed selective estrogen receptor modulators (SERM) compounds that would have usage as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacologic activities and to evaluate their potential clinical use with predictive models of advanced breast cancer. A validated molecular profiling technology was used to classify clinically relevant SERMs based on their impact on ER-α conformation. The functional consequences of these observed mechanistic differences on (i) gene expression, (ii) receptor stability, and (iii) activity in cellular and animal models of advanced endocrine-resistant breast cancer were assessed. The high-affinity SERM bazedoxifene was shown to function as a pure ER-α antagonist in cellular models of breast cancer and effectively inhibited the growth of both tamoxifen-sensitive and -resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ER-α that resulted in its proteasomal degradation, although the latter activity was dispensable for its antagonist efficacy. Bazedoxifene was recently approved for use in the European Union for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer. ©2013 AACR.

  14. Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Gyrd-Hansen, Mads; Lykkesfeldt, Anne E

    2007-01-01

    Antiestrogens are currently used for treating breast cancer patients who have estrogen receptor-positive tumors. However, patients with advanced disease will eventually develop resistance to the drugs. Therefore, compounds effective on antiestrogen-resistant tumors will be of great importance for...

  15. Mouse models of estrogen receptor-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Shakur Mohibi

    2011-01-01

    Full Text Available Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 - 70% of breast cancers are Estrogen Receptor alpha (ER-α positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.

  16. Epithelial-Mesenchymal Transitions and the Expression of Twist in MCF-7/ADR,Human Multidrug-Resistant Breast Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    Fei Zhang; Yurong Shi; Lin Zhang; Bin Zhang; Xiyin Wei; Yi Yang; RUi Wang; Ruifang Niu

    2007-01-01

    OBJECTIVE To study the expression levels of Twist and epithelialmesenchymal transitions in multidrug-resistant MCF-7/ADR breast cancer cells,and to study the relationship between multidrug resistance (MDR) and metastatic potential of the cells.METHODS RT-PCR,immunohislochemical and Western blotting methods were used to examine the changes of expression levels of the transcription factor Twist.E-cadherin and N-cadherin in the MCF-7 breast cancer cell line and its multidrug-resistant variant.MCF-7/ADR.RESULTS In MCF-7 cells,the expression of E-cadherin can be detected,but there is no expression of Twisl or N-cadherin.In MCF-7/ADR cells,E-cadherin expression is lost.bul the expression of two other genes was significantly positive.CONCLUSION Epithelial-mesenchymal transitions induced by Twist,may have a relationship with enhanced invasion and metastatic potential during the development of multidrug-resistant MCF-7/ADR breast cancer cells.

  17. Identification of a putative protein-profile associating with tamoxifen therapy-resistance in breast cancer

    NARCIS (Netherlands)

    A. Umar (Arzu); J.W.M. Martens (John); J.A. Foekens (John); L. Paša-Tolić (Ljiljana); H. Kang; A.M. Timmermans (Mieke); M.P. Look (Maxime); M.E. Meijer van Gelder (Marion); N. Jaitly (Navdeep); M.A. den Bakker (Michael)

    2009-01-01

    textabstractTamoxifen-resistance is a major cause of death in patients with recurrent breast cancer. Current clinical parameters can correctly predict therapy response in only half of the treated patients. Identification of proteins that associate with tamoxifen-resistance is a first step towards

  18. A Novel Docetaxel-Loaded Poly (ɛ-Caprolactone)/Pluronic F68 Nanoparticle Overcoming Multidrug Resistance for Breast Cancer Treatment

    Science.gov (United States)

    Mei, Lin; Zhang, Yangqing; Zheng, Yi; Tian, Ge; Song, Cunxian; Yang, Dongye; Chen, Hongli; Sun, Hongfan; Tian, Yan; Liu, Kexin; Li, Zhen; Huang, Laiqiang

    2009-12-01

    Multidrug resistance (MDR) in tumor cells is a significant obstacle to the success of chemotherapy in many cancers. The purpose of this research is to test the possibility of docetaxel-loaded poly (ɛ-caprolactone)/Pluronic F68 (PCL/Pluronic F68) nanoparticles to overcome MDR in docetaxel-resistance human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial PCL and self-synthesized PCL/Pluronic F68, respectively. PCL/Pluronic F68 nanoparticles were found to be of spherical shape with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere® in the MCF-7 TAX30 cell culture, but the differences were not significant ( p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere® ( p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer.

  19. Knockdown of UbcH10 Enhances the Chemosensitivity of Dual Drug Resistant Breast Cancer Cells to Epirubicin and Docetaxel

    Directory of Open Access Journals (Sweden)

    Cheng Wang

    2015-03-01

    Full Text Available Breast cancer is one of the most common and lethal cancers in women. As a hub gene involved in a diversity of tumors, the ubiquitin-conjugating enzyme H10 (UbcH10, may also play some roles in the genesis and development of breast cancer. In the current study, we found that the expression of UbcH10 was up-regulated in some breast cancer tissues and five cell lines. We established a dual drug resistant cell line MCF-7/EPB (epirubicin/TXT (docetaxel and a lentiviral system expressing UbcH10 shRNA to investigate the effects of UbcH10 knockdown on the chemosensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel. The knockdown of UbcH10 inhibited the proliferation of both MCF-7 and MCF-7/EPB/TXT cells, due to the G1 phase arrest in cell cycle. Furthermore, UbcH10 knockdown increased the sensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel and promoted the apoptosis induced by these two drugs. Protein detection showed that, in addition to inhibiting the expression of Ki67 and cyclin D1, UbcH10 RNAi also impaired the increased BCL-2 and MDR-1 expression levels in MCF-7/EPB/TXT cells, which may contribute to abating the drug resistance in the breast cancer cells. Our research in the current study demonstrated that up-regulation of UbcH10 was involved in breast cancer and its knockdown can inhibit the growth of cancer cells and increase the chemosensitivity of the dual drug resistant breast cancer cells to epirubicin and docetaxel, suggesting that UbcH10 may be a promising target for the therapy of breast cancer.

  20. Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer

    Science.gov (United States)

    Dauchy, Robert T.; Xiang, Shulin; Mao, Lulu; Brimer, Samantha; Wren, Melissa A.; Yuan, Lin; Anbalagan, Muralidharan; Hauch, Adam; Frasch, Tripp; Rowan, Brian G.; Blask, David E.; Hill, Steven M.

    2014-01-01

    Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to anti-estrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of ERα+ MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speeds the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characters were not produced in animals where circadian rhythms were not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to re-establish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen. PMID:25062775

  1. Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.

    Science.gov (United States)

    Choi, Hee-Joo; Joo, Hyeong-Seok; Won, Hee-Young; Min, Kyueng-Whan; Kim, Hyung-Yong; Son, Taekwon; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu

    2018-04-01

    Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen

  2. Mir-1307 regulates cisplatin resistance by targeting Mdm4 in breast cancer expressing wild type P53.

    Science.gov (United States)

    Wang, Xinyan; Zhu, Jianwei

    2018-04-26

    Many chemotherapy regimens are used to treat breast cancer; however, breast cancer cells often develop drug resistance that usually leads to relapse and poor prognosis. MicroRNAs (miRNAs) are short non-coding RNA molecules that post-transcriptionally regulate gene expression and play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. We investigated the roles of miRNAs in the development of drug resistance in human breast cancer cells. MiRNA expression was detected in human breast cancer cell lines MCF-7 and MDA-MB-468 via real time PCR; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, cell viability, colony formation, and luciferase reporter gene assays; Western blot; and immunohistochemistry. MiR-1307 was downregulated while MDM4 was upregulated in MCF-7/cisplatin (CDDP) and MDA-MB-468/CDDP cells compared with parental MCF-7 and MDA-MB-468 cells. in vitro drug sensitivity assay demonstrated that overexpression of miR-1307 sensitized MCF-7/CDDP cells to CDDP. Luciferase activity assay with a reporter containing sequences from the 3' untranslated region of Mdm4 in MCF-7/CDDP cells suggested that Mdm4 was the direct target gene of miR-1307. Ectopic miR-1307 expression reduced the MDM4 protein level and sensitized MCF-7/CDDP cells to CDDP-induced apoptosis. Our findings suggest, for the first time, that miR-1307 could play a role in the development of CDDP resistance in breast cancer, at least in part by modulating apoptosis by targeting Mdm4. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  3. Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

    DEFF Research Database (Denmark)

    Joshi, Tejal; Elias, Daniel; Stenvang, Jan

    2016-01-01

    and 14-3-3 family genes. Integrating the inferred miRNA-target relationships, we investigated the functional importance of 2 central genes, SNAI2 and FYN, which showed increased expression in TamR cells, while their corresponding regulatory miRNA were downregulated. Using specific chemical inhibitors......Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA......-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all Tam...

  4. NFκBP65 transcription factor modulates resistance to doxorubicin through ABC transporters in breast cancer.

    Science.gov (United States)

    Velaei, Kobra; Samadi, Nasser; Soltani, Sina; Barazvan, Balal; Soleimani Rad, Jafar

    2017-07-01

    Shedding light on chemoresistance biology of breast cancer could contribute to enhance the clinical outcome. Intrinsic or acquired resistance to chemotherapy is a major problem in breast cancer treatment. The NFκB pathway by siRNAP65 and JSH-23 as a translocational inhibitor of NFκBP65 in the doxorubicin-resistant MCF-7 (MCF-7/Dox) and MCF-7 cells was blocked. Then, the ABC transporter expression and function were assessed by real-time qRT-PCR and flow cytometry, respectively. Induction of apoptosis was evaluated after inhibition of the NFΚB pathway as well. Our study underlined the upregulation of NFκBP65 and anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax in the MCF-7/Dox cells compared with control MCF-7 cells. Here, we showed that interplay between nuclear factor kappa B P65 (NFkBP65) as a transcriptional regulator and ABC transporters in the MCF-7/Dox cancer cells. We found that inhibition of the elevated expression of NFκBP65 in the resistant breast cancer, whether translocational inhibition or silencing by siRNA, decreased the expression and function of MDR1 and MRP1 efflux pumps. Furthermore, the blockade of NFκBP65 promoted apoptosis via modulating Bcl-2 and BAX expression. After inhibition of the NFκBP65 signaling pathway, elevated baseline expression of survival Bcl-2 gene in the resistant breast cells significantly decreased. Suppression of the NFκB pathway has a profound dual impact on promoting the intrinsic apoptotic pathway and reducing ABC transporter function and expression, which are some of the chemoresistance features. It was speculated that the NFκB pathway directly acts on doxorubicin-induced MDR1 and MRP1 expression in MCF-7/Dox cells.

  5. Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters

    International Nuclear Information System (INIS)

    Němcová-Fürstová, Vlasta; Kopperová, Dana; Balušíková, Kamila; Ehrlichová, Marie; Brynychová, Veronika; Václavíková, Radka; Daniel, Petr; Souček, Pavel; Kovář, Jan

    2016-01-01

    Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to

  6. Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters

    Energy Technology Data Exchange (ETDEWEB)

    Němcová-Fürstová, Vlasta, E-mail: vlasta.furstova@lf3.cuni.cz [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Kopperová, Dana; Balušíková, Kamila [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Ehrlichová, Marie; Brynychová, Veronika; Václavíková, Radka [Toxicogenomics Unit, National Institute of Public Health, Prague (Czech Republic); Daniel, Petr [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Souček, Pavel [Toxicogenomics Unit, National Institute of Public Health, Prague (Czech Republic); Kovář, Jan [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic)

    2016-11-01

    Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to

  7. Breast cancers radiation-resistance: key role of the cancer stem cells marker CD24

    International Nuclear Information System (INIS)

    Bensimon, Julie

    2013-01-01

    This work focuses on the characterization of radiation-resistant breast cancer cells, responsible for relapse after radiotherapy. The 'Cancer Stem Cells' (CSC) theory describes a radiation-resistant cellular sub-population, with enhanced capacity to induce tumors and proliferate. In this work, we show that only the CSC marker CD24-/low defines a radiation resistant cell population, able to transmit the 'memory' of irradiation, expressed as long term genomic instability in the progeny of irradiated cells. We show that CD24 is not only a marker, but is an actor of radiation-response. So, CD24 expression controls cell proliferation in vitro and in vivo, and ROS level before and after irradiation. As a result, CD24-/low cells display enhanced radiation-resistance and genomic stability. For the first time, our results attribute a role to CD24-/low CSCs in the transmission of genomic instability. Moreover, by providing informations on tumor intrinsic radiation-sensitivity, CD24- marker could help to design new radiotherapy protocols. (author)

  8. MicroRNA expression profiles of drug-resistance breast cancer cells and their exosomes.

    Science.gov (United States)

    Zhong, Shanliang; Chen, Xiu; Wang, Dandan; Zhang, Xiaohui; Shen, Hongyu; Yang, Sujin; Lv, Mengmeng; Tang, Jinhai; Zhao, Jianhua

    2016-04-12

    Exosomes have been shown to transmit drug resistance through delivering miRNAs. We aimed to explore their roles in breast cancer. Three resistant sublines were established by exposing parental MDA-MB-231 cell line to docetaxel, epirubicin and vinorelbine, respectively. Preneoadjuvant chemotherapy biopsies and paired surgically-resected specimens embedded in paraffin from 23 breast cancer patients were collected. MiRNA expression profiles of the cell lines and their exosomes were evaluated using microarray. The result showed that most miRNAs in exosomes had a lower expression level than that in cells, however, some miRNAs expressed higher in exosomes than in cells, suggesting a number of miRNAs is concentrated in exosomes. Among the dysregulated miRNAs, 22 miRNAs were consistently up-regulated in exosomes and their cells of origin. We further found that 12 of the 22 miRNAs were significantly up-regulated after preneoadjuvant chemotherapy. Further study of the role of these 12 miRNAs in acquisition of drug resistance is needed to clarify their contribution to chemoresistance.

  9. Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis.

    Science.gov (United States)

    Ruprecht, Benjamin; Zaal, Esther A; Zecha, Jana; Wu, Wei; Berkers, Celia R; Kuster, Bernhard; Lemeer, Simone

    2017-04-15

    HER2/ERBB2-overexpressing breast cancers targeted effectively by the small-molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteome, kinome, and phosphoproteome changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for >7,800 proteins, >300 protein kinases, and >15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance. Our data-driven approach confirmed previously described mechanisms of resistance (e.g., AXL overexpression and PIK3 reactivation), revealed novel pharmacologically actionable targets, and confirmed the expectation of significant heterogeneity in molecular resistance drivers inducing distinct phenotypic changes. Furthermore, our approach identified an extensive and exclusively phosphorylation-mediated reprogramming of glycolytic activity, supported additionally by widespread changes of corresponding metabolites and an increased sensitivity towards glycolysis inhibition. Collectively, our multi-omic analysis offers deeper perspectives on cancer drug resistance and suggests new biomarkers and treatment options for lapatinib-resistant cancers. Cancer Res; 77(8); 1842-53. ©2017 AACR . ©2017 American Association for Cancer Research.

  10. Phosphoproteome and Transcriptome of RA-Responsive and RA-Resistant Breast Cancer Cell Lines.

    Directory of Open Access Journals (Sweden)

    Marilyn Carrier

    Full Text Available Retinoic acid (RA, the main active vitamin A metabolite, controls multiple biological processes such as cell proliferation and differentiation through genomic programs and kinase cascades activation. Due to these properties, RA has proven anti-cancer capacity. Several breast cancer cells respond to the antiproliferative effects of RA, while others are RA-resistant. However, the overall signaling and transcriptional pathways that are altered in such cells have not been elucidated. Here, in a large-scale analysis of the phosphoproteins and in a genome-wide analysis of the RA-regulated genes, we compared two human breast cancer cell lines, a RA-responsive one, the MCF7 cell line, and a RA-resistant one, the BT474 cell line, which depicts several alterations of the "kinome". Using high-resolution nano-LC-LTQ-Orbitrap mass spectrometry associated to phosphopeptide enrichment, we found that several proteins involved in signaling and in transcription, are differentially phosphorylated before and after RA addition. The paradigm of these proteins is the RA receptor α (RARα, which was phosphorylated in MCF7 cells but not in BT474 cells after RA addition. The panel of the RA-regulated genes was also different. Overall our results indicate that RA resistance might correlate with the deregulation of the phosphoproteome with consequences on gene expression.

  11. HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

    Directory of Open Access Journals (Sweden)

    Babak Nami

    2017-04-01

    Full Text Available HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs. HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2, which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

  12. Obesity-associated Breast Cancer: Analysis of risk factors.

    Science.gov (United States)

    Engin, Atilla

    2017-01-01

    Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Furthermore, obese women are at higher risk of all-cause and breast cancer specific mortality when compared to non-obese women with breast cancer. In this context, increased levels of estrogens due to excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, hyperactivation of insulin-like growth factors (IGFs) pathways, adipocyte-derived adipokines, hypercholesterolemia and excessive oxidative stress contribute to the development of breast cancer in obese women. While higher breast cancer risk with hormone replacement therapy is particularly evident among lean women, in postmenopausal women who are not taking exogenous hormones, general obesity is a significant predictor for breast cancer. Moreover, increased plasma cholesterol leads to accelerated tumor formation and exacerbates their aggressiveness. In contrast to postmenopausal women, premenopausal women with high BMI are inversely associated with breast cancer risk. Nevertheless, life-style of women for breast cancer risk is regulated by avoiding the overweight and a high-fat diet. Estrogen-plus-progestin hormone therapy users for more than 5 years have elevated risks of both invasive ductal and lobular breast cancer. Additionally, these cases are more commonly node-positive and have a higher cancer-related mortality. Collectively, in this chapter, the impacts of obesity-related estrogen, cholesterol, saturated fatty acid, leptin and adiponectin concentrations, aromatase activity, leptin and insulin resistance on breast cancer patients are evaluated. Obesity-related prognostic factors of breast cancer also are discussed at molecular basis.

  13. SPIN1, negatively regulated by miR-148/152, enhances Adriamycin resistance via upregulating drug metabolizing enzymes and transporter in breast cancer.

    Science.gov (United States)

    Chen, Xu; Wang, Ya-Wen; Gao, Peng

    2018-05-09

    Spindlin1 (SPIN1), a protein highly expressed in several human cancers, has been correlated with tumorigenesis and development. Alterations of drug metabolizing enzymes and drug transporters are major determinants of chemoresistance in tumor cells. However, whether the metabolizing enzymes and transporters are under the control of SPIN1 in breast cancer chemoresistance has not yet been defined. SPIN1 expression in breast cancer cells and tissues was detected by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Chemosensitivity assays in vitro and in vivo were performed to determine the effect of SPIN1 on Adriamycin resistance. Downstream effectors of SPIN1 were screened by microarray and confirmed by qRT-PCR and Western blot. Luciferase assay and Western blot were used to identify miRNAs regulating SPIN1. We showed that SPIN1 was significantly elevated in drug-resistant breast cancer cell lines and tissues, compared with the chemosensitive ones. SPIN1 enhanced Adriamycin resistance of breast cancer cells in vitro, and downregulation of SPIN1 by miRNA could decrease Adriamycin resistance in vivo. Mechanistically, drug metabolizing enzymes and transporter CYP2C8, UGT2B4, UGT2B17 and ABCB4 were proven to be downstream effectors of SPIN1. Notably, SPIN1 was identified as a direct target of the miR-148/152 family (miR-148a-3p, miR-148b-3p and miR-152-3p). As expected, miR-148a-3p, miR-148b-3p or miR-152-3p could increase Adriamycin sensitivity in breast cancer cells in vitro. Moreover, high expression of SPIN1 or low expression of the miR-148/152 family predicted poorer survival in breast cancer patients. Our results establish that SPIN1, negatively regulated by the miR-148/152 family, enhances Adriamycin resistance in breast cancer via upregulating the expression of drug metabolizing enzymes and drug transporter.

  14. MicroRNA-3646 Contributes to Docetaxel Resistance in Human Breast Cancer Cells by GSK-3?/?-Catenin Signaling Pathway

    OpenAIRE

    Zhang, Xiaohui; Zhong, Shanliang; Xu, Yong; Yu, Dandan; Ma, Tengfei; Chen, Lin; Zhao, Yang; Chen, Xiu; Yang, Sujin; Wu, Yueqin; Tang, Jinhai; Zhao, Jianhua

    2016-01-01

    Acquisition of resistance to docetaxel (Doc) is one of the most important problems in treatment of breast cancer patients, but the underlying mechanisms are still not fully understood. In present study, Doc-resistant MDA-MB-231 and MCF-7 breast cancer cell lines (MDA-MB-231/Doc and MCF-7/Doc) were successfully established in vitro by gradually increasing Doc concentration on the basis of parental MDA-MB-231 and MCF-7 cell lines (MDA-MB-231/S and MCF-7/S). The potential miRNAs relevant to the ...

  15. Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer

    Directory of Open Access Journals (Sweden)

    Bai F

    2018-03-01

    Full Text Available Fang Bai,1–3,* You Yin,4,* Ting Chen,1,* Jihui Chen,1 Meixin Ge,2 Yunshu Lu,2 Fangyuan Xie,5 Jian Zhang,1 Kejin Wu,3 Yan Liu1,6 1Department of Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 2Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 3Department of Breast Surgery, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 4Department of Neurology, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 6Department of Pharmacy, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: Breast cancer is the most common cancer among women. Pemetrexed, a new generation antifolate drug, is one of the primary treatments for breast cancer. However, multidrug resistance (MDR in breast cancer greatly hampers the therapeutic efficacy of chemotherapies such as pemetrexed. Nanomedicine is emerging as a promising alternative technique to overcome cancer MDR. Thus, pemetrexed-loaded d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS liposomes (liposomal pemetrexed were developed as a strategy to overcome MDR to pemetrexed in breast cancer. Materials and methods: Liposomal pemetrexed was developed using the calcium acetate gradient method. The cytotoxic effects, apoptosis-inducing activity, in vivo distribution, and antitumor activity of liposomal pemetrexed were investigated. Results: Liposomal pemetrexed was small in size (160.77 nm, with a small polydispersity of <0.1. The encapsulation efficacy of liposomal pemetrexed was 63.5%, which is rather high for water-soluble drugs in liposomes. The IC50 of liposomal pemetrexed following treatment with MDR breast cancer cells (MCF-7 cells overexpressing ABCC5

  16. News in the studies of multidrug resistance of breast cancer cells

    Directory of Open Access Journals (Sweden)

    A. A. Stavrovskaya

    2015-01-01

    Full Text Available Breast cancer (BC is the most common cancer among women in Russia. One of the main treatment methods of BC is systemic chemotherapy. Multidrug resistance of tumor cells (MDR is the important hindrance on the way to successful chemotherapy. The new data concerning molecular mechanisms of MDR will be presented in this review. The recent data concerning some new biological prognostic markers will be also discussed. There are data showing that transporters of ABC family (ABC transporters influence tumor progression not only by MDR induction but also by the influence on the traits of malignancy in tumor cells. The results of the studies of ABC transporters, participation in the processes of accumulation of tumor stem cells under the influence of chemotherapy will be discussed. The problem of the participation of ABC transporters in the phenomenon of influence of PI3K/AKT/PTEN signal transduction pathway on the MDR regulation is discussed. The results of the studies of the role of microRNA deregulation in breast cancer drug resistance as well as studies of some epigenetic mechanisms of MDR regulation will be considered. Protein phosphatase 2A (PP2A, serine/threonine phosphatase, PTK7 (protein tyrosine kinase 7. fascin (an actin bundling cytoskeletal protein multifunctional YB-1 protein will considered as new BC prognostic markers. The perspectives of MDR studies will be discussed as well.

  17. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial.

    Science.gov (United States)

    Courneya, Kerry S; Segal, Roanne J; Mackey, John R; Gelmon, Karen; Reid, Robert D; Friedenreich, Christine M; Ladha, Aliya B; Proulx, Caroline; Vallance, Jeffrey K H; Lane, Kirstin; Yasui, Yutaka; McKenzie, Donald C

    2007-10-01

    Breast cancer chemotherapy may cause unfavorable changes in physical functioning, body composition, psychosocial functioning, and quality of life (QOL). We evaluated the relative merits of aerobic and resistance exercise in blunting these effects. We conducted a multicenter randomized controlled trial in Canada between 2003 and 2005 that randomly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care (n = 82), supervised resistance exercise (n = 82), or supervised aerobic exercise (n = 78) for the duration of their chemotherapy (median, 17 weeks; 95% CI, 9 to 24 weeks). Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy-Anemia scale. Secondary end points were fatigue, psychosocial functioning, physical fitness, body composition, chemotherapy completion rate, and lymphedema. The follow-up assessment rate for our primary end point was 92.1%, and adherence to the supervised exercise was 70.2%. Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem (P = .015), aerobic fitness (P = .006), and percent body fat (adjusted P = .076). Resistance exercise was superior to usual care for improving self-esteem (P = .018), muscular strength (P exercise groups but did not reach statistical significance. Exercise did not cause lymphedema or adverse events. Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy, but they did improve self-esteem, physical fitness, body composition, and chemotherapy completion rate without causing lymphedema or significant adverse events.

  18. Molecular biology of breast cancer stem cells: potential clinical applications.

    Science.gov (United States)

    Nguyen, Nam P; Almeida, Fabio S; Chi, Alex; Nguyen, Ly M; Cohen, Deirdre; Karlsson, Ulf; Vinh-Hung, Vincent

    2010-10-01

    Breast cancer stem cells (CSC) have been postulated recently as responsible for failure of breast cancer treatment. The purpose of this study is to review breast CSCs molecular biology with respect to their mechanism of resistance to conventional therapy, and to develop treatment strategies that may improve survival of breast cancer patients. A literature search has identified in vitro and in vivo studies of breast CSCs. Breast CSCs overexpress breast cancer resistance protein (BCRP) which allows cancer cells to transport actively chemotherapy agents out of the cells. Radioresistance is modulated through activation of Wnt signaling pathway and overexpression of genes coding for glutathione. Lapatinib can selectively target HER-2 positive breast CSCs and improves disease-free survival in these patients. Metformin may target basal type breast CSCs. Parthenolide and oncolytic viruses are promising targeting agents for breast CSCs. Future clinical trials for breast cancer should include anti-cancer stem cells targeting agents in addition to conventional chemotherapy. Hypofractionation radiotherapy may be indicated for residual disease post chemotherapy. 2010 Elsevier Ltd. All rights reserved.

  19. The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

    International Nuclear Information System (INIS)

    Loh, Yan Ni; Hedditch, Ellen L; Baker, Laura A; Jary, Eve; Ward, Robyn L; Ford, Caroline E

    2013-01-01

    Acquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically. An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays. TamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT. These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt

  20. Paclitaxel and doxorubicin in metastatic breast cancer

    DEFF Research Database (Denmark)

    Gehl, J; Boesgaard, M; Paaske, T

    1996-01-01

    For the past decades the anthracyclines have been regarded as among the most active drugs for the treatment of metastatic breast cancer. However, the 5-year survival rate in patients with stage IV breast cancer continues to be below 20%, and new active drugs and drug combinations clearly must...... be explored. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been demonstrated to be highly effective in treating patients with advanced breast cancer, including those with anthracycline-resistant breast cancer, a fact that has led to efforts to combine paclitaxel and anthracyclines...

  1. Differentially expressed proteins in human MCF-7 breast cancer cells sensitive and resistant to paclitaxel

    Czech Academy of Sciences Publication Activity Database

    Pavlíková, N.; Bartoňová, I.; Balušíková, K.; Kopperová, D.; Halada, Petr; Kovář, J.

    2015-01-01

    Roč. 333, č. 1 (2015), s. 1-10 ISSN 0014-4827 Institutional support: RVO:61388971 Keywords : Breast cancer * Taxane resistance * 2-D electrophoresis Subject RIV: CE - Biochemistry Impact factor: 3.378, year: 2015

  2. Involvement of Cox-2 in the metastatic potential of chemotherapy-resistant breast cancer cells

    International Nuclear Information System (INIS)

    Kang, Ju-Hee; Song, Ki-Hoon; Jeong, Kyung-Chae; Kim, Sunshin; Choi, Changsun; Lee, Chang Hoon; Oh, Seung Hyun

    2011-01-01

    A major problem with the use of current chemotherapy regimens for several cancers, including breast cancer, is development of intrinsic or acquired drug resistance, which results in disease recurrence and metastasis. However, the mechanisms underlying this drug resistance are unknown. To study the molecular mechanisms underlying the invasive and metastatic activities of drug-resistant cancer cells, we generated a doxorubicin-resistant MCF-7 breast cancer cell line (MCF-7/DOX). We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, DNA fragmentation assays, Western blot analysis, cell invasion assays, small interfering RNA (siRNA) transfection, reverse transcription-polymerase chain reaction, experimental lung metastasis models, and gelatin and fibrinogen/plasminogen zymography to study the molecular mechanism of metastatic activities in MCF-7/DOX cells. We found that MCF-7/DOX acquired invasive activities. In addition, Western blot analysis showed increased expression of epidermal growth factor receptor (EGFR) and Cox-2 in MCF-7/DOX cells. Inhibition of Cox-2, phosphoinositide 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase (MAPK) pathways effectively inhibited the invasive activities of MCF-7/DOX cells. Gelatin and fibrinogen/plasminogen zymography analysis showed that the enzymatic activities of matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator were markedly higher in MCF-7/DOX cells than in the MCF-7 cells. In vitro invasion assays and mouse models of lung metastasis demonstrated that MCF-7/DOX cells acquired invasive abilities. Using siRNAs and agonists specific for prostaglandin E (EP) receptors, we found that EP1 and EP3 played important roles in the invasiveness of MCF-7/DOX cells. We found that the invasive activity of MCF-7/DOX cells is mediated by Cox-2, which is induced by the EGFR-activated PI3K/Akt and MAPK pathways. In addition, EP1 and EP3 are important in

  3. Melatonin: an Inhibitor of Breast Cancer

    Science.gov (United States)

    Hill, Steven M.; Belancio, Victoria P.; Dauchy, Robert T.; Xiang, Shulin; Brimer, Samantha; Mao, Lulu; Hauch, Adam; Lundberg, Peter W.; Summers, Whitney; Yuan, Lin; Frasch, Tripp; Blask, David E.

    2015-01-01

    This review discusses recent work on melatonin-mediated circadian regulation and metabolic and molecular signaling mechanisms involved in human breast cancer growth and associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin, via the MT1 receptor, suppresses ERα mRNA expression and ERα transcriptional activity. As well, melatonin regulates the transactivation of other members of the nuclear receptor super-family, estrogen metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (Warburg effect), and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways including inhibition of p38 MAPK and repression of epithelial-to-mesenchymal transition. Studies demonstrate that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models indicate that LEN induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer to drive breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms underpinning the epidemiologic demonstration of elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LEN. PMID:25876649

  4. Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line.

    Science.gov (United States)

    Yurgel, Virginia C; Oliveira, Catiuscia P; Begnini, Karine R; Schultze, Eduarda; Thurow, Helena S; Leon, Priscila M M; Dellagostin, Odir A; Campos, Vinicius F; Beck, Ruy C R; Guterres, Silvia S; Collares, Tiago; Pohlmann, Adriana R; Seixas, Fabiana K

    2014-01-01

    Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX) is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt)2]) and MTX(OEt)2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt)2 solution and MTX(OEt)2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231 cells, MTX(OEt)2-loaded lipid-core nanocapsules were significantly more efficient in inducing apoptosis than the solution of the free drug. S-phase cell cycle arrest was induced only by MTX(OEt)2 solution. The drug nanoencapsulation improved apoptosis induction for the cell line that presents MTX resistance by lack of transport receptors.

  5. Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer.

    Science.gov (United States)

    Gasca, Jessica; Flores, Maria Luz; Giráldez, Servando; Ruiz-Borrego, Manuel; Tortolero, María; Romero, Francisco; Japón, Miguel A; Sáez, Carmen

    2016-08-16

    FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box-protein)-type ubiquitin ligases that targets several oncoproteins for ubiquitination and degradation by the proteasome. FBXW7 regulates cellular apoptosis by targeting MCL1 for ubiquitination. Recently, we identified PLK1 as a new substrate of FBXW7 modulating the intra-S-phase DNA-damage checkpoint. Taxanes are frequently used in breast cancer treatments, but the acquisition of resistance makes these treatments ineffective. We investigated the role of FBXW7 and their substrates MCL1 and PLK1 in regulating the apoptotic response to paclitaxel treatment in breast cancer cells and their expression in breast cancer tissues. Paclitaxel-sensitive MDA-MB-468 and a paclitaxel-resistant MDA-MB-468R subclone were used to study the role of FBXW7 and substrates in paclitaxel-induced apoptosis. Forced expression of FBXW7 or downregulation of MCL1 or PLK1 restored sensitivity to paclitaxel in MDA-MB-468R cells. By contrary, FBXW7-silenced MDA-MB-468 cells became resistant to paclitaxel. The expression of FBXW7 and substrates were studied in 296 invasive carcinomas by immunohistochemistry and disease-free survival was analyzed in a subset of patients treated with paclitaxel. In breast cancer tissues, loss of FBXW7 correlated with adverse prognosis markers and loss of FBXW7 and MCL1 or PLK1 accumulation were associated with diminished disease-free survival in paclitaxel-treated patients. We conclude that FBXW7 regulates the response to paclitaxel by targeting MCL1 and PLK1 in breast cancer cells and thus targeting these substrates may be a valuable adjunct for paclitaxel treatment. Also, FBXW7, MCL1 and PLK1 may be relevant predictive markers of tumor progression and response to paclitaxel treatment.

  6. Poly(ADP-ribose polymerase 1 (PARP1 overexpression in human breast cancer stem cells and resistance to olaparib.

    Directory of Open Access Journals (Sweden)

    Marine Gilabert

    Full Text Available BACKGROUND: Breast cancer stem cells (BCSCs have been recognized as playing a major role in various aspects of breast cancer biology. To identify specific biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched and mature cancer cell populations from the human breast cancer cell line (BCL, BrCA-MZ-01. METHODS: ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+ and mature cancer (ALDH- cell populations. Total proteins were extracted from both fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D DIGE. Differentially-expressed spots were excised and proteins were gel-extracted, digested and identified using MALDI-TOF MS. RESULTS: 2-D DIGE identified poly(ADP-ribose polymerase 1 (PARP1 as overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by western blot and extended to four additional human BCLs. ALDH+ cells from BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression, displayed resistance to olaparib, a specific PARP1 inhibitor. CONCLUSION: An unbiased proteomic approach identified PARP1 as upregulated in ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to clinical resistance to PARP inhibitors.

  7. Understanding breast cancer - The long and winding road.

    Science.gov (United States)

    Lukong, Kiven Erique

    2017-06-01

    Despite a remarkable increase in the depth of our understanding and management of breast cancer in the past 50 years, the disease is still a major public health problem worldwide and poses significant challenges. The palpability of breast tumors has facilitated diagnosis and documentation since ancient times. The earliest descriptions of breast cancer date back to around 3500 BCE. For centuries to follow, theories by Hippocrates (460 BCE) and Galen (200 CE), attributing the cause of breast cancer to an "excess of black bile" and treatment options including the use of opium and castor oil, prevailed. Surgical resection was introduced in the 18th century. The advent of modern medicine led to the development of novel treatment options that include hormonal, targeted and chemo-therapies. There are still several therapeutic challenges including the treatment of triple negative breast cancer (TNBC), and overcoming drug resistance. The increased incidence and awareness of breast cancer has led to significant changes in diagnosis and treatment in recent decades. But, mankind has come a long way. Herein, I have traced how our understanding of breast cancer has evolved from the early description of the disease around 460 BCE as "black bile-containing crab-like tumors" to the conventional as a heterogeneous disease with high degree of diversity between and within tumors, as well as among breast cancer patients. How is breast cancer treated today and how do risk factors, breast cancer subtype and drug resistance contribute to the therapeutic challenges at the turn of the 21st century? Breast cancer remains a serious public health issue worldwide. However, appreciable growth in our understanding of breast cancer in the past century has led to remarkable progress in the early detection, treatment and prevention of the disease. The clinical focus is shifting more towards tailored therapy as more targets are characterized and novel highly innovative approaches are developed

  8. Nanomedicine applications in the treatment of breast cancer: current state of the art

    Directory of Open Access Journals (Sweden)

    Wu D

    2017-08-01

    Full Text Available Di Wu, Mengjie Si, Hui-Yi Xue, Ho-Lun Wong Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA Abstract: Breast cancer is the most common malignant disease in women worldwide, but the current drug therapy is far from optimal as indicated by the high death rate of breast cancer patients. Nanomedicine is a promising alternative for breast cancer treatment. Nanomedicine products such as Doxil® and Abraxane® have already been extensively used for breast cancer adjuvant therapy with favorable clinical outcomes. However, these products were originally designed for generic anticancer purpose and not specifically for breast cancer treatment. With better understanding of the molecular biology of breast cancer, a number of novel promising nanotherapeutic strategies and devices have been developed in recent years. In this review, we will first give an overview of the current breast cancer treatment and the updated status of nanomedicine use in clinical setting, then discuss the latest important trends in designing breast cancer nanomedicine, including passive and active cancer cell targeting, breast cancer stem cell targeting, tumor microenvironment-based nanotherapy and combination nanotherapy of drug-resistant breast cancer. Researchers may get insight from these strategies to design and develop nanomedicine that is more tailored for breast cancer to achieve further improvements in cancer specificity, antitumorigenic effect, antimetastasis effect and drug resistance reversal effect. Keywords: nanomedicine, breast cancer, targeted delivery, drug therapy, drug resistance, tumor microenvironment 

  9. The Role of Exosomes in Breast Cancer.

    Science.gov (United States)

    Lowry, Michelle C; Gallagher, William M; O'Driscoll, Lorraine

    2015-12-01

    Although it has been long realized that eukaryotic cells release complex vesicular structures into their environment, only in recent years has it been established that these entities are not merely junk or debris, but that they are tailor-made specialized minimaps of their cell of origin and of both physiological and pathological relevance. These exosomes and microvesicles (ectosomes), collectively termed extracellular vesicles (EVs), are often defined and subgrouped first and foremost according to size and proposed origin (exosomes approximately 30-120 nm, endosomal origin; microvesicles 120-1000 nm, from the cell membrane). There is growing interest in elucidating the relevance and roles of EVs in cancer. Much of the pioneering work on EVs in cancer has focused on breast cancer, possibly because breast cancer is a leading cause of cancer-related deaths worldwide. This review provides an in-depth summary of such studies, supporting key roles for exosomes and other EVs in breast cancer cell invasion and metastasis, stem cell stimulation, apoptosis, immune system modulation, and anti-cancer drug resistance. Exosomes as diagnostic, prognostic, and/or predictive biomarkers and their potential use in the development of therapeutics are discussed. Although not fully elucidated, the involvement of exosomes in breast cancer development, progression, and resistance is becoming increasingly apparent from preclinical and clinical studies, with mounting interest in the potential exploitation of these vesicles for breast cancer biomarkers, as drug delivery systems, and in the development of future novel breast cancer therapies. © 2015 American Association for Clinical Chemistry.

  10. An integrative analysis of cellular contexts, miRNAs and mRNAs reveals network clusters associated with antiestrogen-resistant breast cancer cells

    Directory of Open Access Journals (Sweden)

    Nam Seungyoon

    2012-12-01

    Full Text Available Abstract Background A major goal of the field of systems biology is to translate genome-wide profiling data (e.g., mRNAs, miRNAs into interpretable functional networks. However, employing a systems biology approach to better understand the complexities underlying drug resistance phenotypes in cancer continues to represent a significant challenge to the field. Previously, we derived two drug-resistant breast cancer sublines (tamoxifen- and fulvestrant-resistant cell lines from the MCF7 breast cancer cell line and performed genome-wide mRNA and microRNA profiling to identify differential molecular pathways underlying acquired resistance to these important antiestrogens. In the current study, to further define molecular characteristics of acquired antiestrogen resistance we constructed an “integrative network”. We combined joint miRNA-mRNA expression profiles, cancer contexts, miRNA-target mRNA relationships, and miRNA upstream regulators. In particular, to reduce the probability of false positive connections in the network, experimentally validated, rather than prediction-oriented, databases were utilized to obtain connectivity. Also, to improve biological interpretation, cancer contexts were incorporated into the network connectivity. Results Based on the integrative network, we extracted “substructures” (network clusters representing the drug resistant states (tamoxifen- or fulvestrant-resistance cells compared to drug sensitive state (parental MCF7 cells. We identified un-described network clusters that contribute to antiestrogen resistance consisting of miR-146a, -27a, -145, -21, -155, -15a, -125b, and let-7s, in addition to the previously described miR-221/222. Conclusions By integrating miRNA-related network, gene/miRNA expression and text-mining, the current study provides a computational-based systems biology approach for further investigating the molecular mechanism underlying antiestrogen resistance in breast cancer cells. In

  11. Targeting FASN for Breast Cancer Treatment by Repositioning PPIs

    Science.gov (United States)

    2017-01-01

    we found that fatty acid synthase (FASN) up-regulation causes resistance to multiple anticancer drugs including doxorubicine and cisplatin ...be accomplished to (1) investigate the mechanism of FASN action in drug resistance in breast cancers; (2) determine efficacy of PPIs as single agents...Tasks proposed in SOW for year 1. Major Task 1: Determine the mechanism of FASN function in breast cancer drug resistance (months 1- 16). For this

  12. Exosome: emerging biomarker in breast cancer

    Science.gov (United States)

    Jia, Yunlu; Chen, Yongxia; Wang, Qinchuan; Jayasinghe, Ushani; Luo, Xiao; Wei, Qun; Wang, Ji; Xiong, Hanchu; Chen, Cong; Xu, Bin; Hu, Wenxian; Wang, Linbo; Zhao, Wenhe; Zhou, Jichun

    2017-01-01

    Exosomes are nano-sized membrane vesicles released by a variety of cell types, and are thought to play important roles in intercellular communications. In breast cancer, through horizontal transfer of various bioactive molecules, such as proteins and mRNAs, exosomes are emerging as local and systemic cell-to-cell mediators of oncogenic information and play an important role on cancer progression. This review outlines the current knowledge and concepts concerning the exosomes involvement in breast cancer pathogenesis (including tumor initiation, invasion and metastasis, angiogenesis, immune system modulation and tumor microenvironment) and cancer therapy resistance. Moreover, the potential use of exosomes as promising diagnostic and therapeutic biomarkers in breast cancer are also discussed. PMID:28402944

  13. Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.

    Science.gov (United States)

    Chinchar, Edmund; Makey, Kristina L; Gibson, John; Chen, Fang; Cole, Shelby A; Megason, Gail C; Vijayakumar, Srinivassan; Miele, Lucio; Gu, Jian-Wei

    2014-01-01

    The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10(6) MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm(3), sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44(+)/CD24(-) or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an

  14. Estrogen receptor positive breast tumors resist chemotherapy by the overexpression of P53 in Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Fatma Ashour

    2018-06-01

    Full Text Available Background and Objectives: Breast cancer (BC is classified according to estrogen receptor (ER status into ER+ and ER− tumors. ER+ tumors have a worse response to chemotherapy compared to ER− tumors. BCL-2, TP53, BAX and NF-ΚB are involved in drug resistance in the ER+ tumors. Recently it was shown that Cancer Stem Cells (CSCs play an important role in drug resistance. In this study we tested the hypothesis that CSCs of the ER+ tumors resist drug through the overexpression of BCL-2, TP53, BAX and NF-ΚB. Methods: CSCs were isolated by anoikis resistance assay from MCF7 (ER+ and MDA-MB-231 (ER− cell lines. Isolated CSCs were treated with doxorubicin (DOX and the mRNA expression levels of BCL-2, TP53, BAX and NFKB were investigated by quantitative real time PCR (qPCR with and without treatment. Results: BCL-2, BAX and NF-ΚB showed decreased expression in MCF7 bulk cancer cells after DOX treatment whereas only BCL-2 and BAX showed decreased expression in MDA-MB-231 bulk cancer cells. Interestingly TP53 was the only gene showed a considerable increase in its expression in CSCs of the ER+ MCF7 cell line compared to bulk cancer cells. Moreover, TP53 was the only gene showing exceptionally higher level of expression in MCF7-CSCs compared to MDA-MB-231-CSCs. Conclusion: Our results suggest that CSCs in the ER+ cells escape the effect of DOX treatment by the elevation of p53 expression. Keywords: Breast cancer, Cancer Stem Cells, Drug resistance, Estrogen receptors

  15. Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

    International Nuclear Information System (INIS)

    Gradishar, William J

    2016-01-01

    Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2- negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed

  16. Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells.

    Science.gov (United States)

    Cheng, Ran; Liu, Ya-Jing; Cui, Jun-Wei; Yang, Man; Liu, Xiao-Ling; Li, Peng; Wang, Zhan; Zhu, Li-Zhang; Lu, Si-Yi; Zou, Li; Wu, Xiao-Qin; Li, Yu-Xia; Zhou, You; Fang, Zheng-Yu; Wei, Wei

    2017-05-02

    Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.

  17. p-Glycoprotein ABCB5 and YB-1 expression plays a role in increased heterogeneity of breast cancer cells: correlations with cell fusion and doxorubicin resistance

    International Nuclear Information System (INIS)

    Yang, Ji Yeon; Ha, Seon-Ah; Yang, Yun-Sik; Kim, Jin Woo

    2010-01-01

    Cancer cells recurrently develop into acquired resistance to the administered drugs. The iatrogenic mechanisms of induced chemotherapy-resistance remain elusive and the degree of drug resistance did not exclusively correlate with reductions of drug accumulation, suggesting that drug resistance may involve additional mechanisms. Our aim is to define the potential targets, that makes drug-sensitive MCF-7 breast cancer cells turn to drug-resistant, for the anti-cancer drug development against drug resistant breast cancer cells. Doxorubicin resistant human breast MCF-7 clones were generated. The doxorubicin-induced cell fusion events were examined. Heterokaryons were identified and sorted by FACS. In the development of doxorubicin resistance, cell-fusion associated genes, from the previous results of microarray, were verified using dot blot array and quantitative RT-PCR. The doxorubicin-induced expression patterns of pro-survival and pro-apoptotic genes were validated. YB-1 and ABCB5 were up regulated in the doxorubicin treated MCF-7 cells that resulted in certain degree of genomic instability that accompanied by the drug resistance phenotype. Cell fusion increased diversity within the cell population and doxorubicin resistant MCF-7 cells emerged probably through clonal selection. Most of the drug resistant hybrid cells were anchorage independent. But some of the anchorage dependent MCF-7 cells exhibited several unique morphological appearances suggesting minor population of the fused cells maybe de-differentiated and have progenitor cell like characteristics. Our work provides valuable insight into the drug induced cell fusion event and outcome, and suggests YB-1, GST, ABCB5 and ERK3 could be potential targets for the anti-cancer drug development against drug resistant breast cancer cells. Especially, the ERK-3 serine/threonine kinase is specifically up-regulated in the resistant cells and known to be susceptible to synthetic antagonists

  18. Interaction of CDCP1 with HER2 Enhances HER2-Driven Tumorigenesis and Promotes Trastuzumab Resistance in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Abdullah Alajati

    2015-04-01

    Full Text Available Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC, leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients.

  19. Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions

    NARCIS (Netherlands)

    Breedveld, Pauline; Zelcer, Noam; Pluim, Dick; Sönmezer, Ozgür; Tibben, Matthijs M.; Beijnen, Jos H.; Schinkel, Alfred H.; van Tellingen, Olaf; Borst, Piet; Schellens, Jan H. M.

    2004-01-01

    The antifolate drug methotrexate (MTX) is transported by breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated protein1-4 (MRP1-4; ABCC1-4). In cancer patients, coadministration of benzimidazoles and MTX can result in profound MTX-induced toxicity coinciding with an

  20. Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer.

    Directory of Open Access Journals (Sweden)

    Praveenkumar K Shetty

    Full Text Available Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK, including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal growth factor receptor (EGFR and Src which further contributes to oncogenesis in Herceptin resistant and triple negative breast cancer (TNBC patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2, a known substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1 cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis, decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.

  1. New developments in the treatment of HER2-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Nahta R

    2012-05-01

    Full Text Available Rita NahtaDepartments of Pharmacology and Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USAAbstract: Approximately 20%–30% of metastatic breast cancers show increased expression of the human epidermal growth factor receptor-2 (HER2 tyrosine kinase. Two HER2-specific therapies are currently approved for clinical treatment of patients with HER2-overexpressing metastatic breast cancer. Trastuzumab is a monoclonal antibody against HER2 and is approved for first-line treatment of HER2-positive metastatic breast cancer. Lapatinib is a small molecule dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases, and is approved for trastuzumab-refractory disease. Although trastuzumab is a highly effective therapy for patients with HER2-overexpressing metastatic breast cancer, a significant number of patients in the initial clinical trials of trastuzumab monotherapy showed resistance to trastuzumab-based therapy. Further, among those who did respond, the initial trials indicated that the median time to progression was less than 1 year. Similarly, lapatinib is effective in a subset of trastuzumab-refractory cases, but the majority of patients display resistance. This review discusses the multiple molecular mechanisms of resistance that have been proposed in the literature. In addition, novel agents that are being tested for efficacy against HER2-positive breast cancer, including the antibodies pertuzumab and trastuzumab-DM1 and the immunotoxin affitoxin, are reviewed. The introduction of trastuzumab has revolutionized the clinical care of patients with HER2-positive metastatic breast cancer and has resulted in dramatic reductions in recurrences of early-stage HER2-positive breast cancer. The development and implementation of gene- and protein-based assays that measure potential molecular predictors of trastuzumab resistance will allow individualization of HER2-targeted therapeutic approaches

  2. MicroRNAs in Breast Cancer: One More Turn in Regulation.

    Science.gov (United States)

    Eroles, Pilar; Asensio, Pilar E; Tormo, Eduardo; Martin, Eduardo T; Pineda, Begoña; Merlo, Begoña P; Espin, Estefanía; Armas, Estefanía E; Lluch, Ana; Hernández, Ana L

    2016-01-01

    MicroRNAs (miRNAs) are small non-coding RNA molecules that critically regulate the expression of genes. MiRNAs are involved in physiological cellular processes; however, their deregulation has been associated with several pathologies, including cancer. In human breast cancer, differently expressed levels of miRNAs have been identified from those in normal breast tissues. Moreover, several miRNAs have been correlated with pathological phenotype, cancer subtype and therapy response in breast cancer. The resistance to therapy is increasingly a problem in patient management, and miRNAs are emerging as novel therapeutic targets and potential predictive biomarkers for treatment. This review provides an overview of the current situation of miRNAs in breast cancer, focusing on their involvement in resistance and the circulating miRNA. The mechanisms of therapeutic resistance regulated by miRNAs, such as the regulation of receptors, the modification of enzymes of drug metabolism, the inhibition of cell cycle control or pro-apoptotic proteins, the alteration of histone activity and the regulation of DNA repair machinery among others, are discussed for breast cancer clinical subtypes. Additionally, in this review, we summarize the recent knowledge that has established miRNA detection in peripheral body fluids as a suitable biomarker. We review the detection of miRNA in liquid biopsies and its implications for the diagnosis and monitoring of breast cancer. This new generation of cancer biomarkers may lead to a significant improvement in patient management.

  3. Alterations in mRNA profiles of trastuzumab‑resistant Her‑2‑positive breast cancer.

    Science.gov (United States)

    Zhao, Bin; Zhao, Yang; Sun, Yan; Niu, Haitao; Sheng, Long; Huang, Dongfang; Li, Li

    2018-05-07

    Breast cancer is one of the most common malignancies in women. Neoadjuvant trastuzumab therapy improves the prognosis of certain Her‑2‑positive breast cancer patients, however around two‑thirds of patients with Her‑2‑positive breast cancer do not benefit from Her‑2‑targeted therapy. To investigate the key mechanisms in trastuzumab resistance, potential biomarkers for neoadjuvant trastuzumab sensitivity were investigated using the gene expression omnibus (GEO) database for mRNA microarray data of Her‑2‑positive breast cancer patients who received neoadjuvant trastuzumab therapy. GEO profiles of 22 patients with a complete response and 48 patients with a partial response were identified in the GSE22358, GSE62327 and GSE66305 datasets. A total of 2,376, 1,000 and 1,152 differentially expressed genes in GSE22358, GSE62327 and GSE66305 datasets were demonstrated, respectively, utilizing GEO2R software. Furthermore, enriched gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were analyzed using the Database for Annotation, Visualization and Integrated Discovery software. Subsequently, a protein‑protein interaction network was established using STRING software. The results demonstrated that low sex‑determining region Y‑box 11 and high Bcl‑2 expression may be employed as markers for neoadjuvant trastuzumab therapy for Her‑2‑positive breast cancer. More importantly, phosphoinositide 3‑kinase/Akt and angiogenesis pathways, which are known to be the key targets of trastuzumab, were activated at a lower level in the partial response patients, while the Wnt and estrogen receptor signaling pathways were activated in these patients. Therefore, combination therapy of trastuzumab and anti‑Wnt or hormone therapy may be a promising treatment modality and should be tested in further studies.

  4. Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity

    Directory of Open Access Journals (Sweden)

    Bruno M. Simões

    2015-09-01

    Full Text Available Breast cancers (BCs typically express estrogen receptors (ERs but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.

  5. Nanomedicine applications in the treatment of breast cancer: current state of the art.

    Science.gov (United States)

    Wu, Di; Si, Mengjie; Xue, Hui-Yi; Wong, Ho-Lun

    2017-01-01

    Breast cancer is the most common malignant disease in women worldwide, but the current drug therapy is far from optimal as indicated by the high death rate of breast cancer patients. Nanomedicine is a promising alternative for breast cancer treatment. Nanomedicine products such as Doxil ® and Abraxane ® have already been extensively used for breast cancer adjuvant therapy with favorable clinical outcomes. However, these products were originally designed for generic anticancer purpose and not specifically for breast cancer treatment. With better understanding of the molecular biology of breast cancer, a number of novel promising nanotherapeutic strategies and devices have been developed in recent years. In this review, we will first give an overview of the current breast cancer treatment and the updated status of nanomedicine use in clinical setting, then discuss the latest important trends in designing breast cancer nanomedicine, including passive and active cancer cell targeting, breast cancer stem cell targeting, tumor microenvironment-based nanotherapy and combination nanotherapy of drug-resistant breast cancer. Researchers may get insight from these strategies to design and develop nanomedicine that is more tailored for breast cancer to achieve further improvements in cancer specificity, antitumorigenic effect, antimetastasis effect and drug resistance reversal effect.

  6. Review of hormonal treatment of breast cancer | Abdulkareem ...

    African Journals Online (AJOL)

    This critical review focuses on the role of steroid hormones and their receptors in the development and treatment of breast cancer, with special reference to estrogen receptors, as well as mechanisms of receptor.ligand interactions, response or resistance to hormonal therapy against breast cancer, in conjunction with other ...

  7. The role of lipolysis stimulated lipoprotein receptor in breast cancer and directing breast cancer cell behavior.

    Directory of Open Access Journals (Sweden)

    Denise K Reaves

    Full Text Available The claudin-low molecular subtype of breast cancer is of particular interest for clinically the majority of these tumors are poor prognosis, triple negative, invasive ductal carcinomas. Claudin-low tumors are characterized by cancer stem cell-like features and low expression of cell junction and adhesion proteins. Herein, we sought to define the role of lipolysis stimulated lipoprotein receptor (LSR in breast cancer and cancer cell behavior as LSR was recently correlated with tumor-initiating features. We show that LSR was expressed in epithelium, endothelium, and stromal cells within the healthy breast tissue, as well as in tumor epithelium. In primary breast tumor bioposies, LSR expression was significantly correlated with invasive ductal carcinomas compared to invasive lobular carcinomas, as well as ERα positive tumors and breast cancer cell lines. LSR levels were significantly reduced in claudin-low breast cancer cell lines and functional studies illustrated that re-introduction of LSR into a claudin-low cell line suppressed the EMT phenotype and reduced individual cell migration. However, our data suggest that LSR may promote collective cell migration. Re-introduction of LSR in claudin-low breast cancer cell lines reestablished tight junction protein expression and correlated with transepithelial electrical resistance, thereby reverting claudin-low lines to other intrinsic molecular subtypes. Moreover, overexpression of LSR altered gene expression of pathways involved in transformation and tumorigenesis as well as enhanced proliferation and survival in anchorage independent conditions, highlighting that reestablishment of LSR signaling promotes aggressive/tumor initiating cell behaviors. Collectively, these data highlight a direct role for LSR in driving aggressive breast cancer behavior.

  8. Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk.

    Science.gov (United States)

    Jung, Su Yon; Ho, Gloria; Rohan, Thomas; Strickler, Howard; Bea, Jennifer; Papp, Jeanette; Sobel, Eric; Zhang, Zuo-Feng; Crandall, Carolyn

    2017-07-01

    Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor. Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways-genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP-cancer relationship explained by traits varied 45-50% between the strata. Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.

  9. Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.

    Science.gov (United States)

    Watson, Spencer S; Dane, Mark; Chin, Koei; Tatarova, Zuzana; Liu, Moqing; Liby, Tiera; Thompson, Wallace; Smith, Rebecca; Nederlof, Michel; Bucher, Elmar; Kilburn, David; Whitman, Matthew; Sudar, Damir; Mills, Gordon B; Heiser, Laura M; Jonas, Oliver; Gray, Joe W; Korkola, James E

    2018-03-28

    Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Sensitivity of docetaxel-resistant MCF-7 breast cancer cells to microtubule-destabilizing agents including vinca alkaloids and colchicine-site binding agents.

    Directory of Open Access Journals (Sweden)

    Richard C Wang

    Full Text Available One of the main reasons for disease recurrence in the curative breast cancer treatment setting is the development of drug resistance. Microtubule targeted agents (MTAs are among the most commonly used drugs for the treatment of breaset cancer and therefore overcoming taxane resistance is of primary clinical importance. Our group has previously demonstrated that the microtubule dynamics of docetaxel-resistant MCF-7TXT cells are insensitivity to docetaxel due to the distinct expression profiles of β-tubulin isotypes in addition to the high expression of p-glycoprotein (ABCB1. In the present investigation we examined whether taxane-resistant breast cancer cells are more sensitive to microtubule destabilizing agents including vinca alkaloids and colchicine-site binding agents (CSBAs than the non-resistant cells.Two isogenic MCF-7 breast cancer cell lines were selected for resistance to docetaxel (MCF-7TXT and the wild type parental cell line (MCF-7CC to examine if taxane-resistant breast cancer cells are sensitive to microtubule-destabilizing agents including vinca alkaloids and CSBAs. Cytotoxicity assays, immunoblotting, indirect immunofluorescence and live imaging were used to study drug resistance, apoptosis, mitotic arrest, microtubule formation, and microtubule dynamics.MCF-7TXT cells were demonstrated to be cross resistant to vinca alkaloids, but were more sensitive to treatment with colchicine compared to parental non-resistant MCF-7CC cells. Cytotoxicity assays indicated that the IC50 of MCF-7TXT cell to vinorelbine and vinblastine was more than 6 and 3 times higher, respectively, than that of MCF-7CC cells. By contrast, the IC50 of MCF-7TXT cell for colchincine was 4 times lower than that of MCF-7CC cells. Indirect immunofluorescence showed that all MTAs induced the disorganization of microtubules and the chromatin morphology and interestingly each with a unique pattern. In terms of microtubule and chromain morphology, MCF-7TXT cells were

  11. Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties

    DEFF Research Database (Denmark)

    Lin, Xue; Li, Jian; Yin, Guangliang

    2013-01-01

    Development of resistance to tamoxifen is an important clinical issue in the treatment of breast cancer. Tamoxifen resistance may be the result of acquisition of epigenetic regulation within breast cancer cells, such as DNA methylation, resulting in changed mRNA expression of genes pivotal for es...

  12. Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism

    Science.gov (United States)

    Goodman, C R; Sato, T; Peck, A R; Girondo, M A; Yang, N; Liu, C; Yanac, A F; Kovatich, A J; Hooke, J A; Shriver, C D; Mitchell, E P; Hyslop, T; Rui, H

    2016-01-01

    Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers. PMID:26096934

  13. APC selectively mediates response to chemotherapeutic agents in breast cancer

    International Nuclear Information System (INIS)

    VanKlompenberg, Monica K.; Bedalov, Claire O.; Soto, Katia Fernandez; Prosperi, Jenifer R.

    2015-01-01

    The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in up to 70 % of sporadic breast cancers depending on subtype; however, the effects of APC mutation on tumorigenic properties remain unexplored. Using the Apc Min/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we identified enhanced breast tumorigenesis and alterations in genes critical in therapeutic resistance independent of Wnt/β-catenin signaling. Apc mutation changed the tumor histopathology from solid to squamous adenocarcinomas, resembling the highly aggressive human metaplastic breast cancer. Mechanistic studies in tumor-derived cell lines demonstrated that focal adhesion kinase (FAK)/Src/JNK signaling regulated the enhanced proliferation downstream of Apc mutation. Despite this mechanistic information, the role of APC in mediating breast cancer chemotherapeutic resistance is currently unknown. We have examined the effect of Apc loss in MMTV-PyMT mouse breast cancer cells on gene expression changes of ATP-binding cassette transporters and immunofluorescence to determine proliferative and apoptotic response of cells to cisplatin, doxorubicin and paclitaxel. Furthermore we determined the added effect of Src or JNK inhibition by PP2 and SP600125, respectively, on chemotherapeutic response. We also used the Aldefluor assay to measure the population of tumor initiating cells. Lastly, we measured the apoptotic and proliferative response to APC knockdown in MDA-MB-157 human breast cancer cells after chemotherapeutic treatment. Cells obtained from MMTV-PyMT;Apc Min/+ tumors express increased MDR1 (multidrug resistance protein 1), which is augmented by treatment with paclitaxel or doxorubicin. Furthermore MMTV-PyMT;Apc Min/+ cells are more resistant to cisplatin and doxorubicin-induced apoptosis, and show a larger population of ALDH positive cells. In the human metaplastic breast cancer cell line MDA-MB-157, APC knockdown led to paclitaxel and cisplatin

  14. Randomized controlled trial to evaluate the effects of progressive resistance training compared to progressive muscle relaxation in breast cancer patients undergoing adjuvant radiotherapy: the BEST study

    International Nuclear Information System (INIS)

    Potthoff, Karin; Steindorf, Karen; Schmidt, Martina E; Wiskemann, Joachim; Hof, Holger; Klassen, Oliver; Habermann, Nina; Beckhove, Philipp; Debus, Juergen; Ulrich, Cornelia M

    2013-01-01

    Cancer-related fatigue (CRF) is one of the most common and distressing side effects of cancer and its treatment. During and after radiotherapy breast cancer patients often suffer from CRF which frequently impairs quality of life (QoL). Despite the high prevalence of CRF in breast cancer patients and the severe impact on the physical and emotional well-being, effective treatment methods are scarce. Physical activity for breast cancer patients has been reported to decrease fatigue, to improve emotional well-being and to increase physical strength. The pathophysiological and molecular mechanisms of CRF and the molecular-biologic changes induced by exercise, however, are poorly understood. In the BEST trial we aim to assess the effects of resistance training on fatigue, QoL and physical fitness as well as on molecular, immunological and inflammatory changes in breast cancer patients during adjuvant radiotherapy. The BEST study is a prospective randomized, controlled intervention trial investigating the effects of a 12-week supervised progressive resistance training compared to a 12-week supervised muscle relaxation training in 160 patients with breast cancer undergoing adjuvant radiotherapy. To determine the effect of exercise itself beyond potential psychosocial group effects, patients in the control group perform a group-based progressive muscle relaxation training. Main inclusion criterion is histologically confirmed breast cancer stage I-III after lumpectomy or mastectomy with indication for adjuvant radiotherapy. Main exclusion criteria are acute infectious diseases, severe neurological, musculosceletal or cardiorespiratory disorders. The primary endpoint is cancer-related fatigue; secondary endpoints include immunological and inflammatory parameters analyzed in peripheral blood, saliva and urine. In addition, QoL, depression, physical performance and cognitive capacity will be assessed. The BEST study is the first randomized controlled trial comparing progressive

  15. Bisphenol A activates EGFR and ERK promoting proliferation, tumor spheroid formation and resistance to EGFR pathway inhibition in estrogen receptor negative inflammatory breast cancer cells

    Science.gov (United States)

    Background: Inflammatory breast cancer (IBC) is a distinct and the deadliest breast cancer variant, which shows a rapid rate of progression and acquired therapeutic resistance. Epidemiological studies suggest that chemical exposure in the environment and consumer products can aff...

  16. Identification of the Interaction between P-Glycoprotein and Anxa2 in Multidrug-resistant Human Breast Cancer Cells

    International Nuclear Information System (INIS)

    Zhang, Hai-chang; Zhang, Fei; Wu, Bing; Han, Jing-hua; Ji, Wei; Zhou, Yan; Niu, Rui-fang

    2012-01-01

    To explore the interaction of Anxa2 with P-Glycoprotein (P-gp) in the migration and invasion of the multidrug-resistant (MDR) human breast cancer cell line MCF-7/ADR. A pair of short hairpin RNA (shRNA) targeting P-gp was transfected into MCF-7/ADR cells, and monoclonal cell strains were screened. The expression of P-gp was detected by Western blot. Transwell chambers were used to observe the cell migration capacity and invasion ability. The interaction between P-gp and Anxa2 was examined by immunoprecipitation and immunofluorescence confocal microscopy analyses. P-gp expression was significantly knocked down, and there were notable decreasing trends in the migration and invasion capability of MDR breast cancer cells (P<0.05). There was a close interaction between Anxa2 and P-gp. MCF-7/ADR is an MDR human breast cancer cell line with high migration and invasion abilities. The knockdown of P-gp notably impaired the migration and invasion abilities of the tumor cells. The interaction of Anxa2 with P-pg may play an important role in the enhanced invasiveness of MDR human breast cancer cells

  17. Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Yu-Jen Chen

    Full Text Available Multi-drug resistance (MDR, an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC transporters and activated Sonic hedgehog (Shh signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX, we examined the effect and mechanism of norcantharidin (NCTD, a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S and DOX-resistant (MCF-7R cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells.

  18. Drug transporters in breast cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Stenvang, Jan; Moreira, José

    2015-01-01

    Despite the advances that have taken place in the past decade, including the development of novel molecular targeted agents, cytotoxic chemotherapy remains the mainstay of cancer treatment. In breast cancer, anthracyclines and taxanes are the two main chemotherapeutic options used on a routine...... basis. Although effective, their usefulness is limited by the inevitable development of resistance, a lack of response to drug-induced cancer cell death. A large body of research has resulted in the characterization of a plethora of mechanisms involved in resistance; ATP-binding cassette transporter...

  19. New developments in breast cancer therapy: role of iron oxide nanoparticles

    Science.gov (United States)

    Thoidingjam, Shivani; Bhan Tiku, Ashu

    2017-06-01

    Breast cancer is one of the leading causes of deaths in females worldwide. The high metastatic rate and drug resistance makes it one of the difficult cancers to treat. Early diagnosis and treatment are keys to better survival of breast cancer patients. Conventional treatment approaches like chemotherapy, radiotherapy and surgery suffer from major drawbacks. Novel approaches to improve cancer therapy with minimal damage to normal tissues and better quality of life for cancer patients need to be developed. Among various approaches used for treatment and diagnosis of breast cancer, use of nanoparticles (NPs) is coming up as a new and promising treatment regime. It can help overcome various limitations of conventional therapies like non-targeted effects, resistance to treatment, late diagnosis, etc. Among various nanoparticles studied for their biomedical applications, especially for breast cancer therapy, iron oxide nanoparticles (IONPs) are perhaps the most exciting due to their biocompatibility, biodegradability, size and properties like superparamagnetism. Besides, IONPs are also the only metal oxide nanoparticles approved for clinical use in magnetic resonance imaging (MRI) which is an added advantage for early detection. Therefore in this mini review, we are discussing the developments made in the use of IONPs for breast cancer therapy over the short span of the last five years i.e. 2010-2015. Since late diagnosis and therapy resistance are important drawbacks in breast cancer therapy, the potential of IONPs to overcome these limitations are also evaluated.

  20. Phytochemicals for breast cancer therapy: current status and future implications.

    Science.gov (United States)

    Siddiqui, Jawed Akhtar; Singh, Aru; Chagtoo, Megha; Singh, Nidhi; Godbole, Madan Madhav; Chakravarti, Bandana

    2015-01-01

    Breast cancer is one of the most common malignancies among women, representing nearly 30% of newly diagnosed cancers every year. Till date, various therapeutic interventions, including surgery, chemotherapy, hormonal therapy, and radiotherapy are available and are known to cause a significant decline in the overall mortality rate. However, therapeutic resistance, recurrence and lack of treatment in metastasis are the major challenges that need to be addressed. Increasing evidence suggests the presence of cancer stem cells (CSCs) in heterogeneous population of breast tumors capable of selfrenewal and differentiation and is considered to be responsible for drug resistance and recurrence. Therefore, compound that can target both differentiated cancer cells, as well as CSCs, may provide a better treatment strategy. Due to safe nature of dietary agents and health products, investigators are introducing them into clinical trials in place of chemotherapeutic agents.This current review focuses on phytochemicals, mainly flavonoids that are in use for breast cancer therapy in preclinical phase. As phytochemicals have several advantages in breast cancer and cancer stem cells, new synthetic series for breast cancer therapy from analogues of most potent natural molecule can be developed via rational drug design approach.

  1. Furanodiene Induces Extrinsic and Intrinsic Apoptosis in Doxorubicin-Resistant MCF-7 Breast Cancer Cells via NF-κB-Independent Mechanism.

    Science.gov (United States)

    Zhong, Zhang-Feng; Yu, Hai-Bing; Wang, Chun-Ming; Qiang, Wen-An; Wang, Sheng-Peng; Zhang, Jin-Ming; Yu, Hua; Cui, Liao; Wu, Tie; Li, De-Qiang; Wang, Yi-Tao

    2017-01-01

    Chemotherapy is used as a primary approach in cancer treatment after routine surgery. However, chemo-resistance tends to occur when chemotherapy is used clinically, resulting in poor prognosis and recurrence. Currently, Chinese medicine may provide insight into the design of new therapies to overcome chemo-resistance. Furanodiene, as a heat-sensitive sesquiterpene, is isolated from the essential oil of Rhizoma Curcumae . Even though mounting evidence claiming that furanodiene possesses anti-cancer activities in various types of cancers, the underlying mechanisms against chemo-resistant cancer are not fully clear. Our study found that furanodiene could display anti-cancer effects by inhibiting cell viability, inducing cell cytotoxicity, and suppressing cell proliferation in doxorubicin-resistant MCF-7 breast cancer cells. Furthermore, furanodiene preferentially causes apoptosis by interfering with intrinsic/extrinsic-dependent and NF-κB-independent pathways in doxorubicin-resistant MCF-7 cells. These observations also prompt that furanodiene may be developed as a promising natural product for multidrug-resistant cancer therapy in the future.

  2. Breast Cancer Prevention

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Prevention (PDQ®)–Patient Version What is prevention? Go ... from starting. Risk-reducing surgery . General Information About Breast Cancer Key Points Breast cancer is a disease in ...

  3. Breast Cancer Treatment

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Treatment (PDQ®)–Patient Version General Information About Breast Cancer Go to Health Professional Version Key Points Breast ...

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

    Science.gov (United States)

    Narayanan, Ramesh; Dalton, James T.

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Ramesh Narayanan

    2016-12-01

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

  6. Functional ablation of pRb activates Cdk2 and causes antiestrogen resistance in human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Hemant Varma

    2007-12-01

    Full Text Available Estrogens are required for the proliferation of hormone dependent breast cancer cells, making estrogen receptor (ER positive tumors amenable to endocrine therapies such as antiestrogens. However, resistance to these agents remains a significant cause of treatment failure. We previously demonstrated that inactivation of the retinoblastoma protein (pRb family tumor suppressors causes antiestrogen resistance in MCF-7 cells, a widely studied model of estrogen responsive human breast cancers. In this study, we investigate the mechanism by which pRb inactivation leads to antiestrogen resistance. Cdk4 and cdk2 are two key cell cycle regulators that can phosphorylate and inactivate pRb, therefore we tested whether these kinases are required in cells lacking pRb function. pRb family members were inactivated in MCF-7 cells by expressing polyomavirus large tumor antigen (PyLT, and cdk activity was inhibited using the cdk inhibitors p16(INK4A and p21(Waf1/Cip1. Cdk4 activity was no longer required in cells lacking functional pRb, while cdk2 activity was required for proliferation in both the presence and absence of pRb function. Using inducible PyLT cell lines, we further demonstrated that pRb inactivation leads to increased cyclin A expression, cdk2 activation and proliferation in antiestrogen arrested cells. These results demonstrate that antiestrogens do not inhibit cdk2 activity or proliferation of MCF-7 cells in the absence of pRb family function, and suggest that antiestrogen resistant breast cancer cells resulting from pRb pathway inactivation would be susceptible to therapies that target cdk2.

  7. Microparticles shed from multidrug resistant breast cancer cells provide a parallel survival pathway through immune evasion.

    Science.gov (United States)

    Jaiswal, Ritu; Johnson, Michael S; Pokharel, Deep; Krishnan, S Rajeev; Bebawy, Mary

    2017-02-06

    Breast cancer is the most frequently diagnosed cancer in women. Resident macrophages at distant sites provide a highly responsive and immunologically dynamic innate immune response against foreign infiltrates. Despite extensive characterization of the role of macrophages and other immune cells in malignant tissues, there is very little known about the mechanisms which facilitate metastatic breast cancer spread to distant sites of immunological integrity. The mechanisms by which a key healthy defense mechanism fails to protect distant sites from infiltration by metastatic cells in cancer patients remain undefined. Breast tumors, typical of many tumor types, shed membrane vesicles called microparticles (MPs), ranging in size from 0.1-1 μm in diameter. MPs serve as vectors in the intercellular transfer of functional proteins and nucleic acids and in drug sequestration. In addition, MPs are also emerging to be important players in the evasion of cancer cell immune surveillance. A comparative analysis of effects of MPs isolated from human breast cancer cells and non-malignant human brain endothelial cells were examined on THP-1 derived macrophages in vitro. MP-mediated effects on cell phenotype and functionality was assessed by cytokine analysis, cell chemotaxis and phagocytosis, immunolabelling, flow cytometry and confocal imaging. Student's t-test or a one-way analysis of variance (ANOVA) was used for comparison and statistical analysis. In this paper we report on the discovery of a new cellular basis for immune evasion, which is mediated by breast cancer derived MPs. MPs shed from multidrug resistant (MDR) cells were shown to selectively polarize macrophage cells to a functionally incapacitated state and facilitate their engulfment by foreign cells. We propose this mechanism may serve to physically disrupt the inherent immune response prior to cancer cell colonization whilst releasing mediators required for the recruitment of distant immune cells. These findings

  8. Involvement of CUL4A in Regulation of Multidrug Resistance to P-gp Substrate Drugs in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yunshan Wang

    2013-12-01

    Full Text Available CUL4A encodes a core component of a cullin-based E3 ubiquitin ligase complex that regulates many critical processes such as cell cycle progression, DNA replication, DNA repair and chromatin remodeling by targeting a variety of proteins for ubiquitination and degradation. In the research described in this report we aimed to clarify whether CUL4A participates in multiple drug resistance (MDR in breast cancer cells. We first transfected vectors carrying CUL4A and specific shCUL4A into breast cancer cells and corresponding Adr cells respectively. Using reverse transcription polymerase chain reactions and western blots, we found that overexpression of CUL4A in MCF7 and MDA-MB-468 cells up-regulated MDR1/P-gp expression on both the transcription and protein levels, which conferred multidrug resistance to P-gp substrate drugs, as determined by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assays. On the other hand, silencing CUL4A in MCF7/Adr and MDA-MB-468/Adr cells led to the opposite effect. Moreover, ERK1/2 in CUL4A-overexpressing cells was highly activated and after treatment with PD98059, an ERK1/2-specific inhibitor, CUL4A-induced expression of MDR1/P-gp was decreased significantly. Lastly, immunohistochemistry in breast cancer tissues showed that P-gp expression had a positive correlation with the expression of CUL4A and ERK1/2. Thus, these results implied that CUL4A and ERK1/2 participated in multi-drug resistance in breast cancer through regulation of MDR1/P-gp expression.

  9. Breast cancer screening

    Science.gov (United States)

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

  10. Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer.

    Science.gov (United States)

    Haricharan, Svasti; Punturi, Nindo; Singh, Purba; Holloway, Kimberly R; Anurag, Meenakshi; Schmelz, Jacob; Schmidt, Cheryl; Lei, Jonathan T; Suman, Vera; Hunt, Kelly; Olson, John A; Hoog, Jeremy; Li, Shunqiang; Huang, Shixia; Edwards, Dean P; Kavuri, Shyam M; Bainbridge, Matthew N; Ma, Cynthia X; Ellis, Matthew J

    2017-10-01

    Significant endocrine therapy-resistant tumor proliferation is present in ≥20% of estrogen receptor-positive (ER + ) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex ( MLH1/3 , PMS1/2 ), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER + breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER + breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. Significance: MutL deficiency in a subset of ER + primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy-resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168-83. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047 . ©2017 American Association for Cancer Research.

  11. The role of neratinib in HER2-driven breast cancer.

    Science.gov (United States)

    Cherian, Mathew A; Ma, Cynthia X

    2017-06-30

    Up to 25% of patients with early-stage HER2+ breast cancer relapse despite adjuvant trastuzumab-based regimens and virtually all patients with metastatic disease eventually die from resistance to existing treatment options. In addition, recent studies indicate that activating HER2 mutations without gene amplification could drive tumor growth in a subset of HER2-ve breast cancer that is not currently eligible for HER2-targeted agents. Neratinib is an irreversible HER kinase inhibitor with activity as extended adjuvant therapy following standard trastuzumab-based adjuvant treatment in a Phase III trial. Phase II trials of neratinib demonstrate promising activity in combination with cytotoxic agents in trastuzumab resistant metastatic HER2+ breast cancer, and either as monotherapy or in combination with fulvestrant for HER2-mutated breast cancers. We anticipate a potential role for neratinib in the therapy of these patient populations.

  12. Chapter 27 -- Breast Cancer Genomics, Section VI, Pathology and Biological Markers of Invasive Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Spellman, Paul T.; Heiser, Laura; Gray, Joe W.

    2009-06-18

    Breast cancer is predominantly a disease of the genome with cancers arising and progressing through accumulation of aberrations that alter the genome - by changing DNA sequence, copy number, and structure in ways that that contribute to diverse aspects of cancer pathophysiology. Classic examples of genomic events that contribute to breast cancer pathophysiology include inherited mutations in BRCA1, BRCA2, TP53, and CHK2 that contribute to the initiation of breast cancer, amplification of ERBB2 (formerly HER2) and mutations of elements of the PI3-kinase pathway that activate aspects of epidermal growth factor receptor (EGFR) signaling and deletion of CDKN2A/B that contributes to cell cycle deregulation and genome instability. It is now apparent that accumulation of these aberrations is a time-dependent process that accelerates with age. Although American women living to an age of 85 have a 1 in 8 chance of developing breast cancer, the incidence of cancer in women younger than 30 years is uncommon. This is consistent with a multistep cancer progression model whereby mutation and selection drive the tumor's development, analogous to traditional Darwinian evolution. In the case of cancer, the driving events are changes in sequence, copy number, and structure of DNA and alterations in chromatin structure or other epigenetic marks. Our understanding of the genetic, genomic, and epigenomic events that influence the development and progression of breast cancer is increasing at a remarkable rate through application of powerful analysis tools that enable genome-wide analysis of DNA sequence and structure, copy number, allelic loss, and epigenomic modification. Application of these techniques to elucidation of the nature and timing of these events is enriching our understanding of mechanisms that increase breast cancer susceptibility, enable tumor initiation and progression to metastatic disease, and determine therapeutic response or resistance. These studies also

  13. Break Breast Cancer Addiction by CRISPR/Cas9 Genome Editing.

    Science.gov (United States)

    Yang, Haitao; Jaeger, MariaLynn; Walker, Averi; Wei, Daniel; Leiker, Katie; Weitao, Tao

    2018-01-01

    Breast cancer is the leading diagnosed cancer for women globally. Evolution of breast cancer in tumorigenesis, metastasis and treatment resistance appears to be driven by the aberrant gene expression and protein degradation encoded by the cancer genomes. The uncontrolled cancer growth relies on these cellular events, thus constituting the cancerous programs and rendering the addiction towards them. These programs are likely the potential anticancer biomarkers for Personalized Medicine of breast cancer. This review intends to delineate the impact of the CRSPR/Cas-mediated genome editing in identification and validation of these anticancer biomarkers. It reviews the progress in three aspects of CRISPR/Cas9-mediated editing of the breast cancer genomes: Somatic genome editing, transcription and protein degradation addictions.

  14. Breast Cancer Overview

    Science.gov (United States)

    ... are here Home > Types of Cancer > Breast Cancer Breast Cancer This is Cancer.Net’s Guide to Breast Cancer. Use the menu below to choose the Overview/ ... social workers, and patient advocates. Cancer.Net Guide Breast Cancer Introduction Statistics Medical Illustrations Risk Factors and Prevention ...

  15. Breast Cancer -- Male

    Science.gov (United States)

    ... 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 ...

  16. Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics.

    Science.gov (United States)

    Sotgia, Federica; Fiorillo, Marco; Lisanti, Michael P

    2017-09-15

    Here, we used a data-mining and informatics approach to discover new biomarkers of resistance to hormonal therapy in breast cancer. More specifically, we investigated whether nuclear-encoded genes associated with mitochondrial biogenesis can be used to predict tumor recurrence, distant metastasis and treatment failure in high-risk breast cancer patients. Overall, this strategy allowed us to directly provide in silico validation of the prognostic value of these mitochondrial components in large and clinically relevant patient populations, with >15 years of follow-up data. For this purpose, we employed a group of 145 ER(+) luminal A breast cancer patients, with lymph-node (LN) metastasis at diagnosis, that were treated with tamoxifen, but not any chemotherapy agents. Using this approach, we identified >60 new individual mitochondrial biomarkers that predicted treatment failure and tumor recurrence, with hazard-ratios (HR) of up to 4.17 ( p =2.2e-07). These include mitochondrial chaperones (HSPD1, HSPA9), membrane proteins (VDAC2, TOMM70A) and anti-oxidants (SOD2), as well as 18 different mitochondrial ribosomal proteins (MRPs) and >20 distinct components of the OXPHOS complexes. In addition, we combined 4 mitochondrial proteins (HSPD1, UQCRB, MRPL15, COX17), to generate a compact mitochondrial gene signature, associated with a HR of 5.34 ( p =1e-09). This signature also successfully predicted distant metastasis and was effective in larger groups of ER(+) ( N =2,447), basal ( N =540) and HER2(+) ( N =193) breast cancers. It was also effective in all breast cancers ( N =3,180), if considered together as a single group. Based on this analysis, we conclude that mitochondrial biogenesis should be considered as a new therapeutic target for overcoming tumor recurrence, distant metastasis and treatment failure in patients with breast cancer. In summary, we identified individual mitochondrial biomarkers and 2 compact mitochondrial gene signatures that can be used to predict

  17. Association of ABCB1, β tubulin I, and III with multidrug resistance of MCF7/DOC subline from breast cancer cell line MCF7.

    Science.gov (United States)

    Li, Wentao; Zhai, Baoping; Zhi, Hui; Li, Yuhong; Jia, Linjiao; Ding, Chao; Zhang, Bin; You, Wei

    2014-09-01

    Docetaxel is a first-line chemotherapeutic agent for treating advanced breast cancer. The development of chemoresistance or multidrug resistance (MDR), however, results in breast cancer chemotherapy failure. This study aims to explore the molecular mechanisms underlying docetaxel-resistance in treatment of breast cancer. The docetaxel-resistant subline MCF7/DOC, derived from the parental sensitive breast cancer cell line MCF7, was established by intermittent exposure to moderate concentrations of docetaxel, followed by examination of its phenotypes. The MCF7/DOC subline showed cross resistance against paclitaxel, doxorubicin, methotrexate, and 5-Fu. Compared to the parental MCF7, MCF7/DOC cells were enlarged with heterogeneous sizes and a cobblestone and polygonal appearance. They were arrested at G2/M phase and proliferated slowly. The colony formation potential of MCF7/DOC in soft agar was significantly increased. MCF7/DOC cells showed reduced intracellular accumulation and increased efflux of rhodamine 123. The mRNA expression level of adenosine triphosphate binding cassette (ABC) transporter family, i.e., ABCB1, ABCC1, ABCC2, ABCG2, and β tubulin isotypes were characterized by quantitative PCR. High-level expression of ABCB1, βI, and βIII tubulin mRNA in MCF7/DOC was detected. Downregulation of ABCB1, βI, and βIII tubulin mediated by three combined siRNAs resulted in stronger growth inhibition of MCF7/DOC than inhibition of the expression of individual genes. ABCB1, βI, and βIII tubulin might contribute to the MDR of MCF7/DOC and be potential therapeutic targets for overcoming MDR of breast cancer.

  18. Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer.

    Science.gov (United States)

    Liu, Junjun; Chen, Xiaosong; Ward, Toby; Mao, Yan; Bockhorn, Jessica; Liu, Xiaofei; Wang, Gen; Pegram, Mark; Shen, Kunwei

    2016-02-01

    Acquired resistance to lapatinib, a human epidermal growth factor receptor 2 kinase inhibitor, remains a clinical problem for women with human epidermal growth factor receptor 2-positive advanced breast cancer, as metastasis is commonly observed in these patients. Niclosamide, an anti-helminthic agent, has recently been shown to exhibit cytotoxicity to tumor cells with stem-like characteristics. This study was designed to identify the mechanisms underlying lapatinib resistance and to determine whether niclosamide inhibits lapatinib resistance by reversing epithelial-mesenchymal transition. Here, two human epidermal growth factor receptor 2-positive breast cancer cell lines, SKBR3 and BT474, were exposed to increasing concentrations of lapatinib to establish lapatinib-resistant cultures. Lapatinib-resistant SKBR3 and BT474 cells exhibited up-regulation of the phenotypic epithelial-mesenchymal transition markers Snail, vimentin and α-smooth muscle actin, accompanied by activation of nuclear factor-кB and Src and a concomitant increase in stem cell marker expression (CD44(high)/CD24(low)), compared to naive lapatinib-sensitive SKBR3 and BT474 cells, respectively. Interestingly, niclosamide reversed epithelial-mesenchymal transition, induced apoptosis and inhibited cell growth by perturbing aberrant signaling pathway activation in lapatinib-resistant human epidermal growth factor receptor 2-positive cells. The ability of niclosamide to alleviate stem-like phenotype development and invasion was confirmed. Collectively, our results demonstrate that lapatinib resistance correlates with epithelial-mesenchymal transition and that niclosamide inhibits lapatinib-resistant cell viability and epithelial-mesenchymal transition. These findings suggest a role of niclosamide or derivatives optimized for more favorable bioavailability not only in reversing lapatinib resistance but also in reducing metastatic potential during the treatment of human epidermal growth factor receptor

  19. Connective tissue growth factor confers drug resistance in breast cancer through concomitant up-regulation of Bcl-xL and cIAP1.

    Science.gov (United States)

    Wang, Ming-Yang; Chen, Pai-Sheng; Prakash, Ekambaranellore; Hsu, Hsing-Chih; Huang, Hsin-Yi; Lin, Ming-Tsan; Chang, King-Jen; Kuo, Min-Liang

    2009-04-15

    Connective tissue growth factor (CTGF) expression is elevated in advanced breast cancer and promotes metastasis. Chemotherapy response is only transient in most metastatic diseases. In the present study, we examined whether CTGF expression could confer drug resistance in human breast cancer. In breast cancer patients who received neoadjuvant chemotherapy, CTGF expression was inversely associated with chemotherapy response. Overexpression of CTGF in MCF7 cells (MCF7/CTGF) enhanced clonogenic ability, cell viability, and resistance to apoptosis on exposure to doxorubicin and paclitaxel. Reducing the CTGF level in MDA-MB-231 (MDA231) cells by antisense CTGF cDNA (MDA231/AS cells) mitigated this drug resistance capacity. CTGF overexpression resulted in resistance to doxorubicin- and paclitaxel-induced apoptosis by up-regulation of Bcl-xL and cellular inhibitor of apoptosis protein 1 (cIAP1). Knockdown of Bcl-xL or cIAP1 with specific small interfering RNAs abolished the CTGF-mediated resistance to apoptosis induced by the chemotherapeutic agents in MCF7/CTGF cells. Inhibition of extracellular signal-regulated kinase (ERK)-1/2 effectively reversed the resistance to apoptosis as well as the up-regulation of Bcl-xL and cIAP1 in MCF7/CTGF cells. A neutralizing antibody against integrin alpha(v)beta(3) significantly attenuated CTGF-mediated ERK1/2 activation and up-regulation of Bcl-xL and cIAP1, indicating that the integrin alpha(v)beta(3)/ERK1/2 signaling pathway is essential for CTGF functions. The Bcl-xL level also correlated with the CTGF level in breast cancer patients. We also found that a COOH-terminal domain peptide from CTGF could exert activities similar to full-length CTGF, in activation of ERK1/2, up-regulation of Bcl-xL/cIAP1, and resistance to apoptosis. We conclude that CTGF expression could confer resistance to chemotherapeutic agents through augmenting a survival pathway through ERK1/2-dependent Bcl-xL/cIAP1 up-regulation.

  20. Resistance to discontinuing breast cancer screening in older women: A qualitative study.

    Science.gov (United States)

    Housten, Ashley J; Pappadis, Monique R; Krishnan, Shilpa; Weller, Susan C; Giordano, Sharon H; Bevers, Therese B; Volk, Robert J; Hoover, Diana S

    2018-06-01

    Screening mammography is associated with reduced breast cancer-specific mortality; however, among older women, evidence suggests that the potential harms of screening may outweigh the benefits. We used a qualitative approach to examine the willingness of older women from different racial/ethnic groups to discontinue breast cancer screening. Women ≥70 years of age who reported having a screening mammogram in the past 3 years and/or reported that they intended to continue screening in the future were recruited for in-depth interviews. Participants who intended to continue screening were asked to describe how the following hypothetical scenarios would impact a decision to discontinue screening: health concerns or limited life expectancy, a physician's recommendation to discontinue, reluctance to undergo treatment, and recommendations from experts or governmental panels to stop screening. Semi-structured, face-to-face interviews were audio-recorded. Data coding and analysis followed inductive and deductive approaches. Regardless of the scenario, participants (n = 29) expressed a strong intention to continue screening. Based on the hypothetical physician recommendations, intentions to continue screening appeared to remain strong. They did not envision a change in their health status that would lead them to discontinue screening and were skeptical of expert/government recommendations. There were no differences observed according to age, race/ethnicity, or education. Among older women who planned to continue screening, intentions to continue breast cancer screening appear to be highly resilient and resistant to recommendations from physicians or expert/government panels. Copyright © 2018 John Wiley & Sons, Ltd.

  1. Break Breast Cancer Addiction by CRISPR/Cas9 Genome Editing

    OpenAIRE

    Yang, Haitao; Jaeger, MariaLynn; Walker, Averi; Wei, Daniel; Leiker, Katie; Weitao, Tao

    2018-01-01

    Breast cancer is the leading diagnosed cancer for women globally. Evolution of breast cancer in tumorigenesis, metastasis and treatment resistance appears to be driven by the aberrant gene expression and protein degradation encoded by the cancer genomes. The uncontrolled cancer growth relies on these cellular events, thus constituting the cancerous programs and rendering the addiction towards them. These programs are likely the potential anticancer biomarkers for Personalized Medicine of brea...

  2. Breast Cancer Surgery

    Science.gov (United States)

    FACTS FOR LIFE Breast Cancer Surgery The goal of breast cancer surgery is to remove the whole tumor from the breast. Some lymph nodes ... might still be in the body. Types of breast cancer surgery There are two types of breast cancer ...

  3. Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells

    Science.gov (United States)

    Wang, Qiang; Jiang, Jun; Ying, Guoguang; Xie, Xiao-Qing; Zhang, Xia; Xu, Wei; Zhang, Xuemin; Song, Erwei; Bu, Hong; Ping, Yi-Fang; Yao, Xiao-Hong; Wang, Bin; Xu, Shilei; Yan, Ze-Xuan; Tai, Yanhong; Hu, Baoquan; Qi, Xiaowei; Wang, Yan-Xia; He, Zhi-Cheng; Wang, Yan; Wang, Ji Ming; Cui, You-Hong; Chen, Feng; Meng, Kun; Wang, Zhaoyi; Bian, Xiu-Wu

    2018-01-01

    The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer. PMID:29393296

  4. The Role of Interferon Regulatory Factor-1 (IRF1) in Overcoming Antiestrogen Resistance in the Treatment of Breast Cancer

    International Nuclear Information System (INIS)

    Schwartz, J.L.; Shajahan, A.N.; Clarke, R.

    2011-01-01

    Resistance to endocrine therapy is common among breast cancer patients with estrogen receptor alpha-positive (ER+) tumors and limits the success of this therapeutic strategy. While the mechanisms that regulate endocrine responsiveness and cell fate are not fully understood, interferon regulatory factor-1 (IRF1) is strongly implicated as a key regulatory node in the underlying signaling network. IRF1 is a tumor suppressor that mediates cell fate by facilitating apoptosis and can do so with or without functional p53. Expression of IRF1 is down regulated in endocrine-resistant breast cancer cells, protecting these cells from IRF1-induced inhibition of proliferation and/or induction of cell death. Nonetheless, when IRF1 expression is induced following IFN treatment, antiestrogen sensitivity is restored by a process that includes the inhibition of pro survival BCL2 family members and caspase activation. These data suggest that a combination of endocrine therapy and compounds that effectively induce IRF1 expression may be useful for the treatment of many ER+ breast cancers. By understanding IRF1 signaling in the context of endocrine responsiveness, we may be able to develop novel therapeutic strategies and better predict how patients will respond to endocrine therapy

  5. [Fibrocystic breast disease--breast cancer sequence].

    Science.gov (United States)

    Habor, V; Habor, A; Copotoiu, C; Panţîru, A

    2010-01-01

    Fibrocystic breast disease has developed a major issue: the breast cancer sequence. Its involvement regarding the increse of breast cancer risk has 2 aspects: it may be either the marker of a prone tissue or a premalignant hystological deffect. Difficult differential diagnosis of benign proliferative breast lession and carcinoma led to the idea of sequency between the two: cancer does not initiate on normal mammary epithelia; it takes several proliferative stages for it to occur. In our series we analized a number of 677 breast surgical procedures where the pathologic examination reveals 115 cases (17%) of coexistence between cancer and fibrocystic breast disease. This aspect has proved to be related to earlier debut of breast cancer, suggesting that epithelial hyperplasia is a risk factor for breast cancer.

  6. Mutation analysis of breast cancer gene BRCA among breast cancer Jordanian females

    International Nuclear Information System (INIS)

    Atoum, Manar F.; Al-Kayed, Sameer A.

    2004-01-01

    To screen mutations of the tumor suppressor breast cancer susceptibility gene 1 (BRCA1) within 3 exons among Jordanian breast cancer females. A total of 135 Jordanian breast cancer females were genetically analyzed by denaturing gradient electrophoresis (DGGE) for mutation detection in 3 BRCA1 exons (2, 11 and 20) between 2000-2002 in Al-Basheer Hospital, Amman, Jordan. Of the studied patients 50 had a family history of breast cancer, 28 had a family history of cancer other than breast cancer, and 57 had no family history of any cancer. Five germline mutations were detected among breast cancer females with a family history of breast cancers (one in exon 2 and 4 mutations in exon 11). Another germline mutation (within exon 11) was detected among breast cancer females with family history of cancer other than breast cancer, and no mutation was detected among breast cancer females with no family history of any cancer or among normal control females. Screening mutations within exon 2, exon 11 and exon 20 showed that most screened mutations were within BRCA1 exon 11 among breast cancer Jordanian families with a family history of breast cancer. (author)

  7. C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells.

    Science.gov (United States)

    Li, Wei; Xu, Ling; Che, Xiaofang; Li, Haizhou; Zhang, Ye; Song, Na; Wen, Ti; Hou, Kezuo; Yang, Yi; Zhou, Lu; Xin, Xing; Xu, Lu; Zeng, Xue; Shi, Sha; Liu, Yunpeng; Qu, Xiujuan; Teng, Yuee

    2018-05-02

    Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance. MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth. MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression. Our results suggested that c-Cbl can reverse tamoxifen

  8. 6 Common Cancers - Breast Cancer

    Science.gov (United States)

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

  9. New protein kinase inhibitors in breast cancer: afatinib and neratinib.

    Science.gov (United States)

    Zhang, Xiaosong; Munster, Pamela N

    2014-06-01

    Human epidermal growth factor receptor (HER) 2 is overexpressed in 20 - 25% of breast cancers, and has historically been a poor prognostic marker. The introduction of trastuzumab, the first fully humanized monoclonal antibody targeting HER2, has drastically changed the outcomes of metastatic breast cancers. However, despite initial response, most patients develop resistance. Recent data suggest that strategies targeting more than one member of HER family may circumvent trastuzumab resistance and confer synergistic effects. Following a literature search on PubMed, national meetings and clinicaltrials.gov using 'afatinib', 'neratinib', 'HER2' and 'breast cancer' as keywords, we critically analyzed the different HER2-targeted therapies for their drug development and evidence-based therapeutic strategies. Afatinib and neratinib, two second-generation tyrosine kinase inhibitors (TKIs) that irreversibly inhibit more than one HER family member, are being actively investigated in clinical trials either as monotherapy or in combination. We reviewed the efficacy and optimal use of these agents in various settings, such as systemic therapy for advanced breast cancer including brain metastases, and neoadjuvant therapy in early-stage breast cancer. HER2-targeted therapies have been widely used and greatly improved the outcome of HER2-positive breast cancer. Despite the accelerated advancement in recent years, several crucial questions remain unanswered, such as how to treat a prior resistance or affect a sanctuary site, that is, CNS metastasis. The novel next-generation TKIs, afatinib and neratinib, were rationally designed to overcome the resistance by targeting multiple HER family members and irreversibly binding the targets. In spite of the encouraging results of the afatinib and neratinib monotherapies, they have not been proven more efficacious in the combination therapies yet, even though multicenter international trials are still ongoing. The key tasks in the future are

  10. MCAM/CD146 promotes tamoxifen resistance in breast cancer cells through induction of epithelial-mesenchymal transition, decreased ER alpha expression and AKT activation

    NARCIS (Netherlands)

    Liang, Yuan-Ke; Zeng, De; Xiao, Ying-Sheng; Wu, Yang; Ouyang, Yan-Xiu; Chen, Min; Li, Yao-Chen; Lin, Hao-Yu; Wei, Xiao-Long; Zhang, Yong-Qu; Kruyt, Frank A. E.; Zhang, Guo-Jun

    2017-01-01

    Tamoxifen resistance presents a prominent clinical challenge in endocrine therapy for hormone sensitive breast cancer. However, the underlying mechanisms that contribute to tamoxifen resistance are not fully understood. In this study, we established a tamoxifen resistant MCF-7 cell line

  11. Metabolic Syndrome and Triple-Negative Breast Cancer: A New Paradigm

    International Nuclear Information System (INIS)

    Davis, A.A.; Kaklamani, V.G.

    2012-01-01

    Triple-negative breast cancers (TNBCs) are aggressive tumors with poor prognosis compared to other breast cancer subtypes. The evidence linking TNBC with the metabolic syndrome, which consists of central obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, has emerged from clinical studies and experiments using cell lines and mouse models. Epidemiological studies have associated abdominal obesity with increased incidence of TNBC. Additionally, insulin resistance, dyslipidemia, and hypertension are associated with increased incidence of breast cancer across all subtypes. The insulin-leptin-adiponectin axis has been implicated mechanistically in breast cancer tumorigenesis. Specifically, increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cell proliferation, survival, cell-cycle regulation, and angio genesis. Insulin, insulin-like growth factor I (IGF-I), and epidermal growth factor receptor (EGFR) may mediate interactions between these two hormones. Further research will facilitate the development of targeted therapeutics and programs to modify lifestyle factors to modulate the insulin-leptin-adiponectin axis for TNBC

  12. Metabolic Syndrome and Triple-Negative Breast Cancer: A New Paradigm

    Energy Technology Data Exchange (ETDEWEB)

    Davis, A A; Kaklamani, V G [Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 (Ukraine)

    2012-07-01

    Triple-negative breast cancers (TNBCs) are aggressive tumors with poor prognosis compared to other breast cancer subtypes. The evidence linking TNBC with the metabolic syndrome, which consists of central obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, has emerged from clinical studies and experiments using cell lines and mouse models. Epidemiological studies have associated abdominal obesity with increased incidence of TNBC. Additionally, insulin resistance, dyslipidemia, and hypertension are associated with increased incidence of breast cancer across all subtypes. The insulin-leptin-adiponectin axis has been implicated mechanistically in breast cancer tumorigenesis. Specifically, increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cell proliferation, survival, cell-cycle regulation, and angio genesis. Insulin, insulin-like growth factor I (IGF-I), and epidermal growth factor receptor (EGFR) may mediate interactions between these two hormones. Further research will facilitate the development of targeted therapeutics and programs to modify lifestyle factors to modulate the insulin-leptin-adiponectin axis for TNBC

  13. Breast cancer

    International Nuclear Information System (INIS)

    Tokunaga, Masayoshi

    1992-01-01

    More than 20-year follow-up of A-bomb survivors in Hiroshima and Nagasaki has a crucial role in determining the relationship of radiation to the occurrence of breast cancer. In 1967, Wanebo et al have first reported 27 cases of breast cancer during the period 1950-1966 among the Adult Health Study population of A-bomb survivors. Since then, follow-up surveys for breast cancer have been made using the Life Span Study (LSS) cohort, and the incidence of breast cancer has increased year by year; that is breast cancer was identified in 231 cases by the first LSS series (1950-1969), 360 cases by the second LSS series (1950-1974), 564 cases by the third LSS series (1950-1980), and 816 cases in the fourth LSS series (1950-1085). The third LSS series have revealed a high risk for radiation-induced breast cancer in women aged 10 or less at the time of exposure (ATE). Both relative and absolute risks are found to be decreased with increasing ages ATE. Based on the above-mentioned findings and other studies on persons exposed medical radiation, radiation-induced breast cancer is characterized by the following: (1) the incidence of breast cancer is linearly increased with increasing radiation doses; (2) both relative and absolute risks for breast cancer are high in younger persons ATE; (3) age distribution of breast cancer in proximally exposed A-bomb survivors is the same as that in both distally A-bomb survivors and non-exposed persons, and there is no difference in histology between the former and latter groups. Thus, immature mammary gland cells before the age of puberty are found to be most radiosensitive. (N.K.)

  14. Breast Cancer Immunotherapy

    Institute of Scientific and Technical Information of China (English)

    Juhua Zhou; Yin Zhong

    2004-01-01

    Breast cancer is a leading cause of cancer-related deaths in women worldwide. Although tumorectomy,radiotherapy, chemotherapy and hormone replacement therapy have been used for the treatment of breast cancer, there is no effective therapy for patients with invasive and metastatic breast cancer. Immunotherapy may be proved effective in treating patients with advanced breast cancer. Breast cancer immunotherapy includes antibody based immunotherapy, cancer vaccine immunotherapy, adoptive T cell transfer immunotherapy and T cell receptor gene transfer immunotherapy. Antibody based immunotherapy such as the monoclonal antibody against HER-2/neu (trastuzumab) is successfully used in the treatment of breast cancer patients with over-expressed HER-2/neu, however, HER-2/neu is over-expressed only in 25-30% of breast cancer patients. Cancer vaccine immunotherapy is a promising method to treat cancer patients. Cancer vaccines can be used to induce specific anti-tumor immunity in breast cancer patients, but cannot induce objective tumor regression. Adoptive T cell transfer immunotherapy is an effective method in the treatment of melanoma patients. Recent advances in anti-tumor T cell generation ex vivo and limited clinical trial data have made the feasibility of adoptive T cell transfer immunotherapy in the treatment of breast cancer patients. T cell receptor gene transfer can redirect the specificity of T cells. Chimeric receptor, scFv(anti-HER-2/neu)/zeta receptor, was successfully used to redirect cytotoxic T lymphocyte hybridoma cells to obtain anti-HER-2/neu positive tumor cells, suggesting the feasibility of treatment of breast cancer patients with T cell receptor gene transfer immunotherapy. Clinical trials will approve that immunotherapy is an effective method to cure breast cancer disease in the near future.

  15. Breast Cancer Immunotherapy

    Institute of Scientific and Technical Information of China (English)

    JuhuaZhou; YinZhong

    2004-01-01

    Breast cancer is a leading cause of cancer-related deaths in women worldwide. Although tumorectomy, radiotherapy, chemotherapy and hormone replacement therapy have been used for the treatment of breast cancer, there is no effective therapy for patients with invasive and metastatic breast cancer. Immunotherapy may be proved effective in treating patients with advanced breast cancer. Breast cancer immunotherapy includes antibody based immunotherapy, cancer vaccine immunotherapy, adoptive T cell transfer immunotherapy and T cell receptor gene transfer immunotherapy. Antibody based immunotherapy such as the monoclonal antibody against HER-2/neu (trastuzumab) is successfully used in the treatment of breast cancer patients with over-expressed HER-2/neu, however, HER-2/neu is over-expressed only in 25-30% of breast cancer patients. Cancer vaccine immunotherapy is a promising method to treat cancer patients. Cancer vaccines can be used to induce specific anti-tumor immunity in breast cancer patients, but cannot induce objective tumor regression. Adoptive T cell transfer immunotherapy is an effective method in the treatment of melanoma patients. Recent advances in anti-tumor T cell generation ex vivo and limited clinical trial data have made the feasibility of adoptive T cell transfer immunotherapy in the treatment of breast cancer patients. T cell receptor gene transfer can redirect the specificity of T cells. Chimeric receptor, scFv(anti-HER-2/neu)/zeta receptor, was successfully used to redirect cytotoxic T lymphocyte hybridoma cells to obtain anti-HER-2/neu positive tumor cells, suggesting the feasibility of treatment of breast cancer patients with T cell receptor gene transfer immunotherapy. Clinical trials will approve that immunotherapy is an effective method to cure breast cancer disease in the near future. Cellular & Molecular Immunology.

  16. Breast Cancer

    Science.gov (United States)

    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. ...

  17. BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Chandan Kanta Das

    2018-03-01

    Full Text Available Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC, and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6 of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549rDOX20 and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-468r5-FU2000 cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1. Furthermore, BAG3 depletion was able to revert the EMT-like transcriptional changes observed in BT-549rDOX20 and MDA-MB-468r5-FU2000 cells. In summary, genetic and pharmacological interference with BAG3 is capable to resensitize TNBC cells to treatment, underscoring its relevance for cell death resistance and as a target to overcome therapy resistance of breast cancer.

  18. BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells.

    Science.gov (United States)

    Das, Chandan Kanta; Linder, Benedikt; Bonn, Florian; Rothweiler, Florian; Dikic, Ivan; Michaelis, Martin; Cinatl, Jindrich; Mandal, Mahitosh; Kögel, Donat

    2018-03-01

    Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC), and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6) of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549 r DOX 20 ) and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-468 r 5-FU 2000 ) cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1. Furthermore, BAG3 depletion was able to revert the EMT-like transcriptional changes observed in BT-549 r DOX 20 and MDA-MB-468 r 5-FU 2000 cells. In summary, genetic and pharmacological interference with BAG3 is capable to resensitize TNBC cells to treatment, underscoring its relevance for cell death resistance and as a target to overcome therapy resistance of breast cancer. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Exosomal MicroRNA MiR-1246 Promotes Cell Proliferation, Invasion and Drug Resistance by Targeting CCNG2 in Breast Cancer.

    Science.gov (United States)

    Li, Xiu Juan; Ren, Zhao Jun; Tang, Jin Hai; Yu, Qiao

    2017-01-01

    Treatment of breast cancer remains a clinical challenge. This study aims to validate exosomal microRNA-1246 (miR-1246) as a serum biomarker for breast cancer and understand the underlying mechanism in breast cancer progression. The expression levels of endogenous and exosomal miRNAs were examined by real time PCR, and the expression level of the target protein was detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study their uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-1246 was estimated by invasion assay and cell viability assay. In this study, we demonstrate that exosomes carrying microRNA can be transferred among different cell lines through direct uptake. miR-1246 is highly expressed in metastatic breast cancer MDA-MB-231 cells compared to non-metastatic breast cancer cells or non-malignant breast cells. Moreover, miR-1246 can suppress the expression level of its target gene, Cyclin-G2 (CCNG2), indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could enhance the viability, migration and chemotherapy resistance of non-malignant HMLE cells. Together, our results support an important role of exosomes and exosomal miRNAs in regulating breast tumor progression, which highlights their potential for applications in miRNA-based therapeutics. © 2017 The Author(s). Published by S. Karger AG, Basel.

  20. Exosomal MicroRNA MiR-1246 Promotes Cell Proliferation, Invasion and Drug Resistance by Targeting CCNG2 in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Xiu Juan Li

    2017-12-01

    Full Text Available Background/Aims: Treatment of breast cancer remains a clinical challenge. This study aims to validate exosomal microRNA-1246 (miR-1246 as a serum biomarker for breast cancer and understand the underlying mechanism in breast cancer progression. Methods: The expression levels of endogenous and exosomal miRNAs were examined by real time PCR, and the expression level of the target protein was detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study their uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-1246 was estimated by invasion assay and cell viability assay. Results: In this study, we demonstrate that exosomes carrying microRNA can be transferred among different cell lines through direct uptake. miR-1246 is highly expressed in metastatic breast cancer MDA-MB-231 cells compared to non-metastatic breast cancer cells or non-malignant breast cells. Moreover, miR-1246 can suppress the expression level of its target gene, Cyclin-G2 (CCNG2, indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could enhance the viability, migration and chemotherapy resistance of non-malignant HMLE cells. Conclusions: Together, our results support an important role of exosomes and exosomal miRNAs in regulating breast tumor progression, which highlights their potential for applications in miRNA-based therapeutics.

  1. HDAC2 and HDAC5 Up-Regulations Modulate Survivin and miR-125a-5p Expressions and Promote Hormone Therapy Resistance in Estrogen Receptor Positive Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Wen-Tsung Huang

    2017-12-01

    Full Text Available Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+ breast cancer patients. Even though dysregulations of histone deacetylases (HDACs are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan–Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

  2. The antipsychotic drug chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-sensitive and tamoxifen-resistant human breast cancer cells

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Clausen, Mathias Porsmose; Bennetzen, Martin

    2009-01-01

    , the compound is now also recognized as a multitargeting drug with diverse potential applications, for example, it has antiproliferative properties and it can reverse resistance toward antibiotics in bacteria. Furthermore, chlorpromazine can reverse multidrug resistance caused by overexpression of P......Tamoxifen resistance is a major clinical problem in the treatment of estrogen receptor a-positive breast tumors. It is, at present, unclear what exactly causes tamoxifen resistance. For decades, chlorpromazine has been used for treating psychotic diseases, such as schizophrenia. However......-sensitive breast cancer cell line, MCF-7, and in a tamoxifen-resistant cell line, established from the MCF-7 cells. Tamoxifen-sensitive and tamoxifen-resistant cells were killed equally well by combined treatment with chlorpromazine and tamoxifen. This synergistic effect could be prevented by addition of estrogen...

  3. The cellular uptake mechanism, intracellular transportation, and exocytosis of polyamidoamine dendrimers in multidrug-resistant breast cancer cells.

    Science.gov (United States)

    Zhang, Jie; Liu, Dan; Zhang, Mengjun; Sun, Yuqi; Zhang, Xiaojun; Guan, Guannan; Zhao, Xiuli; Qiao, Mingxi; Chen, Dawei; Hu, Haiyang

    2016-01-01

    Polyamidoamine dendrimers, which can deliver drugs and genetic materials to resistant cells, are attracting increased research attention, but their transportation behavior in resistant cells remains unclear. In this paper, we performed a systematic analysis of the cellular uptake, intracellular transportation, and efflux of PAMAM-NH2 dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) using sensitive breast cancer cells (MCF-7 cells) as the control. We found that the uptake rate of PAMAM-NH2 was much lower and exocytosis of PAMAM-NH2 was much greater in MCF-7/ADR cells than in MCF-7 cells due to the elimination of PAMAM-NH2 from P-glycoprotein and the multidrug resistance-associated protein in MCF-7/ADR cells. Macropinocytosis played a more important role in its uptake in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH2 aggregated and became more degraded in the lysosomal vesicles of the MCF-7/ADR cells than in those of the MCF-7 cells. The endoplasmic reticulum and Golgi complex were found to participate in the exocytosis rather than endocytosis process of PAMAM-NH2 in both types of cells. Our findings clearly showed the intracellular transportation process of PAMAM-NH2 in MCF-7/ADR cells and provided a guide of using PAMAM-NH2 as a drug and gene vector in resistant cells.

  4. Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer.

    Science.gov (United States)

    Wong, Hilda; Leung, Roland; Kwong, Ava; Chiu, Joanne; Liang, Raymond; Swanton, Charles; Yau, Thomas

    2011-01-01

    Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.

  5. Stages of Breast Cancer

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Treatment (PDQ®)–Patient Version General Information About Breast Cancer Go to Health Professional Version Key Points Breast ...

  6. Rhein Induces Apoptosis in Human Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ching-Yao Chang

    2012-01-01

    Full Text Available Human breast cancers cells overexpressing HER2/neu are more aggressive tumors with poor prognosis, and resistance to chemotherapy. This study investigates antiproliferation effects of anthraquinone derivatives of rhubarb root on human breast cancer cells. Of 7 anthraquinone derivatives, only rhein showed antiproliferative and apoptotic effects on both HER2-overexpressing MCF-7 (MCF-7/HER2 and control vector MCF-7 (MCF-7/VEC cells. Rhein induced dose- and time-dependent manners increase in caspase-9-mediated apoptosis correlating with activation of ROS-mediated activation of NF-κB- and p53-signaling pathways in both cell types. Therefore, this study highlighted rhein as processing anti-proliferative activity against HER2 overexpression or HER2-basal expression in breast cancer cells and playing important roles in apoptotic induction of human breast cancer cells.

  7. A unifying biology of sex steroid-induced apoptosis in prostate and breast cancers

    Science.gov (United States)

    Abderrahman, Balkees; Curpan, Ramona F; Hawsawi, Yousef M; Fan, Ping; Jordan, V Craig

    2018-01-01

    Prostate and breast cancer are the two cancers with the highest incidence in men and women, respectively. Here, we focus on the known biology of acquired resistance to antihormone therapy of prostate and breast cancer and compare laboratory and clinical similarities in the evolution of the disease. Laboratory studies and clinical observations in prostate and breast cancer demonstrate that cell selection pathways occur during acquired resistance to antihormonal therapy. Following sex steroid deprivation, both prostate and breast cancer models show an initial increased acquired sensitivity to the growth potential of sex steroids. Subsequently, prostate and breast cancer cells either become dependent upon the antihormone treatment or grow spontaneously in the absence of hormones. Paradoxically, the physiologic sex steroids now kill a proportion of selected, but vulnerable, resistant tumor cells. The sex steroid receptor complex triggers apoptosis. We draw parallels between acquired resistance in prostate and breast cancer to sex steroid deprivation. Clinical observations and patient trials confirm the veracity of the laboratory studies. We consider therapeutic strategies to increase response rates in clinical trials of metastatic disease that can subsequently be applied as a preemptive salvage adjuvant therapy. The goal of future advances is to enhance response rates and deploy a safe strategy earlier in the treatment plan to save lives. The introduction of a simple evidence-based enhanced adjuvant therapy as a global healthcare strategy has the potential to control recurrence, reduce hospitalization, reduce healthcare costs and maintain a healthier population that contributes to society. PMID:29162647

  8. A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells

    DEFF Research Database (Denmark)

    Thrane, S; Pedersen, A M; Thomsen, M B H

    2015-01-01

    Antiestrogen resistance is a major problem in breast cancer treatment. Therefore, the search for new therapeutic targets and biomarkers for antiestrogen resistance is crucial. In this study, we performed a kinase inhibitor screen on antiestrogen responsive MCF-7 cells and a panel of MCF-7-derived...

  9. Effects of Aerobic and Resistance Exercise on Metabolic Syndrome, Sarcopenic Obesity, and Circulating Biomarkers in Overweight or Obese Survivors of Breast Cancer: A Randomized Controlled Trial.

    Science.gov (United States)

    Dieli-Conwright, Christina M; Courneya, Kerry S; Demark-Wahnefried, Wendy; Sami, Nathalie; Lee, Kyuwan; Buchanan, Thomas A; Spicer, Darcy V; Tripathy, Debu; Bernstein, Leslie; Mortimer, Joanne E

    2018-03-20

    Purpose Metabolic syndrome is associated with an increased risk of cardiovascular disease, type 2 diabetes, and breast cancer recurrence in survivors of breast cancer. This randomized controlled trial assessed the effects of a 16-week combined aerobic and resistance exercise intervention on metabolic syndrome, sarcopenic obesity, and serum biomarkers among ethnically diverse, sedentary, overweight, or obese survivors of breast cancer. Methods Eligible survivors of breast cancer (N = 100) were randomly assigned to exercise (n = 50) or usual care (n = 50). The exercise group participated in supervised moderate-to-vigorous-65% to 85% of heart rate maximum-aerobic and resistance exercise three times per week for 16 weeks. Metabolic syndrome z-score (primary outcome), sarcopenic obesity, and serum biomarkers were measured at baseline, postintervention (4 months), and 3-month follow-up (exercise only). Results Participants were age 53 ± 10.4 years, 46% were obese, and 74% were ethnic minorities. Adherence to the intervention was 95%, and postintervention assessments were available in 91% of participants. Postintervention metabolic syndrome z-score was significantly improved in exercise versus usual care (between-group difference, -4.4; 95% CI, -5.9 to -2.7; P metabolic syndrome variables remained significantly improved compared with baseline in the exercise group ( P exercise effectively attenuated metabolic syndrome, sarcopenic obesity, and relevant biomarkers in an ethnically diverse sample of sedentary, overweight, or obese survivors of breast cancer. Our findings suggest a targeted exercise prescription for improving metabolic syndrome in survivors of breast cancer and support the incorporation of supervised clinical exercise programs into breast cancer treatment and survivorship care plans.

  10. Comparing exercise responses to aerobic plus resistance training between postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy and healthy women.

    Science.gov (United States)

    Paulo, Thais R S de; Winters-Stone, Kerri M; Viezel, Juliana; Rossi, Fabricio E; Aro, Bruna L; Trindade, Ana Carolina A C; Codogno, Jamile S; Freitas Junior, Ismael F

    2018-04-12

    The aim of this study was to explore whether postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy differ from healthy postmenopausal women in their response to the same aerobic + resistance training. The participants were separated into two groups: postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy for an average of 20 months (18 women) and healthy postmenopausal women (24 women). We assessed aerobic capacity (predicted maximum oxygen uptake (VO 2 max) and maximum running velocity test (Vmax)) through a walking test, upper and lower body muscle strength using an estimated one-repetition maximum test, and body composition by dual-energy X-ray absorptiometry at baseline and at three, six, and nine months, respectively. The exercise program was performed three times/week over nine months and consisted of 40 min of machine-based strength training (seated cable row, bench press, leg extension, leg press, and leg curl, as well as bridge, abdominal, and standard plank exercises) followed by 30 min of treadmill walking. Analysis of variance (ANOVA) with repeated measures was used to compare the groups over time. Postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy and healthy postmenopausal women presented similar improvements in estimated lower body strength, predicted VO 2max and V max , and body fat mass. For maximal upper body strength, there was a significant group x time interaction after six months of training (p = 0.01). The healthy postmenopausal women presented a significant increase in upper body strength after six months, while postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy demonstrated an improvement only at nine months of training. The breast cancer survivors undergoing aromatase inhibitor therapy presented increased lean mass while healthy postmenopausal women maintained values over time (Breast cancer: 33.7 ± 3.9(Pre) vs. 34.1

  11. AIB1 is required for the acquisition of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer cells

    International Nuclear Information System (INIS)

    Zhao Wenhui; Zhang Qingyuan; Kang Xinmei; Jin Shi; Lou Changjie

    2009-01-01

    Acquired resistance to tamoxifen has become a serious obstacle in breast cancer treatment. The underlying mechanism responsible for this condition has not been completely elucidated. In this study, a tamoxifen-resistant (Tam-R) MCF-7 breast cancer cell line was developed to mimic the occurrence of acquired tamoxifen resistance as seen in clinical practice. Increased expression levels of HER1, HER2 and the estrogen receptor (ER)-AIB1 complex were found in tamoxifen-resistant cells. EGF stimulation and gefitinib inhibition experiments further demonstrated that HER1/HER2 signaling and AIB1 were involved in the proliferation of cells that had acquired Tam resistance. However, when AIB1 was silenced with AIB1-siRNA in Tam-R cells, the cell growth stimulated by the HER1/HER2 signaling pathway was significantly reduced, and the cells were again found to be inhibited by tamoxifen. These results suggest that the AIB1 protein could be a limiting factor in the HER1/HER2-mediated hormone-independent growth of Tam-R cells. Thus, AIB1 may be a new therapeutic target, and the removal of AIB1 may decrease the crosstalk between ER and the HER1/HER2 pathway, resulting in the restoration of tamoxifen sensitivity in tamoxifen-resistant cells.

  12. Breast cancer

    Science.gov (United States)

    ... can help you know how to prevent breast cancer. Breast implants, using antiperspirants, and wearing underwire bras do not increase the risk for breast cancer. There is also no evidence of a direct ...

  13. An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.

    Science.gov (United States)

    Hanker, Ariella B; Brewer, Monica Red; Sheehan, Jonathan H; Koch, James P; Sliwoski, Gregory R; Nagy, Rebecca; Lanman, Richard; Berger, Michael F; Hyman, David M; Solit, David B; He, Jie; Miller, Vincent; Cutler, Richard E; Lalani, Alshad S; Cross, Darren; Lovly, Christine M; Meiler, Jens; Arteaga, Carlos L

    2017-06-01

    We report a HER2 T798I gatekeeper mutation in a patient with HER2 L869R -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2 L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3 E928G , also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2 T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 L869R but not HER2 L869R/T798I In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2 L869R/T798I -induced signaling and cell growth. Acquisition of HER2 T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2 L869R is a driver mutation. HER2 T798I -mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2 -mutant breast cancer upon clinical progression on neratinib. We speculate that HER2 T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2 -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575-85. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

  14. Breast Cancer: Treatment Options

    Science.gov (United States)

    ... Breast Cancer > Breast Cancer: Treatment Options Request Permissions Breast Cancer: Treatment Options Approved by the Cancer.Net Editorial ... can be addressed as quickly as possible. Recurrent breast cancer If the cancer does return after treatment for ...

  15. Common breast cancer susceptibility loci are associated with triple negative breast cancer

    Science.gov (United States)

    Stevens, Kristen N.; Vachon, Celine M.; Lee, Adam M.; Slager, Susan; Lesnick, Timothy; Olswold, Curtis; Fasching, Peter A.; Miron, Penelope; Eccles, Diana; Carpenter, Jane E.; Godwin, Andrew K.; Ambrosone, Christine; Winqvist, Robert; Schmidt, Marjanka K.; Cox, Angela; Cross, Simon S.; Sawyer, Elinor; Hartmann, Arndt; Beckmann, Matthias W.; Schulz-Wendtland, Rüdiger; Ekici, Arif B.; Tapper, William J; Gerty, Susan M; Durcan, Lorraine; Graham, Nikki; Hein, Rebecca; Nickels, Stephan; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Hans-Peter; Konstantopoulou, Irene; Fostira, Florentia; Pectasides, Dimitrios; Dimopoulos, Athanasios M.; Fountzilas, George; Clarke, Christine L.; Balleine, Rosemary; Olson, Janet E.; Fredericksen, Zachary; Diasio, Robert B.; Pathak, Harsh; Ross, Eric; Weaver, JoEllen; Rüdiger, Thomas; Försti, Asta; Dünnebier, Thomas; Ademuyiwa, Foluso; Kulkarni, Swati; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Ko, Yon-Dschun; Van Limbergen, Erik; Janssen, Hilde; Peto, Julian; Fletcher, Olivia; Giles, Graham G.; Baglietto, Laura; Verhoef, Senno; Tomlinson, Ian; Kosma, Veli-Matti; Beesley, Jonathan; Greco, Dario; Blomqvist, Carl; Irwanto, Astrid; Liu, Jianjun; Blows, Fiona M.; Dawson, Sarah-Jane; Margolin, Sara; Mannermaa, Arto; Martin, Nicholas G.; Montgomery, Grant W; Lambrechts, Diether; dos Santos Silva, Isabel; Severi, Gianluca; Hamann, Ute; Pharoah, Paul; Easton, Douglas F.; Chang-Claude, Jenny; Yannoukakos, Drakoulis; Nevanlinna, Heli; Wang, Xianshu; Couch, Fergus J.

    2012-01-01

    Triple negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiological factors which promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome wide association studies (GWAS) display heterogeneity of effect among breast cancer subtypes as defined by estrogen receptor (ER) and progesterone receptor (PR) status. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple negative breast cancer and 4,978 healthy controls. We identified six single nucleotide polymorphisms (SNPs) significantly associated with risk of triple negative breast cancer, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.11) and rs8100241 (19p13.11). Together, our results provide convincing evidence of genetic susceptibility for triple negative breast cancer. PMID:21844186

  16. Breast Cancer Screening

    International Nuclear Information System (INIS)

    Altaf, Fadwa J.

    2004-01-01

    Breast cancer is a very common health problem in Saudi females that can be reduced by early detection through introducing breast cancer screening. Literature review reveals significant reduction in breast cancer incidence and outcome after the beginning of breast cancer screening. The objectives of this article are to highlight the significance of breast cancer screening in different international societies and to write the major guidelines of breast cancer screening in relation to other departments involved with more emphasis on the Pathology Department guidelines in tissue handling, diagnostic criteria and significance of the diagnosis. This article summaries and acknowledges major work carried out before, and recommends similar modified work in order to meet the requirement for the Saudi society. (author)

  17. TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells

    DEFF Research Database (Denmark)

    Hekmat, Omid; Munk, Stephanie; Fogh, Louise

    2013-01-01

    may explain the resistance phenotype to topoisomerase inhibitors that was observed in cells with high TIMP-1 levels. Pathway analysis showed an enrichment of proteins from functional categories such as apoptosis, cell cycle, DNA repair, transcription factors, drug targets and proteins associated......Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a protein with a potential biological role in drug resistance. To elucidate the unknown molecular mechanisms underlying the association between high TIMP-1 levels and increased chemotherapy resistance, we employed SILAC-based quantitative mass...... spectrometry to analyze global proteome and phosphoproteome differences of MCF-7 breast cancer cells expressing high or low levels of TIMP-1. In TIMP-1 high expressing cells, 312 proteins and 452 phosphorylation sites were up-regulated. Among these were the cancer drug targets topoisomerase 1, 2A and 2B, which...

  18. The breast cancer resistance protein transporter ABCG2 is expressed in the human kidney proximal tubule apical membrane.

    NARCIS (Netherlands)

    Huls, M.; Brown, C.D.; Windass, A.S.; Sayer, R.; Heuvel, J.J.M.W. van den; Heemskerk, S.; Russel, F.G.M.; Masereeuw, R.

    2008-01-01

    The Breast Cancer Resistance Protein (BCRP/ABCG2) is a transporter restricting absorption and enhancing excretion of many compounds including anticancer drugs. This transporter is highly expressed in many tissues; however, in human kidney, only the mRNA was found in contrast to the mouse kidney,

  19. BIM-EL localization: The key to understanding anoikis resistance in inflammatory breast cancer cells.

    Science.gov (United States)

    Buchheit, Cassandra L; Schafer, Zachary T

    2016-01-01

    Inflammatory breast cancer (IBC) is a highly metastatic and rare type of breast cancer, accounting for 2-6% of newly diagnosed breast cancer cases each year. The highly metastatic nature of IBC cells remains poorly understood. Here we describe our recent data regarding the ability of IBC cells to overcome anoikis.

  20. Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry.

    Directory of Open Access Journals (Sweden)

    Cameron M Scott

    Full Text Available DNA methylation can mimic the effects of both germline and somatic mutations for cancer predisposition genes such as BRCA1 and p16INK4a. Constitutional DNA methylation of the BRCA1 promoter has been well described and is associated with an increased risk of early-onset breast cancers that have BRCA1-mutation associated histological features. The role of methylation in the context of other breast cancer predisposition genes has been less well studied and often with conflicting or ambiguous outcomes. We examined the role of methylation in known breast cancer susceptibility genes in breast cancer predisposition and tumor development. We applied the Infinium HumanMethylation450 Beadchip (HM450K array to blood and tumor-derived DNA from 43 women diagnosed with breast cancer before the age of 40 years and measured the methylation profiles across promoter regions of BRCA1, BRCA2, ATM, PALB2, CDH1, TP53, FANCM, CHEK2, MLH1, MSH2, MSH6 and PMS2. Prior genetic testing had demonstrated that these women did not carry a germline mutation in BRCA1, ATM, CHEK2, PALB2, TP53, BRCA2, CDH1 or FANCM. In addition to the BRCA1 promoter region, this work identified regions with variable methylation at multiple breast cancer susceptibility genes including PALB2 and MLH1. Methylation at the region of MLH1 in these breast cancers was not associated with microsatellite instability. This work informs future studies of the role of methylation in breast cancer susceptibility gene silencing.

  1. Exercise after breast cancer treatment: current perspectives

    Directory of Open Access Journals (Sweden)

    Dieli-Conwright CM

    2015-10-01

    Full Text Available Christina M Dieli-Conwright, Breanna Z Orozco Division of Biokinesiology and Physical Therapy, Women's Health and Exercise Laboratory, University of Southern California, Los Angeles, CA, USA Abstract: Over the past 2 decades, great strides have been made in the field of exercise-oncology research, particularly with breast cancer. This area of research is particularly important since there are >2.8 million breast cancer survivors who are in need of an intervention that can offset treatment-related side effects. Noticeable reductions in physical fitness (ie, cardiopulmonary fitness and muscular strength, negative changes in body composition (ie, increase in body mass, decrease in lean body mass, and increase in fat mass, increased fatigue, depression, or anxiety are some of the common side effects of cancer treatments that negatively impact overall quality of life and increase the risk for the development of comorbidities. Exercise plays a vital role in improving cardiopulmonary function, psychological events, muscular strength, and endurance in breast cancer survivors, and thus should be considered as a key factor of lifestyle intervention to reverse negative treatment-related side effects. The purpose of this review is to address current perspectives on the benefits of aerobic and resistance exercise after breast cancer treatments. This review is focused on the well-established benefits of exercise on physical and emotional well-being, bone health, lymphedema management, and the postulated benefits of exercise on risk reduction for recurrence of breast cancer. Keywords: breast cancer, exercise, physical well-being

  2. The expression and significance of multi-drug resistance genes in breast cancer stem cells%乳腺癌干细胞多药耐药基因的表达及意义

    Institute of Scientific and Technical Information of China (English)

    Zhi Li; Chunping Liu; Yanli He; Jinghui Zhang; Tao Huang

    2008-01-01

    Objective:To approach the expressions of MDR1 and BCRP in breast cancer stem cells and differentiated cells.Methods:The breast cancer stem calls were separated from human breast cancer primary tissues and MCF-7 by flow cytometry.Then we measured the expressions of MDR1 and BCRP with different subset cells by Realtime-PCR.Results:Contrasted with breast cancer differentiated cells,the expressions of MDR1 and BCRP in breast cancer stem calls were higher (P<0.01),and the proportion of stem cells rose after chemotherapy (P<0.01).Conclusion:Contrasted with breast cancer differentiated cells,breast cancer stem cells have stronger ability of clrug-resistanca with higher level of multi-drug resistance genes,and it is one of key points for chemotherapy failure of breast cancer.

  3. Comprehensive profiling of DNA repair defects in breast cancer identifies a novel class of endocrine therapy resistance drivers.

    Science.gov (United States)

    Anurag, Meenakshi; Punturi, Nindo; Hoog, Jeremy; Bainbridge, Matthew N; Ellis, Matthew J; Haricharan, Svasti

    2018-05-23

    This study was undertaken to conduct a comprehensive investigation of the role of DNA damage repair (DDR) defects in poor outcome ER+ disease. Expression and mutational status of DDR genes in ER+ breast tumors were correlated with proliferative response in neoadjuvant aromatase inhibitor therapy trials (discovery data set), with outcomes in METABRIC, TCGA and Loi data sets (validation data sets), and in patient derived xenografts. A causal relationship between candidate DDR genes and endocrine treatment response, and the underlying mechanism, was then tested in ER+ breast cancer cell lines. Correlations between loss of expression of three genes: CETN2 (p<0.001) and ERCC1 (p=0.01) from the nucleotide excision repair (NER) and NEIL2 (p=0.04) from the base excision repair (BER) pathways were associated with endocrine treatment resistance in discovery data sets, and subsequently validated in independent patient cohorts. Complementary mutation analysis supported associations between mutations in NER and BER pathways and reduced endocrine treatment response. A causal role for CETN2, NEIL2 and ERCC1 loss in intrinsic endocrine resistance was experimentally validated in ER+ breast cancer cell lines, and in ER+ patient-derived xenograft models. Loss of CETN2, NEIL2 or ERCC1 induced endocrine treatment response by dysregulating G1/S transition, and therefore, increased sensitivity to CDK4/6 inhibitors. A combined DDR signature score was developed that predicted poor outcome in multiple patient cohorts. This report identifies DDR defects as a new class of endocrine treatment resistance drivers and indicates new avenues for predicting efficacy of CDK4/6 inhibition in the adjuvant treatment setting. Copyright ©2018, American Association for Cancer Research.

  4. Inheritance of proliferative breast disease in breast cancer kindreds

    International Nuclear Information System (INIS)

    Skolnick, M.H.; Cannon-Albright, L.A.; Goldgar, D.E.; Ward, J.H.; Marshall, C.J.; Schumann, G.B.; Hogle, H.; McWhorter, W.P.; Wright, E.C.; Tran, T.D.; Bishop, D.T.; Kushner, J.P.; Eyre, H.J.

    1990-01-01

    Previous studies have emphasized that genetic susceptibility to breast cancer is rare and is expressed primarily as premenopausal breast cancer, bilateral breast cancer, or both. Proliferative breast disease (PBD) is a significant risk factor for the development of breast cancer and appears to be a precursor lesion. PBD and breast cancer were studied in 103 women from 20 kindreds that were selected for the presence of two first degree relatives with breast cancer and in 31 control women. Physical examination, screening mammography, and four-quadrant fine-needle breast aspirates were performed. Cytologic analysis of breast aspirates revealed PBD in 35% of clinically normal female first degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggests that genetic susceptibility causes both PBD and breast cancer in these kindreds. This study supports the hypothesis that this susceptibility is responsible for a considerable portion of breast cancer, including unilateral and postmenopausal breast cancer

  5. Autophagy in breast cancer and its implications for therapy

    Science.gov (United States)

    Jain, Kirti; Paranandi, Krishna S; Sridharan, Savitha; Basu, Alakananda

    2013-01-01

    Autophagy is an evolutionarily conserved process of cellular self-digestion that serves as a mechanism to clear damaged organelles and recycle nutrients. Since autophagy can promote cell survival as well as cell death, it has been linked to different human pathologies, including cancer. Although mono-allelic deletion of autophagy-related gene BECN1 in breast tumors originally indicated a tumor suppressive role for autophagy in breast cancer, the intense research during the last decade suggests a role for autophagy in tumor progression. It is now recognized that tumor cells often utilize autophagy to survive various stresses, such as oncogene-induced transformation, hypoxia, endoplasmic reticulum (ER) stress and extracellular matrix detachment. Induction of autophagy by tumor cells may also contribute to tumor dormancy and resistance to anticancer therapies, thus making autophagy inhibitors promising drug candidates for breast cancer treatment. The scientific endeavors continue to define a precise role for autophagy in breast cancer. In this article, we review the current literature on the role of autophagy during the development and progression of breast cancer, and discuss the potential of autophagy modulators for breast cancer treatment. PMID:23841025

  6. Male Breast Cancer

    Science.gov (United States)

    ... types of breast cancer that can occur in men include Paget's disease of the nipple and inflammatory breast cancer. Inherited genes that increase breast cancer risk Some men inherit abnormal (mutated) genes from their parents that ...

  7. E-cadherin and Vimentin as Predictors of Resistance to Preoperative Systemic Therapy in Patients with Advanced Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sonar. S. Panigoro

    2017-01-01

    Full Text Available Loss of E-cadherin and increased vimentin expression are associated with epithelial-mesenchymal transition andcancer stemness which are responsible for treatment resistance. The study aims to evaluate the role of E-cadherin andvimentin as predictors of resistance to preoperative systemic therapy in patients with advanced breast cancer. This wasa cross-sectional analytical study in patients with stage III-IV breast cancer in Dharmais Cancer Hospital and dr. CiptoMangunkusumo National Hospital from July 2015 to April 2016. Patients had biopsy specimens embedded in paraffinblocks. Expressions of E-cadherin and vimentin proteins were done immunohistochemically. Treatment response wasevaluated histopathologically using Miller-Payne criteria on mastectomy specimens. A total of 65 patients were enrolled.Five patients with invasive lobular carcinoma were excluded. Thirty one had chemotherapy and 29 had hormonaltherapy. After treatment, 46 patients were eligible for mastectomy. E-cadherin and vimentin were positive in 28 (60.9%and 11 (20.3% of specimens. Twenty-three (50% patients showed no response. Treatment resistance were associatedwith type of therapy (OR=4.4; 95% CI=1.27-15.41; p=0.017 and vimentin expression (OR=6.75; 95% CI=1.27-30.02;p=0.016. Hormonal therapy (ORadj=6.26; 95%CI=1.59-24.6; p=0.009 and positive vimentin (ORadj=8.75; 95%CI=1.43-57.4; p=0.019 were independent predictors of treatment resistance. In conclusion, E-cadherin and vimentin can beused as predictors of resistance to preoperative systemic therapy in patients with advanced breast cancer. Keywords: breast cancer, cancer stemness, E-cadherin, preoperative therapy, vimentin.   Peran E-cadherin dan Vimentin sebagai Prediktor Resistensi Terapi Sistemik Preoperatif pada Pasien Kanker Payudara Stadium Lanjut Abstrak Hilangnya ekspresi E-cadherin dan meningkatnya ekspresi vimentin dihubungkan dengan epithelial-mesenchymaltransition dan cancer stemness yang bertanggungjawab terhadap

  8. Inflammatory Breast Cancer

    Science.gov (United States)

    ... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... white women. Inflammatory breast tumors are frequently hormone receptor negative, which means they cannot be treated with ...

  9. Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Hao; Li, Ying [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Wang, Yuzhong [Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079 (China); Zhao, Haixia [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Zhang, Jing [Animal Experimental Center of Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Yue, Jiang [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Guo, Austin M., E-mail: Austin_Guo@nymc.edu [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Department of Pharmacology, New York Medical College, Valhalla, NY 10595 (United States); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)

    2014-10-01

    Flavonoids exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Anoikis resistance occurs at multiple key stages of the metastatic cascade. Here, we demonstrate that isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, inhibits human breast cancer metastasis by preventing anoikis resistance, migration and invasion through downregulating cyclooxygenase (COX)-2 and cytochrome P450 (CYP) 4A signaling. ISL induced anoikis in MDA-MB-231 and BT-549 human breast cancer cells as evidenced by flow cytometry and the detection of caspase cleavage. Moreover, ISL inhibited the mRNA expression of phospholipase A2, COX-2 and CYP 4A and decreased the secretion of prostaglandin E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr{sup 458}), phospho-PDK (Ser{sup 241}) and phospho-Akt (Thr{sup 308}). Conversely, the exogenous addition of PGE{sub 2}, WIT003 (a 20-HETE analog) and an EP4 agonist (CAY10580) or overexpression of constitutively active Akt reversed ISL-induced anoikis. ISL exerted the in vitro anti-migratory and anti-invasive activities, whereas the addition of PGE{sub 2}, WIT003 and CAY10580 or overexpression of constitutively active Akt reversed the in vitro anti-migratory and anti-invasive activities of ISL in MDA-MB-231 cells. Notably, ISL inhibited the in vivo lung metastasis of MDA-MB-231 cells, together with decreased intratumoral levels of PGE{sub 2}, 20-HETE and phospho-Akt (Thr{sup 308}). In conclusion, ISL inhibits breast cancer metastasis by preventing anoikis resistance, migration and invasion via downregulating COX-2 and CYP 4A signaling. It suggests that ISL could be a promising multi-target agent for preventing breast cancer metastasis, and anoikis could represent a novel mechanism through which flavonoids may exert the anti-metastatic activities. - Highlights: • Isoliquiritigenin induces anoikis and suppresses

  10. Male Breast Cancer

    Science.gov (United States)

    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. ...

  11. Fibroblast growth factor receptor 4 predicts failure on tamoxifen therapy in patients with recurrent breast cancer

    NARCIS (Netherlands)

    Meijer, Danielle; Sieuwerts, Anieta M.; Look, Maxime P.; van Agthoven, Ton; Foekens, John A.; Dorssers, Lambert C. J.

    2008-01-01

    Tamoxifen treatment of estrogen-dependent breast cancer ultimately loses its effectiveness due to the development of resistance. From a functional screen for identifying genes responsible for tamoxifen resistance in human ZR-75-1 breast cancer cells, fibroblast growth factor (FGF) 17 was recovered.

  12. Developing Breast Cancer Program at Xavier: Genomic and Proteomic Analysis of Signaling Pathways Involved in Xenohormone and MEK5 Regulation of Breast Cancer

    National Research Council Canada - National Science Library

    Wiese, Thomas E

    2005-01-01

    Xavier University (XU) and the Tulane Cancer Center (TCC) will build a core of human talent that will address scientific problems such as drug resistance and the effect of environmental agents on breast cancer (BC...

  13. Developing Breast Cancer Program at Xavier; Genomic and Proteomic Analysis of Signaling Pathways Involved in Xenohormone and MEK5 Regulation of Breast Cancer

    National Research Council Canada - National Science Library

    Wiese, Thomas E

    2006-01-01

    Xavier University (XU) and the Tulane Cancer Center (TCC) will build a core of human talent that will address scientific problems such as drug resistance and the effect of environmental agents on breast cancer (BC...

  14. Developing Breast Cancer Program at Xavier; Genomic and Proteomic Analysis of Signaling Pathways Involved in Xenohormone and MEK5 Regulation of Breast Cancer

    National Research Council Canada - National Science Library

    Wiese, Thomas E

    2007-01-01

    Xavier University (XU) and the Tulane Cancer Center (TCC) will build a core of human talent that will address scientific problems such as drug resistance and the effect of environmental agents on breast cancer (BC...

  15. Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

    Science.gov (United States)

    Sansone, Pasquale; Ceccarelli, Claudio; Berishaj, Marjan; Chang, Qing; Rajasekhar, Vinagolu K; Perna, Fabiana; Bowman, Robert L; Vidone, Michele; Daly, Laura; Nnoli, Jennifer; Santini, Donatella; Taffurelli, Mario; Shih, Natalie N C; Feldman, Michael; Mao, Jun J; Colameco, Christopher; Chen, Jinbo; DeMichele, Angela; Fabbri, Nicola; Healey, John H; Cricca, Monica; Gasparre, Giuseppe; Lyden, David; Bonafé, Massimiliano; Bromberg, Jacqueline

    2016-02-09

    The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.

  16. miR-21 Expression in Cancer Cells may Not Predict Resistance to Adjuvant Trastuzumab in Primary Breast Cancer

    DEFF Research Database (Denmark)

    Nielsen, Boye Schnack; Balslev, Eva; Poulsen, Tim Svenstrup

    2014-01-01

    , predominantly in cancer cells, or in both stromal and cancer cells. There was no obvious difference between the HER2-positive and HER2-negative tumors in terms of the miR-21 expression patterns and intensities. To explore the possibility that miR-21 expression levels and/or cellular localization could predict...... expression patterns and intensities revealed no association between the miR-21 scores in the cancer cell population (p = 0.69) or the stromal cells population (p = 0.13) and recurrent disease after adjuvant trastuzumab. Thus, our findings show that elevated miR-21 expression does not predict resistance......Trastuzumab is established as standard care for patients with HER2-positive breast cancer both in the adjuvant and metastatic setting. However, 50% of the patients do not respond to the trastuzumab therapy, and therefore new predictive biomarkers are highly warranted. MicroRNAs (miRs) constitute...

  17. Understanding drugs in breast cancer through drug sensitivity screening

    NARCIS (Netherlands)

    K. Uhr (Katharina); W.J.C. Prager-van der Smissen (Wendy); A.A.J. Heine (Anouk); B. Ozturk (Bahar); M. Smid (Marcel); H.W.H. Göhlmann (Hinrich W. H.); A. Jager (Agnes); J.A. Foekens (John); J.W.M. Martens (John)

    2015-01-01

    textabstractWith substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign

  18. Increasing Breast Cancer Surveillance among African American Breast Cancer Survivors

    National Research Council Canada - National Science Library

    Thompson, Hayley

    2005-01-01

    ...; they also are at considerable risk for breast cancer recurrence. According to the American Society of Clinical Oncology, survivors should undergo careful breast cancer surveillance, including annual mammography and breast self-exam...

  19. Breast asymmetry and predisposition to breast cancer

    OpenAIRE

    Scutt, Diane; Lancaster, Gillian A; Manning, John T

    2006-01-01

    INTRODUCTION: It has been shown in our previous work that breast asymmetry is related to several of the known risk factors for breast cancer, and that patients with diagnosed breast cancer have more breast volume asymmetry, as measured from mammograms, than age-matched healthy women. METHODS: In the present study, we compared the breast asymmetry of women who were free of breast disease at time of mammography, but who had subsequently developed breast cancer, with that of age-matched healthy ...

  20. Relationship of Predicted Risk of Developing Invasive Breast Cancer, as Assessed with Three Models, and Breast Cancer Mortality among Breast Cancer Patients.

    Directory of Open Access Journals (Sweden)

    Mark E Sherman

    Full Text Available Breast cancer risk prediction models are used to plan clinical trials and counsel women; however, relationships of predicted risks of breast cancer incidence and prognosis after breast cancer diagnosis are unknown.Using largely pre-diagnostic information from the Breast Cancer Surveillance Consortium (BCSC for 37,939 invasive breast cancers (1996-2007, we estimated 5-year breast cancer risk (<1%; 1-1.66%; ≥1.67% with three models: BCSC 1-year risk model (BCSC-1; adapted to 5-year predictions; Breast Cancer Risk Assessment Tool (BCRAT; and BCSC 5-year risk model (BCSC-5. Breast cancer-specific mortality post-diagnosis (range: 1-13 years; median: 5.4-5.6 years was related to predicted risk of developing breast cancer using unadjusted Cox proportional hazards models, and in age-stratified (35-44; 45-54; 55-69; 70-89 years models adjusted for continuous age, BCSC registry, calendar period, income, mode of presentation, stage and treatment. Mean age at diagnosis was 60 years.Of 6,021 deaths, 2,993 (49.7% were ascribed to breast cancer. In unadjusted case-only analyses, predicted breast cancer risk ≥1.67% versus <1.0% was associated with lower risk of breast cancer death; BCSC-1: hazard ratio (HR = 0.82 (95% CI = 0.75-0.90; BCRAT: HR = 0.72 (95% CI = 0.65-0.81 and BCSC-5: HR = 0.84 (95% CI = 0.75-0.94. Age-stratified, adjusted models showed similar, although mostly non-significant HRs. Among women ages 55-69 years, HRs approximated 1.0. Generally, higher predicted risk was inversely related to percentages of cancers with unfavorable prognostic characteristics, especially among women 35-44 years.Among cases assessed with three models, higher predicted risk of developing breast cancer was not associated with greater risk of breast cancer death; thus, these models would have limited utility in planning studies to evaluate breast cancer mortality reduction strategies. Further, when offering women counseling, it may be useful to note that high

  1. High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer

    DEFF Research Database (Denmark)

    Alves, Carla Maria Lourenco; Elias, Daniel; Lyng, Maria B

    2016-01-01

    expression impaired fulvestrant-resistant cell growth and induced apoptosis. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma protein phosphorylation. High CDK6 levels in metastatic samples from two independent cohorts of breast cancer...

  2. The Effect of Breast Cancer Fatalism on Breast Cancer Awareness Among Turkish Women.

    Science.gov (United States)

    Altintas, Hulya Kulakci; Ayyildiz, Tulay Kuzlu; Veren, Funda; Topan, Aysel Kose

    2017-10-01

    The aim of this study was to evaluate the effect of breast cancer fatalism and other factors on breast cancer awareness among Turkish women. This cross-sectional and comparative descriptive study was conducted with 894 women. Data were collected by Personal Information Form, Powe Fatalism Inventory and Champion's Health Belief Model Scale. Seriousness, health motivation, BSE benefits and BSE self-efficacy perceptions of the women were moderate, and susceptibility and BSE barriers perceptions were low. It was determined that awareness of breast cancer of the women was affected by breast cancer fatalism, age, education level, employment status, marital status, family type, economic status, social assurance, menopause status, family history of cancer, family history of breast cancer, knowledge on BSE, source of information on BSE, performing of BSE, frequency of BSE performing, having a problem with breast, having a breast examination in hospital, feeling during breast examination by healthcare professional, sex of healthcare professional for breast examination and their health beliefs (p breast cancer of the women was affected by breast cancer fatalism. In providing breast cancer early diagnosis behaviors, it is recommended to evaluate fatalism perceptions and health beliefs of the women and to arrange educational programs for this purpose.

  3. Breast cancer in men

    Science.gov (United States)

    ... 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 ...

  4. HSA-based multi-target combination therapy: regulating drugs' release from HSA and overcoming single drug resistance in a breast cancer model.

    Science.gov (United States)

    Gou, Yi; Zhang, Zhenlei; Li, Dongyang; Zhao, Lei; Cai, Meiling; Sun, Zhewen; Li, Yongping; Zhang, Yao; Khan, Hamid; Sun, Hongbing; Wang, Tao; Liang, Hong; Yang, Feng

    2018-11-01

    Multi-drug delivery systems, which may be promising solution to overcome obstacles, have limited the clinical success of multi-drug combination therapies to treat cancer. To this end, we used three different anticancer agents, Cu(BpT)Br, NAMI-A, and doxorubicin (DOX), to build human serum albumin (HSA)-based multi-drug delivery systems in a breast cancer model to investigate the therapeutic efficacy of overcoming single drug (DOX) resistance to cancer cells in vivo, and to regulate the drugs' release from HSA. The HSA complex structure revealed that NAMI-A and Cu(BpT)Br bind to the IB and IIA sub-domain of HSA by N-donor residue replacing a leaving group and coordinating to their metal centers, respectively. The MALDI-TOF mass spectra demonstrated that one DOX molecule is conjugated with lysine of HSA by a pH-sensitive linker. Furthermore, the release behavior of three agents form HSA can be regulated at different pH levels. Importantly, in vivo results revealed that the HSA-NAMI-A-Cu(BpT)Br-DOX complex not only increases the targeting ability compared with a combination of the three agents (the NAMI-A/Cu(BpT)Br/DOX mixture), but it also overcomes DOX resistance to drug-resistant breast cancer cell lines.

  5. miR-4443 Participates in the Malignancy of Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Xiu Chen

    Full Text Available Chemo-resistance is the leading cause of failure in cancer therapy, however, much remains to be understood about the intrinsic mechanisms. In the present study, we discovered the novel miR-4443 that regulated malignancy of breast cancer both in vitro and in vivo.We examined the expression of miR-4443 in MDA-MB-231/S and MDA-MB-231 Epirubicin-resistant cell lines with 76 breast cancer formalin-fixed paraffin-embedded tissues by real-time PCR. Also, we investigated the loss- and gain-functions of miR-4443 by MTT assay and flow cytometry. Furthermore, we detected miR-4443 mediated tissue inhibitor of metalloproteinase 2 expression in cells by TargetScan, RT-qPCR and western blot.We identified the up-regulated expression of miR-4443 in Epi-resistant cell lines versus MDA-MB-231/S cell(Epi versus S and in post-chemotherapy FFPE tissues, along with statistically differential expressions in PR(partial response versus SD(stable disease/PD(progressive disease patients. Overexpression of miR-4443 increased the IC50 value of Epi for the target cells transfected, while inhibition of miR-4443 could restored sensitivity of the target cells to Epi. Besides, down-regulation of endogenous miR-4443 by miRNA-inhibitors significantly enhanced Epi-induced apoptosis while up-regulation of miR-4443 by miRNA-mimics lead to less Epi-induced apoptotic cells. Consequently, changes in TIMP2 mRNA and protein expression revealed that miR-4443 mimics suppressed expression of TIMP2 and induced migration in breast cancer cells. Furthermore, TIMP2 expression associated with better prognosis(HR = 0.721, 95%CI: 0.529-0.983.We revealed that miR-4443 induced malignancy of breast cancer mainly in chemo-resistance aspect for the very first time, providing a novel biomarker in breast cancer diagnosis and therapy.

  6. [A paclitaxel-resistant case of recurrent breast cancer responded to combination therapy of capecitabine and trastuzumab].

    Science.gov (United States)

    Marutaka, Masahito; Suguri, Takayasu; Miyake, Mikio; Yoshimura, Kouichi

    2005-12-01

    The patient was a 72-year-old female. Under the supervision of her former doctor, this patient had an operation and adjuvant chemotherapy for progressive breast cancer. During the following period, local recurrence of breast cancer and pulmonary lymphopathia developed. Although medication with paclitaxel was attempted, the focus was resistant to this treatment, and metastasis to the brain was also observed. Due to the dyscrasia above, the patient had difficulty breathing and became bedridden. Subsequently, combination treatment of capecitabine and trastuzumab was attempted. As a result,metastasis in the brain and pulmonary lymphopathia were improved. The patient recovered enough to be discharged at one time. However, his condition took a turn for the worse after the interruption of the combination treatment by a side effect. In conclusion, the combination treatment of capecitabine and trastuzumab is thought to be effective for non-responders to paclitaxel.

  7. [Targeting of the AKT/m-TOR Pathway: Biomarkers of Resistance to Cancer Therapy--
AKT/m-TOR Pathway and Resistance to Cancer Therapy].

    Science.gov (United States)

    Spirina, Liudmila V; Kondakova, Irina V; Tarasenko, Natalia V; Slonimskaya, Elena M; Usynin, Evgeny A; Gorbunov, Alexey K; Yurmazov, Zahar A; Chigevskaya, Svetlana Yu

    2018-01-20

    Resistance to cancer therapy continues to be a major limitation for the successful treatment of cancer. There are many published studies on therapy resistance in breast and prostate cancers; however, there are currently no data on molecular markers associated with resistance. The conflicting data were reported regarding the AKT/m-TOR signaling pathway components as markers predicting resistance. The AKT/m-TOR signaling pathway is involved in the development of many human cancers; its activation is related to cell proliferation, angiogenesis, apoptosis, as well as to therapy resistance. Molecular alterations in the AKT/m-TOR signaling pathway provide a platform to identify universal markers associated with the development of resistance to cancer therapy.

  8. Identification of Personalized Chemoresistance Genes in Subtypes of Basal-Like Breast Cancer Based on Functional Differences Using Pathway Analysis.

    Directory of Open Access Journals (Sweden)

    Tong Wu

    Full Text Available Breast cancer is a highly heterogeneous disease that is clinically classified into several subtypes. Among these subtypes, basal-like breast cancer largely overlaps with triple-negative breast cancer (TNBC, and these two groups are generally studied together as a single entity. Differences in the molecular makeup of breast cancers can result in different treatment strategies and prognoses for patients with different breast cancer subtypes. Compared with other subtypes, basal-like and other ER+ breast cancer subtypes exhibit marked differences in etiologic factors, clinical characteristics and therapeutic potential. Anthracycline drugs are typically used as the first-line clinical treatment for basal-like breast cancer subtypes. However, certain patients develop drug resistance following chemotherapy, which can lead to disease relapse and death. Even among patients with basal-like breast cancer, there can be significant molecular differences, and it is difficult to identify specific drug resistance proteins in any given patient using conventional variance testing methods. Therefore, we designed a new method for identifying drug resistance genes. Subgroups, personalized biomarkers, and therapy targets were identified using cluster analysis of differentially expressed genes. We found that basal-like breast cancer could be further divided into at least four distinct subgroups, including two groups at risk for drug resistance and two groups characterized by sensitivity to pharmacotherapy. Based on functional differences among these subgroups, we identified nine biomarkers related to drug resistance: SYK, LCK, GAB2, PAWR, PPARG, MDFI, ZAP70, CIITA and ACTA1. Finally, based on the deviation scores of the examined pathways, 16 pathways were shown to exhibit varying degrees of abnormality in the various subgroups, indicating that patients with different subtypes of basal-like breast cancer can be characterized by differences in the functional status of

  9. Knockdown of dual specificity phosphatase 4 enhances the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin

    International Nuclear Information System (INIS)

    Liu, Yu; Du, Feiya; Chen, Wei; Yao, Minya; Lv, Kezhen; Fu, Peifen

    2013-01-01

    Background: Breast cancer is the major cause of cancer-related deaths in females world-wide. Doxorubicin-based therapy has limited efficacy in breast cancer due to drug resistance, which has been shown to be associated with the epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms linking the EMT and drug resistance in breast cancer cells remain unclear. Dual specificity phosphatase 4 (DUSP4), a member of the dual specificity phosphatase family, is associated with cellular proliferation and differentiation; however, its role in breast cancer progression is controversial. Methods: We used cell viability assays, Western blotting and immunofluorescent staining, combined with siRNA interference, to evaluate chemoresistance and the EMT in MCF-7 and adriamycin-resistant MCF-7/ADR breast cancer cells, and investigate the underlying mechanisms. Results: Knockdown of DUSP4 significantly increased the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin, and MCF-7/ADR cells which expressed high levels of DUSP4 had a mesenchymal phenotype. Furthermore, knockdown of DUSP4 reversed the EMT in MCF-7/ADR cells, as demonstrated by upregulation of epithelial biomarkers and downregulation of mesenchymal biomarkers, and also increased the chemosensitivity of MCF-7/ADR cells to doxorubicin. Conclusions: DUSP4 might represent a potential drug target for inhibiting drug resistance and regulating the process of the EMT during the treatment of breast cancer. - Highlights: • We used different technologies to prove our conclusion. • DUSP4 knockdown increased doxorubicin chemosensitivity in breast cancer cells. • DUSP4 is a potential target for combating drug resistance in breast cancer. • DUSP4 is a potential target for regulating the EMT in breast cancer

  10. Profile of palbociclib in the treatment of metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Ehab M

    2016-05-01

    Full Text Available Moataz Ehab,1 Mohamad Elbaz2,31Department of Pharmacy Practice, 2Department of Pharmacology, Pharmacy School, Helwan University, Egypt; 3Department of Pathology, The Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USAAbstract: Breast cancer is the most common cancer diagnosed in women. Each year, thousands die either because of disease progression or failure of treatment. Breast cancer is classified into different subtypes based on the molecular expression of estrogen receptor (ER, progesterone receptor, and/or human epidermal growth factor receptor 2 (HER2. These receptors represent important therapeutic targets either through monoclonal antibodies or through small-molecule inhibitors directed toward them. However, up to 40% of patients develop either a primary or a secondary resistance to the current treatments. Therefore, there is an urgent need for investigating new targets in order to overcome the resistance and/or enhance the current therapies. Cell cycle is altered in many human cancers, especially in breast cancer. Cyclin-dependent kinases (CDKs, especially CDK4 and CDK6, play a pivotal role in cell cycle progression that makes them potential targets for new promising therapies. CDK inhibition has shown strong antitumor activities, ranging from cytostatic antiproliferative effects to synergistic effects in combination with other antitumor drugs. In order to overcome the drawbacks of the first-generation CDK inhibitors, recently, new CDK inhibitors have emerged that are more selective to CDK4 and CDK6 such as palbociclib, which is the most advanced CDK4/6 inhibitor in trials. In preclinical studies, palbociclib has shown a very promising antitumor activity, especially against ERα+ breast cancer subtype. Palbociclib has gained world attention, and US the Food and Drug Administration has accelerated its approval for first-line treatment in combination with letrozole for the first-line systematic

  11. AR Expression in Breast Cancer CTCs Associates with Bone Metastases.

    Science.gov (United States)

    Aceto, Nicola; Bardia, Aditya; Wittner, Ben S; Donaldson, Maria C; O'Keefe, Ryan; Engstrom, Amanda; Bersani, Francesca; Zheng, Yu; Comaills, Valentine; Niederhoffer, Kira; Zhu, Huili; Mackenzie, Olivia; Shioda, Toshi; Sgroi, Dennis; Kapur, Ravi; Ting, David T; Moy, Beverly; Ramaswamy, Sridhar; Toner, Mehmet; Haber, Daniel A; Maheswaran, Shyamala

    2018-04-01

    Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER) + breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER + breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients. Implications: This study highlights a role for the AR in breast cancer bone metastasis, and suggests that therapeutic targeting of the AR may benefit patients with metastatic breast cancer. Mol Cancer Res; 16(4); 720-7. ©2018 AACR . ©2018 American Association for Cancer Research.

  12. Downregulation of CD44 reduces doxorubicin resistance of CD44+CD24- breast cancer cells

    Directory of Open Access Journals (Sweden)

    Phuc PV

    2011-06-01

    Full Text Available Pham Van Phuc, Phan Lu Chinh Nhan, Truong Hai Nhung, Nguyen Thanh Tam, Nguyen Minh Hoang, Vuong Gia Tue, Duong Thanh Thuy, Phan Kim NgocLaboratory of Stem Cell Research and Application, University of Science, Vietnam National University, Ho Chi Minh, VietnamBackground: Cells within breast cancer stem cell populations have been confirmed to have a CD44+CD24- phenotype. Strong expression of CD44 plays a critical role in numerous types of human cancers. CD44 is involved in cell differentiation, adhesion, and metastasis of cancer cells.Methods: In this study, we reduced CD44 expression in CD44+CD24- breast cancer stem cells and investigated their sensitivity to an antitumor drug. The CD44+CD24- breast cancer stem cells were isolated from breast tumors; CD44 expression was downregulated with siRNAs followed by treatment with different concentrations of the antitumor drug.Results: The proliferation of CD44 downregulated CD44+CD24- breast cancer stem cells was decreased after drug treatment. We noticed treated cells were more sensitive to doxorubicin, even at low doses, compared with the control groups.Conclusions: It would appear that expression of CD44 is integral among the CD44+CD24- cell population. Reducing the expression level of CD44, combined with doxorubicin treatment, yields promising results for eradicating breast cancer stem cells in vitro. This study opens a new direction in treating breast cancer through gene therapy in conjunction with chemotherapy.Keywords: antitumor drugs, breast cancer stem cells, CD44, CD44+CD24- cells, doxorubicin

  13. β-Elemene Reverses Chemoresistance of Breast Cancer Cells by Reducing Resistance Transmission via Exosomes

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2015-07-01

    Full Text Available Background: Currently, exosomes that act as mediators of intercellular communication are being researched extensively. Our previous studies confirmed that these exosomes contain microRNAs (miRNAs that could alter chemo-susceptibility, which is partly attributed to the successful intercellular transfer of multidrug resistance (MDR-specific miRNAs. We also confirmed that β-elemene could influence MDR-related miRNA expression and regulate the expression of the target genes PTEN and Pgp, which may lead to the reversal of the chemoresistant breast cancer (BCA cells. We are the first to report these findings, and we propose the following logical hypothesis: β-elemene can mediate MDR-related miRNA expression in cells, thereby affecting the exosome contents, reducing chemoresistance transmission via exosomes, and reversing the drug resistance of breast cancer cells. Methods: MTT-cytotoxic, miRNA microarray, real-time quantitative PCR, Dual Luciferase Activity Assay, and Western blot analysis were performed to investigate the impact of β-elemene on the expression of chemoresistance specific miRNA and PTEN as well as Pgp in chemoresistant BCA exosomes. Results: Drug resistance can be reversed by β-elemene related to exosomes. There were 104 differentially expressed miRNAs in the exosomes of two chemoresistant BCA cells: adriacin (Adr - resistant MCF-7 cells (MCF-7/Adr and docetaxel (Doc - resistant MCF-7 cells (MCF-7/Doc that underwent treatment. Of these, 31 miRNAs were correlated with the constant changes in the MDR. The expression of miR-34a and miR-452 can lead to changes in the characteristics of two chemoresistant BCA exosomes: MCF-7/Adr exosomes (A/exo and MCF-7/Doc exosomes (D/exo. The PTEN expression affected by β-elemene was significantly increased, and the Pgp expression affected by β-elemene was significantly decreased in both cells and exosomes. β-elemene induced a significant increase in the apoptosis rate in both MCF-7/Doc and MCF-7

  14. Breast MRI in pregnancy-associated breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Shin Jung; Shin, Sang Soo [Dept. of of Radiology, Chonnam National University Hospital, Gwangju (Korea, Republic of); Lim, Hyo Soon; Baek, Jang Mi; Seon, Hyun Ju; Heo, Suk Hee; Kim, Jin Woong; Park, Min Ho [Chonnam National University Medical School, Chonnam National University Hwasun Hospital, Hwasun (Korea, Republic of)

    2017-03-15

    The purpose of this study was to evaluate the usefulness of MR imaging and to describe the MR imaging findings of pregnancy-associated breast cancer. From 2006 to 2013, MR images of 23 patients with pregnancy-associated breast cancer were retrospectively evaluated. MR images were reviewed to evaluate lesion detection and imaging findings of pregnancy-associated breast cancer. MR images were analyzed by using the Breast Imaging Reporting and Data System and an additional MR-detected lesion with no mammographic or sonographic abnormality was determined. MR imaging depicted breast cancer in all patients, even in marked background parenchymal enhancement. Pregnancy-associated breast cancer was seen as a mass in 20 patients and as non-mass enhancement with segmental distribution in 3 patients. The most common features of the masses were irregular shape (85%), non-circumscribed margin (85%), and heterogeneous enhancement (60%). An additional site of cancer was detected with MR imaging in 5 patients (21.7%) and the type of surgery was changed. Pregnancy-associated breast cancer was usually seen as an irregular mass with heterogeneous enhancement on MR images. Although these findings were not specific, MR imaging was useful in evaluating the disease extent of pregnancy-associated breast cancer.

  15. Breast MRI in pregnancy-associated breast cancer

    International Nuclear Information System (INIS)

    Kim, Shin Jung; Shin, Sang Soo; Lim, Hyo Soon; Baek, Jang Mi; Seon, Hyun Ju; Heo, Suk Hee; Kim, Jin Woong; Park, Min Ho

    2017-01-01

    The purpose of this study was to evaluate the usefulness of MR imaging and to describe the MR imaging findings of pregnancy-associated breast cancer. From 2006 to 2013, MR images of 23 patients with pregnancy-associated breast cancer were retrospectively evaluated. MR images were reviewed to evaluate lesion detection and imaging findings of pregnancy-associated breast cancer. MR images were analyzed by using the Breast Imaging Reporting and Data System and an additional MR-detected lesion with no mammographic or sonographic abnormality was determined. MR imaging depicted breast cancer in all patients, even in marked background parenchymal enhancement. Pregnancy-associated breast cancer was seen as a mass in 20 patients and as non-mass enhancement with segmental distribution in 3 patients. The most common features of the masses were irregular shape (85%), non-circumscribed margin (85%), and heterogeneous enhancement (60%). An additional site of cancer was detected with MR imaging in 5 patients (21.7%) and the type of surgery was changed. Pregnancy-associated breast cancer was usually seen as an irregular mass with heterogeneous enhancement on MR images. Although these findings were not specific, MR imaging was useful in evaluating the disease extent of pregnancy-associated breast cancer

  16. Breast cancer prevention.

    Science.gov (United States)

    Euhus, David M; Diaz, Jennifer

    2015-01-01

    Breast cancer is the most common cancer in women with 232,670 new cases estimated in the USA for 2014. Approaches for reducing breast cancer risk include lifestyle modification, chemoprevention, and prophylactic surgery. Lifestyle modification has a variety of health benefits with few associated risks and is appropriate for all women regardless of breast cancer risk. Chemoprevention options have expanded rapidly, but most are directed at estrogen receptor positive breast cancer and uptake is low. Prophylactic surgery introduces significant additional risks of its own and is generally reserved for the highest risk women. © 2014 Wiley Periodicals, Inc.

  17. Hormone resistance in two MCF-7 breast cancer cell lines is associated with reduced mTOR signaling, decreased glycolysis and increased sensitivity to cytotoxic drugs

    Directory of Open Access Journals (Sweden)

    Euphemia Yee Leung

    2014-09-01

    Full Text Available The mTOR pathway is a key regulator of multiple cellular signaling pathways and is a potential target for therapy. We have previously developed two hormone-resistant sub-lines of the MCF-7 human breast cancer line, designated TamC3 and TamR3, which were characterized by reduced mTOR signaling, reduced cell volume and resistance to mTOR inhibition. Here we show that these lines exhibit increased sensitivity to carboplatin, oxaliplatin, 5-fluorouracil, camptothecin, doxorubicin, paclitaxel, docetaxel and hydrogen peroxide. The mechanisms underlying these changes have not yet been characterized but may include a shift from glycolysis to mitochondrial respiration. If this phenotype is found in clinical hormone-resistant breast cancers, conventional cytotoxic therapy may be a preferred option for treatment.

  18. Understanding drugs in breast cancer through drug sensitivity screening.

    Science.gov (United States)

    Uhr, Katharina; Prager-van der Smissen, Wendy J C; Heine, Anouk A J; Ozturk, Bahar; Smid, Marcel; Göhlmann, Hinrich W H; Jager, Agnes; Foekens, John A; Martens, John W M

    2015-01-01

    With substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign the right drug to the right patient. To achieve this goal drug screenings on breast cancer cell lines are a promising approach. In this study a large-scale drug screening of 37 compounds was performed on a panel of 42 breast cancer cell lines representing the main breast cancer subtypes. Clustering, correlation and pathway analyses were used for data analysis. We found that compounds with a related mechanism of action had correlated IC50 values and thus grouped together when the cell lines were hierarchically clustered based on IC50 values. In total we found six clusters of drugs of which five consisted of drugs with related mode of action and one cluster with two drugs not previously connected. In total, 25 correlated and four anti-correlated drug sensitivities were revealed of which only one drug, Sirolimus, showed significantly lower IC50 values in the luminal/ERBB2 breast cancer subtype. We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.

  19. Role of MicroRNA Regulation in Obesity-Associated Breast Cancer: Nutritional Perspectives.

    Science.gov (United States)

    Kasiappan, Ravi; Rajarajan, Dheeran

    2017-11-01

    Breast cancer is the most common malignancy diagnosed in women, and the incidence of breast cancer is increasing every year. Obesity has been identified as one of the major risk factors for breast cancer progression. The mechanisms by which obesity contributes to breast cancer development is not yet understood; however, there are a few mechanisms counted as potential producers of breast cancer in obesity, including insulin resistance, chronic inflammation and inflammatory cytokines, adipokines, and sex hormones. Recent emerging evidence suggests that alterations in microRNA (miRNA) expressions are found in several diseases, including breast cancer and obesity; however, miRNA roles in obesity-linked breast cancer are beginning to unravel. miRNAs are thought to be potential noninvasive biomarkers for diagnosis and prognosis of cancer patients with comorbid conditions of obesity as well as therapeutic targets. Recent studies have evidenced that nutrients and other dietary factors protect against cancer and obesity through modulation of miRNA expressions. Herein, we summarize a comprehensive overview of up-to-date information related to miRNAs and their molecular targets involved in obesity-associated breast cancer. We also address the mechanisms by which dietary factors modulate miRNA expression and its protective roles in obesity-associated breast cancer. It is hoped that this review would provide new therapeutic strategies for the treatment of obesity-associated breast cancer to reduce the burden of breast cancer. © 2017 American Society for Nutrition.

  20. Breast carcinoma - diagnostics, therapy and resistance

    International Nuclear Information System (INIS)

    Kuzma-Richert, A.; Saczko, J.; Kulbacka, J.

    2011-01-01

    Breast cancer is a pathologically and clinically heterogeneous disease with a variable prognosis. This type of cancer is the most common female cancer in Poland. According to data collected up to 2004, approximately 12,000 new breast cancer cases per year were diagnosed in women in Poland, and approximately 5000 patients died yearly of breast cancer. The authors present the histopathology, diagnostics, classification and general types of systemic therapy of breast cancer. (authors)

  1. Breast cancer

    OpenAIRE

    Gablerová, Pavlína

    2010-01-01

    In this work the topic of breast cancer treated more generally and mainly focused on risk factors for the development. The theoretical part describes the general knowledge about breast cancer as a stage or treatment. The practical part is to have clarified the risk factors that have some bearing on the diagnosis of breast cancer. What level are involved in the probability of occurrence? Can we eliminate them? As a comparison of risk factors examined in the Czech Republic, England, Australia a...

  2. Prevention of breast cancer.

    Science.gov (United States)

    Olver, Ian N

    2016-11-21

    Modifiable lifestyle factors may reduce the risk of developing breast cancer. Obesity is associated particularly with post-menopausal breast cancer. Diet is important, and exercise equivalent to running for up to 8 hours each week reduces the risk of breast cancer, both in its own right and through reducing obesity. Alcohol consumption may be responsible for 5.8% of breast cancers in Australia and it is recommended to reduce this to two standard drinks per day. Drinking alcohol and smoking increases the risk for breast cancer and, therefore, it is important to quit tobacco smoking. Prolonged use of combined oestrogen and progesterone hormone replacement therapy and oral contraceptives may increase breast cancer risk and this must be factored into individual decisions about their use. Ionising radiation, either from diagnostic or therapeutic radiation or through occupational exposure, is associated with a high incidence of breast cancer and exposure may be reduced in some cases. Tamoxifen chemoprevention may reduce the incidence of oestrogen receptor positive cancer in 51% of women with high risk of breast cancer. Uncommon but serious side effects include thromboembolism and uterine cancer. Raloxifene, which can also reduce osteoporosis, can be used in post-menopausal women and is not associated with the development of uterine cancer. Surgical prophylaxis with bilateral mastectomy and salpingo-oophorectomy can reduce the risk of breast cancer in patients carrying BRCA1 or BRCA2 mutations. For preventive treatments, mammographic screening can identify other women at high risk.

  3. Interrelationships of Prenatal and Postnatal Growth, Hormones, Diet, and Breast Cancer

    National Research Council Canada - National Science Library

    Sanderson, Maureen

    2006-01-01

    ... activity would modify the effect of insulin resistance on breast cancer. Specific aims were: 1) to undergo intensive training in cancer biology, and nutritional, molecular and genetic epidemiology, 2...

  4. Practical consensus recommendations on management of triple-negative metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    R Rangarao

    2018-01-01

    Full Text Available Patients with breast cancer along with metastatic estrogen and progesterone receptor (ER/PR- and human epidermal growth factor receptor 2 (HER2-negative tumors are referred to as having metastatic triple-negative breast cancer (mTNBC disease. Resistance to current standard therapies such as anthracyclines or taxanes limits the available options for previously treated patients with metastatic TNBC to a small number of non-cross-resistant regimens, and there is currently no preferred standard chemotherapy. Clinical experience suggests that many women with triple-negative metastatic breast cancer (MBC relapse quickly. Expert oncologist discussed about new chemotherapeutic strategies and agents used in treatment of mTNBC and the expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists.

  5. Stages of Male Breast Cancer

    Science.gov (United States)

    ... 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 ...

  6. Osteopontin splice variants are differential predictors of breast cancer treatment responses.

    Science.gov (United States)

    Zduniak, Krzysztof; Agrawal, Anil; Agrawal, Siddarth; Hossain, Md Monir; Ziolkowski, Piotr; Weber, Georg F

    2016-07-11

    Osteopontin is a marker for breast cancer progression, which in previous studies has also been associated with resistance to certain anti-cancer therapies. It is not known which splice variants may mediate treatment resistance. Here we analyze the association of osteopontin variant expression before treatment, differentiated according to immunohistochemistry with antibodies to exon 4 and to the osteopontin-c splice junction respectively, with the ensuing therapy responses in 119 Polish breast cancer patients who presented between 1995 and 2008. We found from Cox hazard models, logrank test and Wilcoxon test that osteopontin exon 4 was associated with a favorable response to tamoxifen, but a poor response to chemotherapy with CMF (cyclophosphamide, methotrexate, fluorouracil). Osteopontin-c is prognostic, but falls short of being a significant predictor for sensitivity to treatment. The addition of osteopontin splice variant immunohistochemistry to standard pathology work-ups has the potential to aid decision making in breast cancer treatment.

  7. Osteopontin splice variants are differential predictors of breast cancer treatment responses

    International Nuclear Information System (INIS)

    Zduniak, Krzysztof; Agrawal, Anil; Agrawal, Siddarth; Hossain, Md Monir; Ziolkowski, Piotr; Weber, Georg F.

    2016-01-01

    Osteopontin is a marker for breast cancer progression, which in previous studies has also been associated with resistance to certain anti-cancer therapies. It is not known which splice variants may mediate treatment resistance. Here we analyze the association of osteopontin variant expression before treatment, differentiated according to immunohistochemistry with antibodies to exon 4 and to the osteopontin-c splice junction respectively, with the ensuing therapy responses in 119 Polish breast cancer patients who presented between 1995 and 2008. We found from Cox hazard models, logrank test and Wilcoxon test that osteopontin exon 4 was associated with a favorable response to tamoxifen, but a poor response to chemotherapy with CMF (cyclophosphamide, methotrexate, fluorouracil). Osteopontin-c is prognostic, but falls short of being a significant predictor for sensitivity to treatment. The addition of osteopontin splice variant immunohistochemistry to standard pathology work-ups has the potential to aid decision making in breast cancer treatment

  8. Molecular Modification of Metadherin/MTDH Impacts the Sensitivity of Breast Cancer to Doxorubicin.

    Directory of Open Access Journals (Sweden)

    Zhenchuan Song

    Full Text Available Breast cancer is a leading cause of death in women and with an increasing worldwide incidence. Doxorubicin, as a first-line anthracycline-based drug is conventional used on breast cancer clinical chemotherapy. However, the drug resistances limited the curative effect of the doxorubicin therapy in breast cancer patients, but the molecular mechanism determinants of breast cancer resistance to doxorubicin chemotherapy are not fully understood. In order to explore the association between metadherin (MTDH and doxorubicin sensitivity, the differential expressions of MTDH in breast cancer cell lines and the sensitivity to doxorubicin of breast cancer cell lines were investigated.The mRNA and protein expression of MTDH were determined by real-time PCR and Western blot in breast cancer cells such as MDA-MB-231, MCF-7, MDA-MB-435S, MCF-7/ADR cells. Once MTDH gene was knocked down by siRNA in MCF-7/ADR cells and overexpressed by MTDH plasmid transfection in MDA-MB-231 cells, the cell growth and therapeutic sensitivity of doxorubicin were evaluated using MTT and the Cell cycle assay and apoptosis rate was determined by flow cytometry.MCF-7/ADR cells revealed highly expressed MTDH and MDA-MB-231 cells had the lowest expression of MTDH. After MTDH gene was knocked down, the cell proliferation was inhibited, and the inhibitory rate of cell growth and apoptosis rate were enhanced, and the cell cycle arrest during the G0/G1 phase in the presence of doxorubicin treatment. On the other hand, the opposite results were observed in MDA-MB-231 cells with overexpressed MTDH gene.MTDH gene plays a promoting role in the proliferation of breast cancer cells and its high expression may be associated with doxorubicin sensitivity of breast cancer.

  9. Breast cancer imaging

    International Nuclear Information System (INIS)

    Funke, M.; Villena, C.

    2008-01-01

    Advances in female breast imaging have substantially influenced the diagnosis, therapy, and prognosis of breast cancer in the past few years. Mammography using conventional or digital technique is considered the gold standard for the early detection of breast cancer. Other modalities such as breast ultrasound and contrast-enhanced magnetic resonance imaging of the breast play an important role in diagnostic imaging, staging, and follow-up of breast cancer. Percutaneous needle biopsy is a faster, less invasive, and more cost-effective method than surgical biopsy for verifying the histological diagnosis. New methods such as breast tomosynthesis, contrast-enhanced mammography, and positron emission tomography promise to further improve breast imaging. Further studies are mandatory to adapt these new methods to clinical needs and to evaluate their performance in clinical practice. (orig.) [de

  10. Efficacy and mechanism of action of Proellex, an antiprogestin in aromatase overexpressing and Letrozole resistant T47D breast cancer cells.

    Science.gov (United States)

    Gupta, Akash; Mehta, Rajeshwari; Alimirah, Fatouma; Peng, Xinjian; Murillo, Genoveva; Wiehle, Ronald; Mehta, Rajendra G

    2013-01-01

    Aromatase inhibitors (AI) are considered as a first line therapy for ER+PR+ breast cancers. However, many patients acquire resistance to AI. In this study, we determined the response of antiprogestin CDB-4124 (Proellex) on the aromatase overexpressing and Letrozole resistant cell lines and also studies its mechanism of action in inhibition of breast cancer cell proliferation. For these studies we generated aromatase overexpressing T47D (T47Darom) and respective control (T47Dcon) breast cancer cell lines by stable transfection with plasmid containing CYP19A1 gene, or empty vector respectively. Letrozole resistant cell line (T47DaromLR) was generated by incubating T47Darom for 75 weeks in the presence of 10 μM Letrozole. Cell proliferation was determined by MTT or crystal violet assays. Gene expressions were quantified by QRT-PCR whereas proteins were identified by western blot analyses, flow cytometry and immunofluorescence staining. Aromatase activity was determined by estradiol ELISA. The effects of Proellex on the anchorage independent growth were measured by soft agar colony formation. Statistical differences between the various groups were determined by Student's 't' test or ANOVA followed by Bonferroni's post hoc test. Results showed that T47Darom and T47DaromLR cell lines had significantly higher aromatase expression (mRNA; 80-90 fold and protein) and as a result exhibited increased aromatization of testosterone to estradiol as compared to T47Dcon. Both these cell lines showed enhanced growth in the presence of Testosterone (50-60%). In T47DaromLR cells increased PR-B and EGFR expression as compared to T47Dcon cells was observed. Proellex and other known aromatase inhibitors (Letrozole, Anastrozole, and Exemestane) inhibited testosterone induced cell proliferation and anchorage independent growth of T47Darom cells. Cell growth inhibition was significantly greater when cells were treated with Proellex alone or in combination with other AIs as compared to AIs

  11. Analysis of the individual radio sensitivity of breast cancer patients

    International Nuclear Information System (INIS)

    Auer, Judith

    2013-01-01

    Individual radiosensitivity has a crucial impact on radiotherapy related side effects. A prediction of individual radiosensitivity could avoid these side effects. Our aim was to study a breast cancer collective for its variation of individual radiosensitivity. Peripheral blood samples were obtained from 129 individuals. 67 breast cancer patients and 62 healthy and age matched individuals were looked at and their individual radiosensitivity was estimated by a 3-color Fluorescence in situ hybridization approach. Blood samples were obtained (i) before starting adjuvant radiotherapy and were in vitro irradiated by 2 Gy; (ii) after 5 single doses of 1.8 Gy and after 72 h had elapsed. DNA of lymphocytes was probed with whole chromosome painting for chromosomes 1, 2 and 4. The rate of breaks per metaphase was analyzed and used as a predictor of individual radiosensitivity. Breast cancer patients were distinctly more radio-sensitive compared to healthy controls. Additionally the distribution of the cancer patients' radiosensitivity was broader. A subgroup of 9 rather radio-sensitive and 9 rather radio-resistant patients was identified. A subgroup of patients aged between 40 and 50 was distinctly more radio-sensitive than younger or older patients. The in vivo irradiation approach was not applicable to detect individual radiosensitivity. In the breast cancer collective a distinctly resistant and sensitive subgroup is identified, which could be subject for treatment adjustment. Especially in the range of age 40 to 50 patients have an increased radiosensitivity. An in vivo irradiation in a breast cancer collective is not suitable to estimate individual radiosensitivity due to a low deposed dose.

  12. Progressive resistance training and stretching following surgery for breast cancer: study protocol for a randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Ward Leigh C

    2006-12-01

    Full Text Available Abstract Background Currently 1 in 11 women over the age of 60 in Australia are diagnosed with breast cancer. Following treatment, most breast cancer patients are left with shoulder and arm impairments which can impact significantly on quality of life and interfere substantially with activities of daily living. The primary aim of the proposed study is to determine whether upper limb impairments can be prevented by undertaking an exercise program of prolonged stretching and resistance training, commencing soon after surgery. Methods/design We will recruit 180 women who have had surgery for early stage breast cancer to a multicenter single-blind randomized controlled trial. At 4 weeks post surgery, women will be randomly assigned to either an exercise group or a usual care (control group. Women allocated to the exercise group will perform exercises daily, and will be supervised once a week for 8 weeks. At the end of the 8 weeks, women will be given a home-based training program to continue indefinitely. Women in the usual care group will receive the same care as is now typically provided, i.e. a visit by the physiotherapist and occupational therapist while an inpatient, and receipt of pamphlets. All subjects will be assessed at baseline, 8 weeks, and 6 months later. The primary measure is arm symptoms, derived from a breast cancer specific questionnaire (BR23. In addition, range of motion, strength, swelling, pain and quality of life will be assessed. Discussion This study will determine whether exercise commencing soon after surgery can prevent secondary problems associated with treatment of breast cancer, and will thus provide the basis for successful rehabilitation and reduction in ongoing problems and health care use. Additionally, it will identify whether strengthening exercises reduce the incidence of arm swelling. Trial Registration The protocol for this study is registered with the Australian Clinical Trials Registry (ACTRN012606000050550.

  13. Breast Cancer Disparities

    Science.gov (United States)

    ... 2.65 MB] Read the MMWR Science Clips Breast Cancer Black Women Have Higher Death Rates from Breast ... of Page U.S. State Info Number of Additional Breast Cancer Deaths Among Black Women, By State SOURCE: National ...

  14. Role of IGF1R in breast cancer subtypes, stemness, and lineage differentiation

    Directory of Open Access Journals (Sweden)

    Susan M Farabaugh

    2015-04-01

    Full Text Available Insulin-like growth factor (IGF signaling is fundamental for growth and survival. A large body of evidence (laboratory, epidemiological, and clinical implicates the exploitation of this pathway in cancer. Up to 50% of breast tumors express the activated form of the IGF1 receptor (IGF1R. Breast cancers are categorized into subtypes based upon hormone and ERRB2 receptor expression and/or gene expression profiling. Even though IGF1R influences tumorigenic phenotypes and drug resistance across all breast cancer subtypes, it has specific expression and function in each. In some subtypes, IGF1R levels correlate with a favorable prognosis, while in others it is associated with recurrence and poor prognosis, suggesting different actions based upon cellular and molecular contexts. In this review, we examine IGF1R expression and function as it relates to breast cancer subtype and therapy-acquired resistance. Additionally, we discuss the role of IGF1R in stem cell maintenance and lineage differentiation and how these cell fate influences may alter the differentiation potential and cellular composition of breast tumors.

  15. Breast cancer

    African Journals Online (AJOL)

    A collaborative article gives an overview of breast cancer in LICs, ... approach to the problem; therefore they are published as two separate ... attached to the diagnosis of breast cancer. ... Their founding statement in its early form is included.

  16. Detecting and treating breast cancer resistance to EGFR inhibitors

    Science.gov (United States)

    Moonlee, Sun-Young; Bissell, Mina J.; Furuta, Saori; Meier, Roland; Kenny, Paraic A.

    2016-04-05

    The application describes therapeutic compositions and methods for treating cancer. For example, therapeutic compositions and methods related to inhibition of FAM83A (family with sequence similarity 83) are provided. The application also describes methods for diagnosing cancer resistance to EGFR inhibitors. For example, a method of diagnosing cancer resistance to EGFR inhibitors by detecting increased FAM83A levels is described.

  17. DIAGNOSIS OF MUCINOUS BREAST CANCER

    Directory of Open Access Journals (Sweden)

    E. К. Saribekyan

    2014-01-01

    Full Text Available The paper presents the diagnostic results of 27 patients with mucinous breast cancer, which is a rare type of invasive ductal breast cancer accounting for less than 2% of all breast cancers. The role of radiological, histological and cytological examination in the diagnosis of mucinous breast cancer is evaluated. In cases with large tumors, it was difficult to differentiate mucinous breast cancer from fibrocystic and other benign breast lesions.

  18. Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations.

    Science.gov (United States)

    Kourie, Hampig Raphael; Chaix, Marie; Gombos, Andrea; Aftimos, Phillippe; Awada, Ahmad

    2016-08-01

    Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development. This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug. The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

  19. Identification of breast cancer cell subtypes sensitive to ATG4B inhibition.

    Science.gov (United States)

    Bortnik, Svetlana; Choutka, Courtney; Horlings, Hugo M; Leung, Samuel; Baker, Jennifer H; Lebovitz, Chandra; Dragowska, Wieslawa H; Go, Nancy E; Bally, Marcel B; Minchinton, Andrew I; Gelmon, Karen A; Gorski, Sharon M

    2016-10-11

    Autophagy, a lysosome-mediated degradation and recycling process, functions in advanced malignancies to promote cancer cell survival and contribute to cancer progression and drug resistance. While various autophagy inhibition strategies are under investigation for cancer treatment, corresponding patient selection criteria for these autophagy inhibitors need to be developed. Due to its central roles in the autophagy process, the cysteine protease ATG4B is one of the autophagy proteins being pursued as a potential therapeutic target. In this study, we investigated the expression of ATG4B in breast cancer, a heterogeneous disease comprised of several molecular subtypes. We examined a panel of breast cancer cell lines, xenograft tumors, and breast cancer patient specimens for the protein expression of ATG4B, and found a positive association between HER2 and ATG4B protein expression. We showed that HER2-positive cells, but not HER2-negative breast cancer cells, require ATG4B to survive under stress. In HER2-positive cells, cytoprotective autophagy was dependent on ATG4B under both starvation and HER2 inhibition conditions. Combined knockdown of ATG4B and HER2 by siRNA resulted in a significant decrease in cell viability, and the combination of ATG4B knockdown with trastuzumab resulted in a greater reduction in cell viability compared to trastuzumab treatment alone, in both trastuzumab-sensitive and -resistant HER2 overexpressing breast cancer cells. Together these results demonstrate a novel association of ATG4B positive expression with HER2 positive breast cancers and indicate that this subtype is suitable for emerging ATG4B inhibition strategies.

  20. Breast Cancer Subtype Specific Classifiers of Response to Neoadjuvant Chemotherapy Do Not Outperform Classifiers Trained on All Subtypes

    NARCIS (Netherlands)

    de Ronde, Jorma J.; Bonder, Marc Jan; Lips, Esther H.; Rodenhuis, Sjoerd; Wessels, Lodewyk F. A.

    2014-01-01

    Introduction: Despite continuous efforts, not a single predictor of breast cancer chemotherapy resistance has made it into the clinic yet. However, it has become clear in recent years that breast cancer is a collection of molecularly distinct diseases. With ever increasing amounts of breast cancer

  1. Versican G3 domain modulates breast cancer cell apoptosis: a mechanism for breast cancer cell response to chemotherapy and EGFR therapy.

    Directory of Open Access Journals (Sweden)

    William Weidong Du

    Full Text Available Overexpression of EGFR and versican has been reported in association with breast cancers. Considered oncogenic, these molecules may be attractive therapeutic targets. Possessing anti-apoptotic and drug resistant properties, overexpression of these molecules is accompanied by selective sensitization to the process of apoptosis. In this study, we exogenously expressed a versican G3 construct in breast cancer cell lines and analyzed the effects of G3 on cell viability in fetal bovine serum free conditioned media and evaluated the effects of apoptotic agent C2-ceramide, and chemotherapeutic agents including Docetaxel, Doxorubicin, and Epirubicin. Versican G3 domain enhanced tumor cell resistance to apoptosis when cultured in serum free medium, Doxorubicin, or Epirubicin by up-regulating pERK and GSK-3β (S9P. However, it could be prevented by selective EGFR inhibitor AG 1478 and selective MEK inhibitor PD 98059. Both AG 1478 and PD 98059 enhanced expression of pSAPK/JNK, while selective JNK inhibitor SP 600125 enhanced expression of GSK-3β (S9P. Versican G3 promoted cell apoptosis induced by C2-ceramide or Docetaxel by enhancing expression of pSAPK/JNK and decreasing expression of GSK-3β (S9P, an observation blocked by AG 1478 or SP 6000125. Inhibition of endogenous versican expression by siRNA or reduction of versican G3's expression by linking G3 with 3'UTR prevented G3 modulated cell apoptosis. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents may in part explain a potential mechanism for breast cancer cell resistance to chemotherapy and EGFR therapy. The apoptotic effects of chemotherapeutics depend upon the activation and balance of down stream signals in the EGFR pathway. GSK-3β (S9P appears to function as a key checkpoint in this balance of apoptosis and anti-apoptosis. Investigation and potential consideration of targeting GSK-3β (S9P merits further study.

  2. Versican G3 domain modulates breast cancer cell apoptosis: a mechanism for breast cancer cell response to chemotherapy and EGFR therapy.

    Science.gov (United States)

    Du, William Weidong; Yang, Burton B; Yang, Bing L; Deng, Zhaoqun; Fang, Ling; Shan, Sze Wan; Jeyapalan, Zina; Zhang, Yaou; Seth, Arun; Yee, Albert J

    2011-01-01

    Overexpression of EGFR and versican has been reported in association with breast cancers. Considered oncogenic, these molecules may be attractive therapeutic targets. Possessing anti-apoptotic and drug resistant properties, overexpression of these molecules is accompanied by selective sensitization to the process of apoptosis. In this study, we exogenously expressed a versican G3 construct in breast cancer cell lines and analyzed the effects of G3 on cell viability in fetal bovine serum free conditioned media and evaluated the effects of apoptotic agent C2-ceramide, and chemotherapeutic agents including Docetaxel, Doxorubicin, and Epirubicin. Versican G3 domain enhanced tumor cell resistance to apoptosis when cultured in serum free medium, Doxorubicin, or Epirubicin by up-regulating pERK and GSK-3β (S9P). However, it could be prevented by selective EGFR inhibitor AG 1478 and selective MEK inhibitor PD 98059. Both AG 1478 and PD 98059 enhanced expression of pSAPK/JNK, while selective JNK inhibitor SP 600125 enhanced expression of GSK-3β (S9P). Versican G3 promoted cell apoptosis induced by C2-ceramide or Docetaxel by enhancing expression of pSAPK/JNK and decreasing expression of GSK-3β (S9P), an observation blocked by AG 1478 or SP 6000125. Inhibition of endogenous versican expression by siRNA or reduction of versican G3's expression by linking G3 with 3'UTR prevented G3 modulated cell apoptosis. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents may in part explain a potential mechanism for breast cancer cell resistance to chemotherapy and EGFR therapy. The apoptotic effects of chemotherapeutics depend upon the activation and balance of down stream signals in the EGFR pathway. GSK-3β (S9P) appears to function as a key checkpoint in this balance of apoptosis and anti-apoptosis. Investigation and potential consideration of targeting GSK-3β (S9P) merits further study.

  3. Exploring the breast cancer patient journey: do breast cancer survivors need menopause management support?

    Science.gov (United States)

    Tanna, Nuttan; Buijs, Helene; Pitkin, Joan

    2011-12-01

    Breast cancer survivors can be expected to suffer from menopause symptoms with estrogen deprivation due to cancer treatments, in addition to natural menopause-related estrogen loss. To gain an understanding of what support breast cancer patients have when they suffer from menopausal symptoms, and utilize findings to further inform National Health Service (NHS) care provision for breast cancer survivors. Qualitative study with focus group sessions targeting Caucasian and Asian women with breast cancer. Patient stories, with women describing their breast cancer journey and speaking about support received for any menopausal symptoms. Thematic data analysis of transcription. Breast cancer patients were not sure if they had menopausal symptoms or whether this was due to their breast cancer condition or treatment. Patients had an attitude of acceptance of menopausal symptoms and reported trying to cope with these by themselves. This research identifies a need for more information that is culturally sensitive on managing menopause symptoms, both as side-effects of breast cancer treatments as well as for affect on quality of life during the survivorship phase. Our work also gives insight into cultural remedies used for hot flushes by Asian patients, which they consider as 'cooling' foods. Breast cancer patients want to know whether side-effects of cancer treatment persist long term and how these can be managed. There is a need for improved patient support within any new NHS service models that are developed along breast cancer patient pathways, and inclusion of personalized advice for menopause symptoms.

  4. The Effect of Simvastatin on Breast Cancer Cell Growth in Women With Stage I-II Breast Cancer

    Science.gov (United States)

    2018-03-02

    Invasive Breast Carcinoma; Stage I Breast Cancer AJCC v7; Stage IA Breast Cancer AJCC v7; Stage IB Breast Cancer AJCC v7; Stage II Breast Cancer AJCC v6 and v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7

  5. Sex Hormone Receptor Repertoire in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Gerald M. Higa

    2013-01-01

    Full Text Available Classification of breast cancer as endocrine sensitive, hormone dependent, or estrogen receptor (ER positive refers singularly to ERα. One of the oldest recognized tumor targets, disruption of ERα-mediated signaling, is believed to be the mechanistic mode of action for all hormonal interventions used in treating this disease. Whereas ERα is widely accepted as the single most important predictive factor (for response to endocrine therapy, the presence of the receptor in tumor cells is also of prognostic value. Even though the clinical relevance of the two other sex hormone receptors, namely, ERβ and the androgen receptor remains unclear, two discordant phenomena observed in hormone-dependent breast cancers could be causally related to ERβ-mediated effects and androgenic actions. Nonetheless, our understanding of regulatory molecules and resistance mechanisms remains incomplete, further compromising our ability to develop novel therapeutic strategies that could improve disease outcomes. This review focuses on the receptor-mediated actions of the sex hormones in breast cancer.

  6. Novel oral administrated paclitaxel micelles with enhanced bioavailability and antitumor efficacy for resistant breast cancer.

    Science.gov (United States)

    Zhang, Ting; Luo, Jingwen; Fu, Yao; Li, Hanmei; Ding, Rui; Gong, Tao; Zhang, Zhirong

    2017-02-01

    Paclitaxel (PTX) is a widely used antineoplastic drug in clinic. Due to poor aqueous solubility, it is administrated by intravenous infusion of cremophor EL containing formulation with serious adverse effects. The low oral bioavailability is a great challenge for oral formulation development. In addition, P-gp mediated multidrug resistance limit its clinical use in various resistant cancers. In this study, a novel super-antiresistant PTX micelle formulation for oral administration was developed. A P-gp inhibitor, bromotetrandrine (W198) was co-encapsulated in the micelle. The micelles were composed of Solutol HS 15 and d-a-tocopheryl polyethylene glycol succinate to avoid Cremophor EL induced toxicity. The micelles were round with a mean particle size of ∼13nm and an encapsulation efficiency of ∼90%. A series of in vitro evaluations were performed in non-resistant MCF-7 cells and resistant MCF-7/Adr cells. The super-antiresistant PTX micelles showed higher cell uptake efficiency, significantly increased cytotoxicity and antimitotic effect in drug resistant MCF-7/Adr cells when compared with Taxol and other PTX micelle formulations. Compared with Taxol, the super-antiresistant PTX micelles significantly improved bioavailability after oral administration in rats, and inhibited tumor growth in multidrug resistance xenografted MCF-7/Adr nude mice. In summary, the noval super-antiresistant PTX micelles showed a great potential for oral delivery of PTX against resistant breast cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Fyn is an important molecule in cancer pathogenesis and drug resistance

    DEFF Research Database (Denmark)

    Elias, Daniel; Ditzel, Henrik

    2015-01-01

    Fyn is a non-receptor tyrosine kinase that belongs to the Src family kinases (SFKs) which under normal physiological conditions is involved in signal transduction pathways in the nervous system, as well as the development and activation of T lymphocytes. In cancer, Fyn contributes...... to the development and progression of several cancer types through its involvement in the control of cell growth, death, morphogenic transformation and cellular motility. Enhanced expression and/or activation of Fyn is observed in various cancers, including melanoma, glioblastoma, squamous cell carcinoma, prostate...... and breast cancers. Recent studies have demonstrated the importance of Fyn in the resistance or susceptibility of cancer cells to some anti-cancer treatments. We have recently shown that Fyn is upregulated in tamoxifen-resistant breast cancer cell lines and demonstrated that it plays a key role...

  8. Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer.

    Directory of Open Access Journals (Sweden)

    Xinyu Wu

    Full Text Available The purpose of this study was to determine the role of long-chain fatty acyl-CoA synthetase 4 (ACSL4 in breast cancer. Public databases were utilized to analyze the relationship between ACSL4 mRNA expression and the presence of steroid hormone and human epidermal growth factor receptor 2 (HER2 in both breast cancer cell lines and tissue samples. In addition, cell lines were utilized to assess the consequences of either increased or decreased levels of ACSL4 expression. Proliferation, migration, anchorage-independent growth and apoptosis were used as biological end points. Effects on mRNA expression and signal transduction pathways were also monitored. A meta-analysis of public gene expression databases indicated that ACSL4 expression is positively correlated with a unique subtype of triple negative breast cancer (TNBC, characterized by the absence of androgen receptor (AR and therefore referred to as quadruple negative breast cancer (QNBC. Results of experiments in breast cancer cell lines suggest that simultaneous expression of ACSL4 and a receptor is associated with hormone resistance. Forced expression of ACSL4 in ACSL4-negative, estrogen receptor α (ER-positive MCF-7 cells resulted in increased growth, invasion and anchorage independent growth, as well as a loss of dependence on estrogen that was accompanied by a reduction in the levels of steroid hormone receptors. Sensitivity to tamoxifen, triacsin C and etoposide was also attenuated. Similarly, when HER2-positive, ACSL4-negative, SKBr3 breast cancer cells were induced to express ACSL4, the proliferation rate increased and the apoptotic effect of lapatinib was reduced. The growth stimulatory effect of ACSL4 expression was also observed in vivo in nude mice when MCF-7 control and ACSL4-expressing cells were utilized to induce tumors. Our data strongly suggest that ACSL4 can serve as both a biomarker for, and mediator of, an aggressive breast cancer phenotype.

  9. Archives of Breast Cancer: An Academic Multidisciplinary Breast Cancer Forum

    Directory of Open Access Journals (Sweden)

    Ahmad Kaviani

    2014-05-01

    Full Text Available Welcome to Archives of Breast Cancer (ABC, a new journal with sole focus on breast diseases and especially breast cancer. Breast cancer is a devastating disease that impacts many women and threatens their health and wellbeing. A large number of health professionals from a wide spectrum of clinical disciplines, such as surgery, medical oncology, public health, pathology, radiation oncology, diagnostic radiology, and nuclear medicine, are involved in dealing with such a challenging and common disease.The concept of applying a multidisciplinary approach to clinical and non-clinical aspects of breast cancer has been found to be of vital importance to the understanding of this prevalent type of cancer. Such collaboration can also improve the quantity and quality of the research in this field. To this end, journals which choose to publish multidisciplinary articles as their primary focus can serve as the academic forum to share ideas from a variety of expertise. Archives of Breast Cancer can certainly add to the depth and quality of the research in the field. Articles on a single topic would be readily available to the readers from multiple disciplines and all in one journal. This would eventually lead to fruitful interaction among specialists seeking to investigate this disease, yet,from different perspectives. The benefits of this interaction in the process of devising appropriate strategies and approaches in dealing with the problem are crystal clear.The world of medical sciences has witnessed an abundant increase in the quality and quantity of breast-cancer-related research. In the past 20 years, the number of published articles indexed in PubMed from 1994 to 2014 is more than 5 times than the number published before 1993 (about 170,000 compared to 30,000. Meanwhile, the number of PubMed indexed medical journals dedicated to breast cancer research has also risen from 5 in 1993 to 17 in 2014. This increasing trend highlights an essential need for

  10. Breast cancer statistics, 2011.

    Science.gov (United States)

    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. Copyright © 2011 American Cancer Society, Inc.

  11. Breast Cancer (For Kids)

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Breast Cancer KidsHealth / For Kids / Breast Cancer What's in this ... for it when they are older. What Is Breast Cancer? The human body is made of tiny building ...

  12. Rad51 expression levels predict synthetic lethality and metastatic potential in high grade breast cancers

    International Nuclear Information System (INIS)

    Wiegmans, A.P.; Al-Ejeh, F.; Khanna, K.K.

    2012-01-01

    Among women with breast cancer, 30-40% will develop metastatic disease and only achieve an overall survival of less than 5 years. Despite new-targeted therapy, breast tumors that harbour similar histology or molecular phenotype differ in their response to treatment. To uncover potential new therapeutic targets and improve outcome, we performed data mining of cancer micro array databases. We found that high expression of the homologous recombination protein, RAD51, was significantly associated with high-grade breast cancer, aggressive subtypes and increased risk of metastasis. We confirmed using immunohistochemistry that RAD5 1 was highly expressed in metastatic tumours and high-grade triple negative, HER2+ and luminal-B tumours. This provided a rationale for targeting RAD5 1 in high-grade, therapy-resistant breast cancers. Here, we report for the first time preclinical evaluation of RAD5 1 as a therapeutic target. We found that, in-vitro high RAD5 expressing cell lines were resistant to PARP inhibitor while knockdown reversed this resistance. In-vivo, knockdown of RAD5 1 inhibited metastatic progression using a syngeneic breast cancer model and the seeding of human xenografts to distant sites, including brain and lung. Concurrent PARP inhibition reduced primary tumor growth and delayed metastasis supporting synthetic lethality in-vivo. Together these insights provide pre-clinical data demonstrating RAD5 1 as a new biomarker and potential therapeutic target against aggressive metastatic breast cancer. (author)

  13. Bypassing multidrug resistance in human breast cancer cells with lipid/polymer particle assemblies

    Directory of Open Access Journals (Sweden)

    Li B

    2012-01-01

    Full Text Available Bo Li1, Hui Xu2, Zhen Li1, Mingfei Yao1, Meng Xie1, Haijun Shen1, Song Shen1, Xinshi Wang1, Yi Jin11College of Pharmaceutical sciences, Zhejiang University, Hangzhou, 2No. 202 Hospital of People's Liberation Army, Shenyang, ChinaBackground: Multidrug resistance (MDR mediated by the overexpression of adenosine triphosphate (ATP-binding cassette (ABC transporters, such as P-glycoprotein (P-gp, remains one of the major obstacles to effective cancer chemotherapy. In this study, lipid/particle assemblies named LipoParticles (LNPs, consisting of a dimethyldidodecylammonium bromide (DMAB-modified poly(lactic-co-glycolic acid (PLGA nanoparticle core surrounded by a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC shell, were specially designed for anticancer drugs to bypass MDR in human breast cancer cells that overexpress P-gp.Methods: Doxorubicin (DOX, a chemotherapy drug that is a P-gp substrate, was conjugated to PLGA and encapsulated in the self-assembled LNP structure. Physiochemical properties of the DOX-loaded LNPs were characterized in vitro. Cellular uptake, intracellular accumulation, and cytotoxicity were compared in parental Michigan Cancer Foundation (MCF-7 cells and P-gp-overexpressing, resistant MCF-7/adriamycin (MCF-7/ADR cells.Results: This study found that the DOX formulated in LNPs showed a significantly increased accumulation in the nuclei of drug-resistant cells relative to the free drug, indicating that LNPs could alter intracellular traffic and bypass drug efflux. The cytotoxicity of DOX loaded-LNPs had a 30-fold lower half maximal inhibitory concentration (IC50 value than free DOX in MCF-7/ADR, measured by the colorimetric cell viability (MTT assay, correlated with the strong nuclear retention of the drug.Conclusion: The results show that this core-shell lipid/particle structure could be a promising strategy to bypass MDR.Keywords: chemotherapy, drug delivery, polymeric nanoparticles, multidrug resistance

  14. Who's talking about breast cancer? Analysis of daily breast cancer posts on the internet.

    Science.gov (United States)

    Quinn, Edel M; Corrigan, Mark A; McHugh, Seamus M; Murphy, David; O'Mullane, John; Hill, Arnold D; Redmond, Henry Paul

    2013-02-01

    Breast cancer is the cancer most commonly searched for on the internet. Our aim was to assess daily new breast cancer related posting on the internet. We analyzed numbers of new daily posts for common cancers for one month and subsequently analyzed content of 1426 breast cancer related posts. We also assessed use of online discussion forums for breast cancer related dialogue. Breast related topics had significantly more posts per day compared to others (mean 66.7, p Anonymous posts were common (55%) and less likely to be accurate (p internet has become a primary forum within which health information, particularly relating to breast cancer, is both sought and shared. Increasingly information is provided by patients themselves. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Breast Cancer Risk in American Women

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Risk in American Women On This Page What ... risk of developing the disease. Personal history of breast cancer : Women who have had breast cancer are more ...

  16. Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line

    Directory of Open Access Journals (Sweden)

    Yurgel VC

    2014-03-01

    Full Text Available Virginia C Yurgel,1,* Catiuscia P Oliveira,2,* Karine R Begnini,1 Eduarda Schultze,1 Helena S Thurow,1 Priscila MM Leon,1 Odir A Dellagostin,1 Vinicius F Campos,1 Ruy CR Beck,2 Silvia S Guterres,2 Tiago Collares,1 Adriana R Pohlmann,2–4 Fabiana K Seixas11Programa de Pós-Graduação em Biotecnologia (PPGB, Grupo de Pesquisa em Oncologia Celular e Molecular, Laboratório de Genômica Funcional, Biotecnologia/Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil; 2Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 3Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 4Centro de Nanociência e Nanotecnologia, CNANO-UFRGS, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil*These authors contributed equally to this workAbstract: Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt2] and MTX(OEt2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt2 solution and MTX(OEt2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231

  17. Mammographic Breast Density in Malaysian Women with Breast Cancer

    International Nuclear Information System (INIS)

    Noriah Jamal; Humairah Samad Cheung

    2016-01-01

    The objective of this study was to examine the mammographic breast density of women with breast cancer detected on voluntary mammographic screening at two selected screening centers in Malaysia. This was a retrospective study of Full-Field Digital Mammography (FFDM) images of 150 Malaysian women with biopsy-proven breast cancer. The study population comprised 73 Malays (37.7 %), 59 Chinese (39.3 %) and 18 Indians (12.0 %). The Tabar breast density Patterns (I - V) were used to evaluate mammographic breast density. Data were analyzed using descriptive statistics. The results were compared with findings from a similar study on a group of 668 women who did not have breast cancer. The results showed that 44.7 % of the study population had dense breasts (Patterns IV and V), 14.7 % had predominantly fatty breasts (Patterns II and III) while 40.7 % had Pattern I. The proportion of study population with dense breasts decreased with age. In conclusion, the proportion of women with dense breasts decreased with age. Majority of the women with cancer (44.7 %) had dense breasts of Tabar Patterns IV and V, which has been associated with increased risk of breast cancer detected by voluntary mammographic screening. The results support the notion that increased breast density is a risk factor of breast cancer. (author)

  18. A systematic review of dual targeting in HER2-positive breast cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Tuxen, Malgorzata K; Nielsen, Dorte Lisbet

    2014-01-01

    BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both...... the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present...... of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described. CONCLUSION: Dual blockade is likely to represent a substantial advance for patients...

  19. Breast cancer in systemic lupus

    DEFF Research Database (Denmark)

    Bernatsky, S.; Ramsey-Goldman, R.; Petri, M.

    2017-01-01

    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...

  20. MDM2 Antagonist Nutlin-3a Reverses Mitoxantrone Resistance by Inhibiting Breast Cancer Resistance Protein Mediated Drug Transport

    Science.gov (United States)

    Zhang, Fan; Throm, Stacy L.; Murley, Laura L.; Miller, Laura A.; Zatechka, D. Steven; Guy, R. Kiplin; Kennedy, Rachel; Stewart, Clinton F.

    2011-01-01

    Breast cancer resistance protein (BCRP; ABCG2), a clinical marker for identifying the side population (SP) cancer stem cell subgroup, affects intestinal absorption, brain penetration, hepatobiliary excretion, and multidrug resistance of many anti-cancer drugs. Nutlin-3a is currently under pre-clinical investigation in a variety of solid tumor and leukemia models as a p53 reactivation agent, and has been recently demonstrated to also have p53 independent actions in cancer cells. In the present study, we first report that nutlin-3a can inhibit the efflux function of BCRP. We observed that although the nutlin-3a IC50 did not differ between BCRP over-expressing and vector control cells, nutlin-3a treatment significantly potentiated the cells to treatment with the BCRP substrate mitoxantrone. Combination index calculations suggested synergism between nutlin-3a and mitoxantrone in cell lines over-expressing BCRP. Upon further investigation, it was confirmed that nutlin-3a increased the intracellular accumulation of BCRP substrates such as mitoxantrone and Hoechst 33342 in cells expressing functional BCRP without altering the expression level or localization of BCRP. Interestingly, nutlin-3b, considered virtually “inactive” in disrupting the MDM2/p53 interaction, reversed Hoechst 33342 efflux with the same potency as nutlin-3a. Intracellular accumulation and bi-directional transport studies using MDCKII cells suggested that nutlin-3a is not a substrate of BCRP. Additionally, an ATPase assay using Sf9 insect cell membranes over-expressing wild-type BCRP indicated that nutlin-3a inhibits BCRP ATPase activity in a dose-dependent fashion. In conclusion, our studies demonstrate that nutlin-3a inhibits BCRP efflux function, which consequently reverses BCRP-related drug resistance. PMID:21459080

  1. Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer.

    Science.gov (United States)

    Fagan-Solis, Katerina D; Reaves, Denise K; Rangel, M Cristina; Popoff, Michel R; Stiles, Bradley G; Fleming, Jodie M

    2014-07-02

    Translational exploration of bacterial toxins has come to the forefront of research given their potential as a chemotherapeutic tool. Studies in select tissues have demonstrated that Clostridium perfringens iota toxin binds to CD44 and lipolysis stimulated lipoprotein receptor (LSR) cell-surface proteins. We recently demonstrated that LSR expression correlates with estrogen receptor positive breast cancers and that LSR signaling directs aggressive, tumor-initiating cell behaviors. Herein, we identify the mechanisms of iota toxin cytotoxicity in a tissue-specific, breast cancer model with the ultimate goal of laying the foundation for using iota toxin as a targeted breast cancer therapy. In vitro model systems were used to determine the cytotoxic effect of iota toxin on breast cancer intrinsic subtypes. The use of overexpression and knockdown technologies confirmed the roles of LSR and CD44 in regulating iota toxin endocytosis and induction of cell death. Lastly, cytotoxicity assays were used to demonstrate the effect of iota toxin on a validated set of tamoxifen resistant breast cancer cell lines. Treatment of 14 breast cancer cell lines revealed that LSR+/CD44- lines were highly sensitive, LSR+/CD44+ lines were slightly sensitive, and LSR-/CD44+ lines were resistant to iota cytotoxicity. Reduction in LSR expression resulted in a significant decrease in toxin sensitivity; however, overexpression of CD44 conveyed toxin resistance. CD44 overexpression was correlated with decreased toxin-stimulated lysosome formation and decreased cytosolic levels of iota toxin. These findings indicated that expression of CD44 drives iota toxin resistance through inhibition of endocytosis in breast cancer cells, a role not previously defined for CD44. Moreover, tamoxifen-resistant breast cancer cells exhibited robust expression of LSR and were highly sensitive to iota-induced cytotoxicity. Collectively, these data are the first to show that iota toxin has the potential to be an

  2. Observed and Predicted Risk of Breast Cancer Death in Randomized Trials on Breast Cancer Screening.

    Science.gov (United States)

    Autier, Philippe; Boniol, Mathieu; Smans, Michel; Sullivan, Richard; Boyle, Peter

    2016-01-01

    The role of breast screening in breast cancer mortality declines is debated. Screening impacts cancer mortality through decreasing the number of advanced cancers with poor diagnosis, while cancer treatment works through decreasing the case-fatality rate. Hence, reductions in cancer death rates thanks to screening should directly reflect reductions in advanced cancer rates. We verified whether in breast screening trials, the observed reductions in the risk of breast cancer death could be predicted from reductions of advanced breast cancer rates. The Greater New York Health Insurance Plan trial (HIP) is the only breast screening trial that reported stage-specific cancer fatality for the screening and for the control group separately. The Swedish Two-County trial (TCT)) reported size-specific fatalities for cancer patients in both screening and control groups. We computed predicted numbers of breast cancer deaths, from which we calculated predicted relative risks (RR) and (95% confidence intervals). The Age trial in England performed its own calculations of predicted relative risk. The observed and predicted RR of breast cancer death were 0.72 (0.56-0.94) and 0.98 (0.77-1.24) in the HIP trial, and 0.79 (0.78-1.01) and 0.90 (0.80-1.01) in the Age trial. In the TCT, the observed RR was 0.73 (0.62-0.87), while the predicted RR was 0.89 (0.75-1.05) if overdiagnosis was assumed to be negligible and 0.83 (0.70-0.97) if extra cancers were excluded. In breast screening trials, factors other than screening have contributed to reductions in the risk of breast cancer death most probably by reducing the fatality of advanced cancers in screening groups. These factors were the better management of breast cancer patients and the underreporting of breast cancer as the underlying cause of death. Breast screening trials should publish stage-specific fatalities observed in each group.

  3. Ovarian and Breast Cancer Spheres Are Similar in Transcriptomic Features and Sensitive to Fenretinide

    Directory of Open Access Journals (Sweden)

    Haiwei Wang

    2013-01-01

    Full Text Available Cancer stem cells (CSCs are resistant to chemotherapy and are ability to regenerate cancer cell populations, thus attracting much attention in cancer research. In this report, we first demonstrated that sphere cells from ovarian cancer cell line A2780 shared many features of CSCs, such as resistance to cisplatin and able to initiate tumors in an efficient manner. Then, we conducted cDNA microarray analysis on spheres from ovarian A2780 cells, and from breast MCF7 and SUM159 cells, and found that molecular pathways underlying spheres from these cancer cell lines were similar to a large extent, suggesting that similar mechanisms are involved in the genesis of CSCs in both ovarian and breast cancer types. In addition, we showed that spheres from these cancer types were highly sensitive to fenretinide, a stimulus of oxidative stress-mediated apoptosis in cancer cells. Thus, our results not only provide important insights into mechanisms underlying CSCs in ovarian and breast cancer, but also lead to the development of more sophisticated protocols of cancer therapy in near future.

  4. Benign breast disease, mammographic breast density, and the risk of breast cancer.

    Science.gov (United States)

    Tice, Jeffrey A; O'Meara, Ellen S; Weaver, Donald L; Vachon, Celine; Ballard-Barbash, Rachel; Kerlikowske, Karla

    2013-07-17

    Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk. We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided. Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses. Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis.

  5. [Hormonotherapy for breast cancer prevention: What about women with genetic predisposition to breast cancer?].

    Science.gov (United States)

    Sénéchal, Claire; Reyal, Fabien; Callet, Nasrine; This, Pascale; Noguès, Catherine; Stoppa-Lyonnet, Dominique; Fourme, Emmanuelle

    2016-03-01

    In France, women carrying BRCA1/2 mutation, at an identified high risk of breast cancer are recommended to undergo breast MRI screening. That screening does not however prevent the risk of developing a breast cancer. The only alternative to breast cancer screening available in France is surgical prevention by prophylactic mastectomy. An interesting option for women who wish to reduce their breast cancer risk, but are unready for prophylactic mastectomy is a preventive hormonal treatment by aromatase inhibitors, or selective estrogens receptor modulators (SERMs). Reliable clinical trials show the efficiency of tamoxifen, raloxifen, exemestane, and anastrozole especially, in reducing breast cancer incidence by 33%, 34%, 65% and 53% respectively. This article tries to sum up the main published trials of breast cancer prevention with hormonal treatment, and presents the latest American and English clinical guidelines concerning hormonal prevention for women at high risk of breast cancer, and starts thinking about the possibilities of hormonoprevention, especially among women carrying a BRCA1/2 mutation in France. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  6. Metabolic Syndrome and Breast Cancer Risk.

    Science.gov (United States)

    Wani, Burhan; Aziz, Shiekh Aejaz; Ganaie, Mohammad Ashraf; Mir, Mohammad Hussain

    2017-01-01

    The study was meant to estimate the prevalence of metabolic syndrome in patients with breast cancer and to establish its role as an independent risk factor on occurrence of breast cancer. Fifty women aged between 40 and 80 years with breast cancer and fifty controls of similar age were assessed for metabolic syndrome prevalence and breast cancer risk factors, including age at menarche, reproductive status, live births, breastfeeding, and family history of breast cancer, age at diagnosis of breast cancer, body mass index, and metabolic syndrome parameters. Metabolic syndrome prevalence was found in 40.0% of breast cancer patients, and 18.0% of those in control group ( P = 0.02). An independent and positive association was seen between metabolic syndrome and breast cancer risk (odds ratio = 3.037; 95% confidence interval 1.214-7.597). Metabolic syndrome is more prevalent in breast cancer patients and is an independent risk factor for breast cancer.

  7. Improved detection of breast cancer on FDG-PET cancer screening using breast positioning device

    International Nuclear Information System (INIS)

    Kaida, Hayato; Ishibashi, Masatoshi; Fujii, Teruhiko; Kurata, Seiji; Ogo, Etsuyo; Hayabuchi, Naofumi; Tanaka, Maki

    2008-01-01

    The aim of this study was to investigate the detection rate of breast cancer by positron emission tomography cancer screening using a breast positioning device. Between January 2004 and January 2006, 1,498 healthy asymptomatic individuals underwent cancer screening by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) at our institution; 660 of 1498 asymptomatic healthy women underwent breast PET imaging in the prone position using the breast positioning device to examine the mammary glands in addition to whole-body PET imaging. All subjects that showed abnormal 18 F-FDG uptake in the mammary glands were referred for further examination or surgery at our institution or a local hospital. Our data were compared with the histopathological findings or findings of other imaging modalities in our institution and replies from the doctors at another hospital. Of the 660 participants, 7 (1.06%) were found to have breast cancers at a curable stage. All the seven cancers were detected by breast PET imaging, but only five of these were detected by whole-body PET imaging; the other two were detected by breast PET imaging using the breast positioning device. In cancer screening, prone breast imaging using a positioning device may help to improve the detection rate of breast cancer. However, overall cancer including mammography and ultrasonography screening should be performed to investigate the false-negative cases and reduce false-positive cases. The effectiveness of prone breast PET imaging in cancer screening should be investigated using a much larger number of cases in the near future. (author)

  8. Identification of the Mechanisms Underlying Antiestrogen Resistance: Breast Cancer Research Partnership between FIU-UM Braman Family Breast Cancer Institute

    National Research Council Canada - National Science Library

    Roy, Deodutta

    2008-01-01

    This research proposal has two primary objectives which are to (1) increase FIU investigators' research expertise and competitive ability to succeed as independent breast cancer researchers; and (2...

  9. Early Diagnosis of Breast Cancer.

    Science.gov (United States)

    Wang, Lulu

    2017-07-05

    Early-stage cancer detection could reduce breast cancer death rates significantly in the long-term. The most critical point for best prognosis is to identify early-stage cancer cells. Investigators have studied many breast diagnostic approaches, including mammography, magnetic resonance imaging, ultrasound, computerized tomography, positron emission tomography and biopsy. However, these techniques have some limitations such as being expensive, time consuming and not suitable for young women. Developing a high-sensitive and rapid early-stage breast cancer diagnostic method is urgent. In recent years, investigators have paid their attention in the development of biosensors to detect breast cancer using different biomarkers. Apart from biosensors and biomarkers, microwave imaging techniques have also been intensely studied as a promising diagnostic tool for rapid and cost-effective early-stage breast cancer detection. This paper aims to provide an overview on recent important achievements in breast screening methods (particularly on microwave imaging) and breast biomarkers along with biosensors for rapidly diagnosing breast cancer.

  10. Activating HER2 mutations in HER2 gene amplification negative breast cancer.

    Science.gov (United States)

    Bose, Ron; Kavuri, Shyam M; Searleman, Adam C; Shen, Wei; Shen, Dong; Koboldt, Daniel C; Monsey, John; Goel, Nicholas; Aronson, Adam B; Li, Shunqiang; Ma, Cynthia X; Ding, Li; Mardis, Elaine R; Ellis, Matthew J

    2013-02-01

    Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment. We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs.

  11. Opioids and breast cancer recurrence

    DEFF Research Database (Denmark)

    Cronin-Fenton, Deirdre P; Heide-Jørgensen, Uffe; Ahern, Thomas P

    2015-01-01

    BACKGROUND: Opioids may alter immune function, thereby potentially affecting cancer recurrence. The authors investigated the association between postdiagnosis opioid use and breast cancer recurrence. METHODS: Patients with incident, early stage breast cancer who were diagnosed during 1996 through...... 2008 in Denmark were identified from the Danish Breast Cancer Cooperative Group Registry. Opioid prescriptions were ascertained from the Danish National Prescription Registry. Follow-up began on the date of primary surgery for breast cancer and continued until breast cancer recurrence, death......, emigration, 10 years, or July 31, 2013, whichever occurred first. Cox regression models were used to compute hazard ratios and 95% confidence intervals associating breast cancer recurrence with opioid prescription use overall and by opioid type and strength, immunosuppressive effect, chronic use (≥6 months...

  12. Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer.

    Science.gov (United States)

    Shan, Naing Lin; Wahler, Joseph; Lee, Hong Jin; Bak, Min Ji; Gupta, Soumyasri Das; Maehr, Hubert; Suh, Nanjoo

    2017-10-01

    Triple-negative breast cancer is one of the least responsive breast cancer subtypes to available targeted therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early breast cancer prevention may therefore play an important role in delaying the progression of triple-negative breast cancer. Cancer stem cells are a subset of cancer cells that are thought to be responsible for tumor progression, treatment resistance, and metastasis. We have previously shown that vitamin D compounds, including a Gemini vitamin D analog BXL0124, suppress progression of ductal carcinoma in situ in vivo and inhibit cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of vitamin D compounds in regulating breast cancer stem-like cells and differentiation in triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(OH) 2 D 3 and BXL0124 on cancer stem cell markers in the triple-negative breast cancer cell line, SUM159. Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(OH) 2 D 3 and BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in breast cancer stem cell maintenance. In addition, the vitamin D compounds up-regulated myoepithelial differentiating markers, cytokeratin 14 and smooth muscle actin, and down-regulated the luminal marker, cytokeratin 18. Cytokeratin 5, a biomarker associated with basal-like breast cancer, was found to be significantly down-regulated by the vitamin D compounds. These results suggest

  13. Breast cancer screening

    International Nuclear Information System (INIS)

    Vandenbroucke, A.

    1987-01-01

    Many studies have shown that breast cancer screening is able to reduce breast cancer mortality, including the HIP study, the Swedish Trial and the Netherlands studies. Mammography is considered as the most effective method for breast cancer screening but it might be unfeasible for some reasons: - the population acceptability of the method might be low. Indeed, most populations of the South of Europe are less compliant to mass screening than populations of the North of Europe; - the medical equipment and personnel - radiologists and pathologists - might be insufficient; - it might be too costly for the National Health Service, specially where the incidence rate of breast cancer is relatively low (i.e. Greece, Portugal). The validity of screening tests is judged by their sensitivity and their specificity

  14. Breast cancer screening with digital breast tomosynthesis.

    Science.gov (United States)

    Skaane, Per

    2017-01-01

    To give an overview of studies comparing full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) in breast cancer screening. The implementation of tomosynthesis in breast imaging is rapidly increasing world-wide. Experimental clinical studies of relevance for DBT screening have shown that tomosynthesis might have a great potential in breast cancer screening, although most of these retrospective reading studies are based on small populations, so that final conclusions are difficult to draw from individual reports. Several retrospective studies and three prospective trials on tomosynthesis in breast cancer screening have been published so far, confirming the great potential of DBT in mammography screening. The main results of these screening studies are presented. The retrospective screening studies from USA have all shown a significant decrease in the recall rate using DBT as adjunct to mammography. Most of these studies have also shown an increase in the cancer detection rate, and the non-significant results in some studies might be explained by a lack of statistical power. All the three prospective European trials have shown a significant increase in the cancer detection rate. The retrospective and the prospective screening studies comparing FFDM and DBT have all demonstrated that tomosynthesis has a great potential for improving breast cancer screening. DBT should be regarded as a better mammogram that could improve or overcome limitations of the conventional mammography, and tomosynthesis might be considered as the new technique in the next future of breast cancer screening.

  15. Treating ER+ Breast Cancer with CDK4/6 Inhibitors.

    Science.gov (United States)

    2017-08-01

    Data from the MONARCH2, PALOMA-1, and TREnd trials strongly support using CDK4/6 inhibitors alongside standard endocrine therapy for advanced ER-positive breast cancer. Including these targeted agents not only improves progression-free survival but may reverse acquired resistance to hormone treatment. ©2017 American Association for Cancer Research.

  16. Breast Cancer Rates by State

    Science.gov (United States)

    ... Associated Lung Ovarian Prostate Skin Uterine Cancer Home Breast Cancer Rates by State Language: English (US) Español (Spanish) ... from breast cancer each year. Rates of Getting Breast Cancer by State The number of people who get ...

  17. Taraxacum officinale dandelion extract efficiently inhibited the breast cancer stem cell proliferation

    OpenAIRE

    Ngu Van Trinh; Nghi Doan-Phuong Dang; Diem Hong Tran; Phuc Van Pham

    2016-01-01

    Background: Breast cancer stem cells (BCSCs) play an important role in breast cancer initiation, metastasis, recurrence, and drug resistance. Therefore, targeting BCSCs is an essential strategy to suppress cancer growth. This study aimed to evaluate the effects of dandelion Taraxacum officinale extracts on BCSC proliferation in vitro in 2D and 3D cell culture platforms. Materials and Methods: The BCSCs were maintained under standard conditions, verified for expression of CD44 and CD24 surface...

  18. Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, Martina E., E-mail: m.schmidt@dkfz.de [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany); Meynköhn, Anna; Habermann, Nina [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany); Wiskemann, Joachim [Division of Medical Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg (Germany); Oelmann, Jan; Hof, Holger; Wessels, Sabine [Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg (Germany); Klassen, Oliver [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany); Debus, Jürgen; Potthoff, Karin [Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg (Germany); Steindorf, Karen; Ulrich, Cornelia M. [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany)

    2016-02-01

    Purpose: To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. Methods and Materials: Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R{sup 2} effect-size measures for mediation were calculated. Results: The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. Conclusions: This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast

  19. Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial

    International Nuclear Information System (INIS)

    Schmidt, Martina E.; Meynköhn, Anna; Habermann, Nina; Wiskemann, Joachim; Oelmann, Jan; Hof, Holger; Wessels, Sabine; Klassen, Oliver; Debus, Jürgen; Potthoff, Karin; Steindorf, Karen; Ulrich, Cornelia M.

    2016-01-01

    Purpose: To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. Methods and Materials: Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R"2 effect-size measures for mediation were calculated. Results: The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. Conclusions: This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast

  20. Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein.

    Science.gov (United States)

    Grandjean, Thomas R B; Chappell, Mike J; Yates, James T W; Jones, Kevin; Wood, Gemma; Coleman, Tanya

    2011-11-01

    A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent breast cancer resistance protein inhibitor, Fumitremorgin C (FTC), present is described. FTC is reported to almost completely annul resistance mediated by BCRP in vitro. This non-linear compartmental model has seven macroscopic sub-units, with 14 rate parameters. It describes the relationship between the concentration of Hoechst 33342 and FTC, initially spiked in the medium, and the observed change in fluorescence due to Hoechst 33342 binding to DNA. Structural identifiability analysis has been performed using two methods, one based on the similarity transformation/exhaustive modelling approach and the other based on the differential algebra approach. The analyses demonstrated that all models derived are uniquely identifiable for the experiments/observations available. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used for parameter fitting and to obtain numerical solutions for the system equations. Model fits gave very good agreement with in vitro data provided by AstraZeneca across a variety of experimental scenarios. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  1. Propranolol and survival from breast cancer

    DEFF Research Database (Denmark)

    Cardwell, Chris R; Pottegård, Anton; Vaes, Evelien

    2016-01-01

    BACKGROUND: Preclinical studies have demonstrated that propranolol inhibits several pathways involved in breast cancer progression and metastasis. We investigated whether breast cancer patients who used propranolol, or other non-selective beta-blockers, had reduced breast cancer-specific or all......-cause mortality in eight European cohorts. METHODS: Incident breast cancer patients were identified from eight cancer registries and compiled through the European Cancer Pharmacoepidemiology Network. Propranolol and non-selective beta-blocker use was ascertained for each patient. Breast cancer-specific and all......-analysis techniques. Dose-response analyses by number of prescriptions were also performed. Analyses were repeated investigating propranolol use before cancer diagnosis. RESULTS: The combined study population included 55,252 and 133,251 breast cancer patients in the analysis of breast cancer-specific and all...

  2. Inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer

    Institute of Scientific and Technical Information of China (English)

    Zhao Li; Ma Yongjie; Gu Feng; Fu Li

    2014-01-01

    Background Paclitaxel (PAC) is the first-line chemotherapy drug for most breast cancer patients,but clinical studies showed that some breast cancer patients were insensitive to PAC,which led to chemotherapy failure.It was reported that Notch1 signaling participated in drug resistance of breast cancer.Here,we show whether Notch1 expression is related to PAC sensitivity of breast cancer.Methods We employed Notch1 siRNA and Notch1 inhibitor,N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT),to down regulate Notch1 expression in human breast cancer cells MDA-MB-231,and detected the inhibition effect by Western blotting and reverse trans cription-polymerase chain reaction,respectively.After 24 hours exposure to different concentration of PAC (0,1,5,10,15,20,and 25 μg/ml),the viability of the control group and experimental group cells was tested by MTT.We also examined the expression of Notch1 in PAC sensitive and nonsensitive breast cancer patients,respectively by immunohistochemistry (IHC).The PAC sensitivity of breast cancer patients were identified by collagen gel droplet embedded culture-drug sensitivity test (CD-DST).Results Down regulation of Notch1 expression by Notch1siRNA interference or Notch1 inhibitor increased the PAC sensitivity in MDA-MB-231 cells (P <0.05).Also,the expression of Notch1 in PAC sensitive patients was much lower than that of PAC non-sensitive patients (P <0.01).Conclusion Notch1 expression has an effect on PAC sensitivity in breast cancer patients,and the inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer.

  3. Application of 99Tcm-MIBI scintimammography to diagnose P-gP of breast cancer

    International Nuclear Information System (INIS)

    Zhao Tao

    2004-01-01

    The article discuss the advances in 99 Tc m -sestamibi scintimammography to diagnose P-glycoprotein of breast cancer in multidrug resistance. As a kind of noninvasive fuctional test imaging technology, SPECT can be used to diagnose P-glycoprotein expression in breast cancer and can make decision for clinical treatment. (authors)

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

    Energy Technology Data Exchange (ETDEWEB)

    May, Felicity EB, E-mail: F.E.B.May@ncl.ac.uk [Northern Institute for Cancer Research and Department of Pathology, Faculty of Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne (United Kingdom)

    2014-05-23

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

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

    International Nuclear Information System (INIS)

    May, Felicity EB

    2014-01-01

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

  6. Breast Cancer in Men

    Science.gov (United States)

    ... ultrasound or a breast MRI cannot rule out breast cancer then you will need a biopsy to confirm diagnosis. If diagnosed When first diagnosed with breast cancer, many men are in shock. After all, ...

  7. Risk of primary non-breast cancer after female breast cancer by age at diagnosis

    DEFF Research Database (Denmark)

    Mellemkjær, Lene; Christensen, Jane; Frederiksen, Kirsten Skovsgaard

    2011-01-01

    Women diagnosed with breast cancer at young age have been shown to be at higher risk of developing a new primary cancer than women diagnosed at older ages, but little is known about whether adjustment for calendar year of breast cancer diagnosis, length of follow-up, and/or breast cancer treatment...

  8. Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

    Directory of Open Access Journals (Sweden)

    Yang XL

    2014-06-01

    Full Text Available Xiao Li Yang, Feng Juan Lin, Ya Jie Guo, Zhi Min Shao, Zhou Luo Ou Key Laboratory of Breast Cancer in Shanghai, Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China Abstract: Chemoresistance is a major cause of cancer treatment failure and leads to a reduction in the survival rate of cancer patients. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK pathways are aberrantly activated in many malignant tumors, including breast cancer, which may indicate an association with breast cancer chemoresistance. In this study, we generated a chemoresistant human breast cancer cell line, MDA-MB-231/gemcitabine (simplified hereafter as “231/Gem”, from MDA-MB-231 human breast cancer cells. Flow cytometry studies revealed that with the same treatment concentration of gemcitabine, 231/Gem cells displayed more robust resistance to gemcitabine, which was reflected by fewer apoptotic cells and enhanced percentage of S-phase cells. Through the use of inverted microscopy, Cell Counting Kit-8, and Transwell assays, we found that compared with parental 231 cells, 231/Gem cells displayed more morphologic projections, enhanced cell proliferative ability, and improved cell migration and invasion. Mechanistic studies revealed that the PI3K/AKT/mTOR and mitogen-activated protein kinase kinase (MEK/MAPK signaling pathways were activated through elevated expression of phosphorylated (p-extracellular signal-regulated kinase (ERK, p-AKT, mTOR, p-mTOR, p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy in 231/Gem in comparison to control cells. However, there was no change in the expression of Cyclin D1 and p-adenosine monophosphate-activated protein kinase (AMPK. In culture, inhibitors of PI3K/AKT and mTOR, but not of MEK/MAPK, could reverse the enhanced proliferative

  9. Gestational Breast Cancer: Report of A Case and Literature Review

    Directory of Open Access Journals (Sweden)

    Filipa Paixão-Barradas

    2016-03-01

    Full Text Available Background: Gestational or pregnancy-associated breast cancer is defined as breast cancer diagnosed during pregnancy, within the first postpartum year, or during lactation. Breast cancer is one of the most common cancers in nonpregnant and pregnant women. Case presentation: A 29-year-old pregnant woman presented at eight weeks gestational age with a palpable breast nodule. On breast ultrasound evaluation, only probably benign findings were detected. The pregnancy was uneventful until the third trimester when she started to have a severe back pain which became gradually resistant to medical therapy. Therefore, at 33 weeks, she was assisted at an emergency care facility and a highly suspicious breast mass was detected. A core biopsy was performed that revealed an invasive ductal carcinoma grade 3 with lymph node metastasis. After several imaging studies, it was diagnosed as a stage 4 breast cancer with bone, liver, and pulmonary metastasis. At thirty four weeks gestation, the pregnancy was terminated by C-section and she started to receive palliative radiation therapy one week later. She also received several cycles of palliative chemotherapy. Nineteenth months after C-section, progression of the disease was observed and a cerebellar metastasis was found. Unfortunately, two months later, her clinical condition deteriorated and the patient died.Conclusion: Gestational breast cancer represents a clinical situation of utmost important in which the health of both the mother and the fetus should be taken into account. Diagnosis is difficult due to the physiological changes of the mammary glands during pregnancy and lactation, and it usually occurs at an advanced stage.

  10. Hierarchical clustering of breast cancer methylomes revealed differentially methylated and expressed breast cancer genes.

    Directory of Open Access Journals (Sweden)

    I-Hsuan Lin

    Full Text Available Oncogenic transformation of normal cells often involves epigenetic alterations, including histone modification and DNA methylation. We conducted whole-genome bisulfite sequencing to determine the DNA methylomes of normal breast, fibroadenoma, invasive ductal carcinomas and MCF7. The emergence, disappearance, expansion and contraction of kilobase-sized hypomethylated regions (HMRs and the hypomethylation of the megabase-sized partially methylated domains (PMDs are the major forms of methylation changes observed in breast tumor samples. Hierarchical clustering of HMR revealed tumor-specific hypermethylated clusters and differential methylated enhancers specific to normal or breast cancer cell lines. Joint analysis of gene expression and DNA methylation data of normal breast and breast cancer cells identified differentially methylated and expressed genes associated with breast and/or ovarian cancers in cancer-specific HMR clusters. Furthermore, aberrant patterns of X-chromosome inactivation (XCI was found in breast cancer cell lines as well as breast tumor samples in the TCGA BRCA (breast invasive carcinoma dataset. They were characterized with differentially hypermethylated XIST promoter, reduced expression of XIST, and over-expression of hypomethylated X-linked genes. High expressions of these genes were significantly associated with lower survival rates in breast cancer patients. Comprehensive analysis of the normal and breast tumor methylomes suggests selective targeting of DNA methylation changes during breast cancer progression. The weak causal relationship between DNA methylation and gene expression observed in this study is evident of more complex role of DNA methylation in the regulation of gene expression in human epigenetics that deserves further investigation.

  11. Mammographic density and breast cancer risk in breast screening assessment cases and women with a family history of breast cancer.

    Science.gov (United States)

    Duffy, Stephen W; Morrish, Oliver W E; Allgood, Prue C; Black, Richard; Gillan, Maureen G C; Willsher, Paula; Cooke, Julie; Duncan, Karen A; Michell, Michael J; Dobson, Hilary M; Maroni, Roberta; Lim, Yit Y; Purushothaman, Hema N; Suaris, Tamara; Astley, Susan M; Young, Kenneth C; Tucker, Lorraine; Gilbert, Fiona J

    2018-01-01

    Mammographic density has been shown to be a strong independent predictor of breast cancer and a causative factor in reducing the sensitivity of mammography. There remain questions as to the use of mammographic density information in the context of screening and risk management, and of the association with cancer in populations known to be at increased risk of breast cancer. To assess the association of breast density with presence of cancer by measuring mammographic density visually as a percentage, and with two automated volumetric methods, Quantra™ and VolparaDensity™. The TOMosynthesis with digital MammographY (TOMMY) study of digital breast tomosynthesis in the Breast Screening Programme of the National Health Service (NHS) of the United Kingdom (UK) included 6020 breast screening assessment cases (of whom 1158 had breast cancer) and 1040 screened women with a family history of breast cancer (of whom two had breast cancer). We assessed the association of each measure with breast cancer risk in these populations at enhanced risk, using logistic regression adjusted for age and total breast volume as a surrogate for body mass index (BMI). All density measures showed a positive association with presence of cancer and all declined with age. The strongest effect was seen with Volpara absolute density, with a significant 3% (95% CI 1-5%) increase in risk per 10 cm 3 of dense tissue. The effect of Volpara volumetric density on risk was stronger for large and grade 3 tumours. Automated absolute breast density is a predictor of breast cancer risk in populations at enhanced risk due to either positive mammographic findings or family history. In the screening context, density could be a trigger for more intensive imaging. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Contralateral breast cancer risk

    International Nuclear Information System (INIS)

    Unnithan, Jaya; Macklis, Roger M.

    2001-01-01

    The use of breast-conserving treatment approaches for breast cancer has now become a standard option for early stage disease. Numerous randomized studies have shown medical equivalence when mastectomy is compared to lumpectomy followed by radiotherapy for the local management of this common problem. With an increased emphasis on patient involvement in the therapeutic decision making process, it is important to identify and quantify any unforeseen risks of the conservation approach. One concern that has been raised is the question of radiation- related contralateral breast cancer after breast radiotherapy. Although most studies do not show statistically significant evidence that patients treated with breast radiotherapy are at increased risk of developing contralateral breast cancer when compared to control groups treated with mastectomy alone, there are clear data showing the amount of scattered radiation absorbed by the contralateral breast during a routine course of breast radiotherapy is considerable (several Gy) and is therefore within the range where one might be concerned about radiogenic contralateral tumors. While radiation related risks of contralateral breast cancer appear to be small enough to be statistically insignificant for the majority of patients, there may exist a smaller subset which, for genetic or environmental reasons, is at special risk for scatter related second tumors. If such a group could be predicted, it would seem appropriate to offer either special counselling or special prevention procedures aimed at mitigating this second tumor risk. The use of genetic testing, detailed analysis of breast cancer family history, and the identification of patients who acquired their first breast cancer at a very early age may all be candidate screening procedures useful in identifying such at- risk groups. Since some risk mitigation strategies are convenient and easy to utilize, it makes sense to follow the classic 'ALARA' (as low as reasonably

  13. Radiologic aspects of breast cancers detected through a breast cancer screening program

    International Nuclear Information System (INIS)

    Azavedo, E.; Svane, G.

    1991-01-01

    Early detection in breast cancer and reduced mortality in women with this disease is today attributed to widespread use of mammography. High-quality performance is essential in all steps of breast cancer screening programs in order to avoid unnecessary anxiety and surgery in the women concerned. This report presents radiologic aspects of screening cancers. A total of 8370 asymptomatic women aged 50-69 years were screened with 2-view mammography, of which only 70 (0.84 percent) were selected for surgery after a thorough work-up. Cancers were verified histologically in 61 women and 9 showed non-malignant histology, giving a cancer detection rate of 7.3 cancers per thousand screened asymptomatic women. The benign/malignant ratio in the operated cases is thus approximately 1:7. The cancers detected showed all existing types of mammographic features where 77 percent (47 cases) showed rather typical findings, such as spiculated densities both with and without microcalcifications. The results indicate that surgery can be minimized without impairing the breast cancer detection rate. Radiologists in screening programs should be aware that a large proportion of non-palpable breast cancers present in rather unconventional forms. This point is important in order to maintain a high cancer detection rate and thereby justify the widespread use of mammography as a screening tool for breast cancer in asymptomatic women. (author). 20 refs.; 1 tab

  14. Breast cancer staging

    Science.gov (United States)

    ... 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. ...

  15. Breast cancer resistance protein (Bcrp1/Abcg2) limits net intestinal uptake of quercetin in rats by facilitating apical efflux of glucuronides

    NARCIS (Netherlands)

    Sesink, A.L.A.; Arts, I.C.W.; Boer, de V.C.J.; Breedveld, P.; Schellens, J.H.M.; Hollman, P.C.H.; Russel, F.G.M.

    2005-01-01

    The intestinal absorption of the flavonoid quercetin in rats is limited by the secretion of glucuronidated metabolites back into the gut lumen. The objective of this study was to determine the role of the intestinal efflux transporters breast cancer resistance protein (Bcrp1)/Abcg2 and multidrug

  16. Breast cancer resistance protein (Bcrp1/Abcg2) limits net intestinal uptake of quercetin in rats by facilitating apical efflux of glucuronides.

    NARCIS (Netherlands)

    Sesink, A.L.; Arts, I.C.; Boer, V.C. de; Breedveld, P.; Schellens, J.H.; Hollman, P.C.H.; Russel, F.G.M.

    2005-01-01

    The intestinal absorption of the flavonoid quercetin in rats is limited by the secretion of glucuronidated metabolites back into the gut lumen. The objective of this study was to determine the role of the intestinal efflux transporters breast cancer resistance protein (Bcrp1)/Abcg2 and multidrug

  17. Targeted Therapy for Breast Cancer Prevention

    Science.gov (United States)

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

    2013-01-01

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

  18. Hormone Therapy for Breast Cancer

    Science.gov (United States)

    ... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... sensitive breast cancer cells contain proteins called hormone receptors that become activated when hormones bind to them. ...

  19. Ultrasound screening of contralateral breast after surgery for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Seung Ja [Department of Radiology, Seoul Metropolitan Government Seoul National University, Boramae Medical Center (Korea, Republic of); Chung, Se-Yeong; Chang, Jung Min; Cho, Nariya [Department of Radiology, Seoul National University Hospital (Korea, Republic of); Han, Wonshik [Department of Surgery, Seoul National University Hospital (Korea, Republic of); Moon, Woo Kyung, E-mail: moonwk@snu.ac.kr [Department of Radiology, Seoul National University Hospital (Korea, Republic of)

    2015-01-15

    Highlights: • The addition of supplemental US to mammography depicted additional 5.0 cancers per 1000 postoperative women. • Positive biopsy rate of mammography-detected lesions was 66.7% (4 of 6) and that of US-detected lesions was 40.0% (6 of 15). • US can be helpful to detect mammographically occult breast cancer in the contralateral breast in women with previous history of cancer and dense breast. - Abstract: Objective: To determine whether supplemental screening ultrasound (US) to mammography could improve cancer detection rate of the contralateral breast in patients with a personal history of breast cancer and dense breasts. Materials and methods: During a one-year study period, 1314 screening patients with a personal history of breast cancer and dense breasts simultaneously underwent mammography and breast US. BI-RADS categories were given for mammography or US-detected lesions in the contralateral breast. The reference standard was histology and/or 1-year imaging follow-up, and the cancer rate according to BI-RADS categories and cancer detection rate and positive biopsy rate according to detection modality were analyzed. Results: Of 1314 patients, 84 patients (6.4%) were categorized as category 3 with one interval cancer and one cancer which was upgraded to category 4A after 6-month follow-up US (2.5% cancer rate, 95% CIs 1.5–9.1%). Fifteen patients (1.1%) had category 4A or 4B lesions in the contralateral breast. Four lesions were detected on mammography (two lesions were also visible on US) and 11 lesions were detected on US and 5 cancers were confirmed (33.3%, 95% CIs 15.0–58.5%). Six patients (0.5%) had category 4C lesions, 2 detected on mammography and 4 on US and 4 cancers were confirmed (66.7%, 95% CIs 29.6–90.8%). No lesions were categorized as category 5 in the contralateral breast. Cancer detection rate by mammography was 3.3 per 1000 patients and that by US was 5.0 per 1000 patients, therefore overall cancer detection rate by

  20. Ultrasound screening of contralateral breast after surgery for breast cancer

    International Nuclear Information System (INIS)

    Kim, Seung Ja; Chung, Se-Yeong; Chang, Jung Min; Cho, Nariya; Han, Wonshik; Moon, Woo Kyung

    2015-01-01

    Highlights: • The addition of supplemental US to mammography depicted additional 5.0 cancers per 1000 postoperative women. • Positive biopsy rate of mammography-detected lesions was 66.7% (4 of 6) and that of US-detected lesions was 40.0% (6 of 15). • US can be helpful to detect mammographically occult breast cancer in the contralateral breast in women with previous history of cancer and dense breast. - Abstract: Objective: To determine whether supplemental screening ultrasound (US) to mammography could improve cancer detection rate of the contralateral breast in patients with a personal history of breast cancer and dense breasts. Materials and methods: During a one-year study period, 1314 screening patients with a personal history of breast cancer and dense breasts simultaneously underwent mammography and breast US. BI-RADS categories were given for mammography or US-detected lesions in the contralateral breast. The reference standard was histology and/or 1-year imaging follow-up, and the cancer rate according to BI-RADS categories and cancer detection rate and positive biopsy rate according to detection modality were analyzed. Results: Of 1314 patients, 84 patients (6.4%) were categorized as category 3 with one interval cancer and one cancer which was upgraded to category 4A after 6-month follow-up US (2.5% cancer rate, 95% CIs 1.5–9.1%). Fifteen patients (1.1%) had category 4A or 4B lesions in the contralateral breast. Four lesions were detected on mammography (two lesions were also visible on US) and 11 lesions were detected on US and 5 cancers were confirmed (33.3%, 95% CIs 15.0–58.5%). Six patients (0.5%) had category 4C lesions, 2 detected on mammography and 4 on US and 4 cancers were confirmed (66.7%, 95% CIs 29.6–90.8%). No lesions were categorized as category 5 in the contralateral breast. Cancer detection rate by mammography was 3.3 per 1000 patients and that by US was 5.0 per 1000 patients, therefore overall cancer detection rate by

  1. Efficacy of breast conservation therapy in early stage bilateral breast cancer

    International Nuclear Information System (INIS)

    Lee, Misa M.; Chen, Luci M.; Heimann, Ruth; Powers, Claire; Weichselbaum, Ralph R.

    1996-01-01

    PURPOSE: To evaluate outcome of patients with bilateral breast cancer as compared to unilateral breast cancer treated with breast conservation therapy. This is a complex issue, however, we address this by comparing (1) synchronous bilateral breast cancer patients, (2) metachronous bilateral breast cancer patients from the time of diagnosis of the second breast primary, and (3) unilateral breast cancer patients. The authors recognize that there are inherent biases in these comparisons. MATERIALS AND METHODS: A total of 60 bilateral patients and 1080 unilateral patients treated with breast conservation therapy from 1977-1994 were analyzed for outcome. Of the 60 bilateral patients, 44 were metachronous bilateral breast cancer patients (MBBC) and 16 were synchronous breast cancer patients (SBBC). Patients with bilateral breast cancer had local-regional disease with the following tumor stages: DCIS=8%, T1=80%, T2=12%, pathologic N0=90%, pathologic N+=10%. Unilateral patients had the following tumor stages: DCIS=10%, T1=66%, T2=20%, T3=1.2%, Tx=2%, pathological N0=80%, pathological N+=19%, and NX=1%. The majority of patients received lumpectomy and axillary node dissection followed by radiation therapy. The median size of the lesions were 1.4cm and 1.5cm for bilateral and unilateral patients, respectively. Median total dose to the primary tumor was 60Gy for both unilateral and bilateral patients. Of the 44 metachronous bilateral breast cancer patients, 14 patients received breast conservation for both the first and second lesions while 30 patients had breast conservation for only the second metachronous breast lesion. Thus 58 lesions in the 44 patients were treated with breast conservation therapy in the patients with metachronous bilateral breast cancer. Of the synchronous bilateral breast cancer patients, 13 out of 16 patients had breast conserving therapy for both breasts, and 3 patients received mastectomy for the second synchronous breast tumor. The median follow

  2. Radiation-induced breast cancer

    International Nuclear Information System (INIS)

    Finnerty, N.A.; Buzdar, A.U.; Blumenschein, G.R.

    1984-01-01

    Between 1975 and 1983, sixteen patients with a history of irradiation at an early age to the head, neck, or chest areas for a variety of conditions in whom breast cancer subsequently developed were seen at out institute. The median latent period between the irradiation and the development of breast cancer was 420 months. The distribution of patients by stage of the disease and the median age at diagnosis of this subgroup was similar to the breast cancer observed in the general population. The subsequent course of this disease was also similar to the breast cancer observed in the general population. A substantial number of women have been exposed to irradiation at a young age, and these women are at a higher risk of having breast cancer develop. These women should be closely observed to discover the disease in an early curable stage

  3. Hereditary forms of breast cancer

    International Nuclear Information System (INIS)

    Bella, V.

    2009-01-01

    Breast cancer is the most common oncologic disease in the female population. Besides the sporadic occurrence it occurs in the familial and hereditary form. Persons with the occurrence of positive family anamnesis of breast cancer should be actively investigated. In the indicated cases it is necessary to send the woman to genetic examination. In case that the hereditary form of breast cancer is affirmed it is necessary to examine her family relatives. Women with the hereditary form of breast cancer occur in about 5 – 10 % portion from all women diagnosed with breast cancer. Nowadays we already know that 80 % of hereditary breast cancers are due to germ mutations in BRCA 1 and BRCA 2 gene. Persons with detected gene mutations must be dispensarized in the centres intended for it. (author)

  4. Genetics Home Reference: breast cancer

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions Breast cancer Breast cancer Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Breast cancer is a disease in which certain cells in ...

  5. Awareness and current knowledge of breast cancer.

    Science.gov (United States)

    Akram, Muhammad; Iqbal, Mehwish; Daniyal, Muhammad; Khan, Asmat Ullah

    2017-10-02

    Breast cancer remains a worldwide public health dilemma and is currently the most common tumour in the globe. Awareness of breast cancer, public attentiveness, and advancement in breast imaging has made a positive impact on recognition and screening of breast cancer. Breast cancer is life-threatening disease in females and the leading cause of mortality among women population. For the previous two decades, studies related to the breast cancer has guided to astonishing advancement in our understanding of the breast cancer, resulting in further proficient treatments. Amongst all the malignant diseases, breast cancer is considered as one of the leading cause of death in post menopausal women accounting for 23% of all cancer deaths. It is a global issue now, but still it is diagnosed in their advanced stages due to the negligence of women regarding the self inspection and clinical examination of the breast. This review addresses anatomy of the breast, risk factors, epidemiology of breast cancer, pathogenesis of breast cancer, stages of breast cancer, diagnostic investigations and treatment including chemotherapy, surgery, targeted therapies, hormone replacement therapy, radiation therapy, complementary therapies, gene therapy and stem-cell therapy etc for breast cancer.

  6. Breast cancer patterns and lifetime risk of developing breast cancer among Puerto Rican females.

    Science.gov (United States)

    Nazario, C M; Figueroa-Vallés, N; Rosario, R V

    2000-03-01

    The purpose of this study was to evaluate the epidemiologic patterns of breast cancer and to estimate the lifetime risk probability of developing breast cancer among Hispanic females using cancer data from Puerto Rico. The age-adjusted breast cancer incidence rate (per 100,000) in Puerto Rico increased from 15.3 in 1960-1964 to 43.3 in 1985-1989. The age-adjusted breast cancer mortality rate (per 100,000) increased from 5.7 to 10.6 comparing the same two time periods (1960-1964 vs 1985-1989). Nevertheless, in 1985-1989 breast cancer incidence rate was higher in US White females (110.8 per 100,000) compared to Puerto Rican females (51.4 per 100,000; age-adjusted to the 1970 US standard population). The breast cancer mortality rate was also higher in US White females (27.4 per 100,000) than in Puerto Rican females (15.1 per 100,000; age-adjusted to the 1970 US standard population) during 1985-1989. A multiple decrement life table was constructed applying age-specific incidence and mortality rates from cross-sectional data sets (1980-1984 and 1985-1989 data for Puerto Rican females and 1987-1989 SEER data sets for US White and Black females) to a hypothetical cohort of 10,000,000 women. The probability of developing invasive breast cancer was computed for the three groups using the long version of DEVCAN: Probability of DEVeloping CANcer software, version 3.3. The lifetime risk of developing breast cancer was 5.4% for Puerto Rican females, compared to 8.8% for US Black females and 13.0% for US White females. Lifetime risk for Puerto Rican females increased from 4.5% in 1980-1984 to 5.4% in 1985-1989. Lifetime risk of breast cancer appears to be increasing in Puerto Rico, but remains lower than the probability for US White females. Therefore, the application of lifetime probability of developing invasive breast cancer estimated for the US female population will overestimate the risk for the Puerto Rican female population.

  7. Breast cancer epidemiology and risk factors

    International Nuclear Information System (INIS)

    Broeders, M. J. M.; Verbeek, A. L. M.

    1997-01-01

    Breast cancer is the most common malignancy among women in the Western society. Over the past decades it has become apparent that breast cancer incidence rates are increasing steadily, whereas the mortality rates for breast cancer have remained relatively constant. Information through the media on this rising number of cases has increased breast health awareness but has also introduced anxiety in the female population. This combination of factors has made the need for prevention of breast cancer an urgent matter. Breast cancer does not seem to be a single disease entity. A specific etiologic factor may therefore have more influence on one form may therefore have more influence on one form of breast cancer than another. So far though, as shown in their summary of current knowledge on established and dubious risk factors, no risk factors have been identified that can explain a major part of the incidence. Efforts to identify other ways for primary prevention have also been discouraging, even though breast cancer is one of the most investigated tumours world-wide. Thus, at this point i time, the most important strategy to reduce breast cancer mortality is early detection through individual counselling and organised breast screening programs. The recent isolation of breast cancer susceptibility genes may introduce new ways to reduce the risk of breast cancer in a small subset of women

  8. Breast Cancer and Bone Loss

    Science.gov (United States)

    ... Menopause Map Featured Resource Find an Endocrinologist Search Breast Cancer and Bone Loss July 2010 Download PDFs English ... G. Komen Foundation What is the link between breast cancer and bone loss? Certain treatments for breast cancer ...

  9. Treatment Option Overview (Breast Cancer)

    Science.gov (United States)

    ... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... only hormone therapy after a hysterectomy . Selective estrogen receptor modulators (SERMs). Aromatase inhibitors . Less exposure of breast ...

  10. Identifying Breast Cancer Oncogenes

    Science.gov (United States)

    2011-10-01

    cells we observed that it promoted transformation of HMLE cells, suggesting a tumor suppressive role of Merlin in breast cancer (Figure 4B). A...08-1-0767 TITLE: Identifying Breast Cancer Oncogenes PRINCIPAL INVESTIGATOR: Yashaswi Shrestha...Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 W81XWH-08-1-0767 Identifying Breast Cancer Oncogenes Yashaswi Shrestha Dana-Farber

  11. Breast cancer literacy and health beliefs related to breast cancer screening among American Indian women.

    Science.gov (United States)

    Roh, Soonhee; Burnette, Catherine E; Lee, Yeon-Shim; Jun, Jung Sim; Lee, Hee Yun; Lee, Kyoung Hag

    2018-08-01

    The purpose of this article is to examine the health beliefs and literacy about breast cancer and their relationship with breast cancer screening among American Indian (AI) women. Using the Health Belief Model (HBM) and hierarchical logistic regression with data from a sample of 286 AI female adults residing in the Northern Plains, we found that greater awareness of breast cancer screening was linked to breast cancer screening practices. However, perceived barriers, one of the HBM constructs, prevented such screening practices. This study suggested that culturally relevant HBM factors should be targeted when developing culturally sensitive breast cancer prevention efforts.

  12. Computed tomography of the breast cancer

    International Nuclear Information System (INIS)

    Chung, Soo Young; Lee, Yul; Bae, Sang Hoon; Yoon, Jong Sup; Lee, Ki Chu

    1985-01-01

    The indication of computed tomography for the breast lesion are 1) Unusually extensive or small breast caused technical difficulties in performing mammograms. 2) Questionable mammographic findings, especially in dense proliferative breast parenchyme. 3) Microcancer. 4) Suspicious regional lymph node enlargement or invasive of the chest wall by breast cancer. The diagnosis of breast CT in breast cancer is based on pathologic anatomic changes and characteristic increase of mean CT No. of lesion following contrast enhancement. Authors analysed CT of the 34 patients who were clinically suspected breast cancer, and compared with mammography. The results are as follows: 1. Pathological diagnosis of 34 cases were 27 cases of breast cancer, 4 cases of fibrocystic disease, 2 cases of fibroadenoma, and 1 case of intraductal papilloma. The diagnostic accuracy of CT in 27 breast cancer was 93% (25 cases) and mammography 71% (19 case). 2. Correct diagnosis of CT in 7 benign breast disease is in 5 cases and mammography in 5 cases. 3. The most important finding of CT in breast cancer is characteristic increase of CT No. of lesion following contrast enhancement (200 ml, 65%): over average 50 HU in 19 cases of 27 breast cancers, 30-50 HU in a 6 cases, 20-30 HU in 2 cases with tumor necrosis. 4. Computed with mammography, other more valuable CT findings of breast cancer are axillary lymph node enlargement and adjacentic pectoral muscle invasion. 5. In conclusion, breast CT is considered as valuable diagnostic tool in evaluation of breast cancer, but not of benign breast disease

  13. Computed tomography of the breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Soo Young; Lee, Yul; Bae, Sang Hoon; Yoon, Jong Sup; Lee, Ki Chu [Hallym University Medical Center, Seoul (Korea, Republic of)

    1985-12-15

    The indication of computed tomography for the breast lesion are 1) Unusually extensive or small breast caused technical difficulties in performing mammograms. 2) Questionable mammographic findings, especially in dense proliferative breast parenchyme. 3) Microcancer. 4) Suspicious regional lymph node enlargement or invasive of the chest wall by breast cancer. The diagnosis of breast CT in breast cancer is based on pathologic anatomic changes and characteristic increase of mean CT No. of lesion following contrast enhancement. Authors analysed CT of the 34 patients who were clinically suspected breast cancer, and compared with mammography. The results are as follows: 1. Pathological diagnosis of 34 cases were 27 cases of breast cancer, 4 cases of fibrocystic disease, 2 cases of fibroadenoma, and 1 case of intraductal papilloma. The diagnostic accuracy of CT in 27 breast cancer was 93% (25 cases) and mammography 71% (19 case). 2. Correct diagnosis of CT in 7 benign breast disease is in 5 cases and mammography in 5 cases. 3. The most important finding of CT in breast cancer is characteristic increase of CT No. of lesion following contrast enhancement (200 ml, 65%): over average 50 HU in 19 cases of 27 breast cancers, 30-50 HU in a 6 cases, 20-30 HU in 2 cases with tumor necrosis. 4. Computed with mammography, other more valuable CT findings of breast cancer are axillary lymph node enlargement and adjacentic pectoral muscle invasion. 5. In conclusion, breast CT is considered as valuable diagnostic tool in evaluation of breast cancer, but not of benign breast disease.

  14. Male breast cancer

    DEFF Research Database (Denmark)

    Lautrup, Marianne D; Thorup, Signe S; Jensen, Vibeke

    2018-01-01

    OBJECTIVE: Describe prognostic parameters of Danish male breast cancer patients (MBCP) diagnosed from 1980-2009. Determine all-cause mortality compared to the general male population and analyze survival/mortality compared with Danish female breast cancer patients (FBCP) in the same period...

  15. Unemployment among breast cancer survivors.

    Science.gov (United States)

    Carlsen, Kathrine; Ewertz, Marianne; Dalton, Susanne Oksbjerg; Badsberg, Jens Henrik; Osler, Merete

    2014-05-01

    Though about 20% of working age breast cancer survivors do not return to work after treatment, few studies have addressed risk factors for unemployment. The majority of studies on occupational consequences of breast cancer focus on non-employment, which is a mixture of sickness absence, unemployment, retirement pensions and other reasons for not working. Unemployment in combination with breast cancer may represent a particular challenge for these women. The aim of the present study is therefore to analyze the risk for unemployment in the years following diagnosis and treatment for breast cancer. This study included 14,750 women diagnosed with breast cancer in Denmark 2001-2009 identified through a population-based clinical database and linked with information from Danish administrative population based registers for information on labour market affiliation, socio-demography and co-morbid conditions. Multivariable analyses were performed by Cox's proportional hazard models. Two years after treatment, 81% of patients were still part of the work force, 10% of which were unemployed. Increasing duration of unemployment before breast cancer was associated with an adjusted HR = 4.37 (95% CI: 3.90-4.90) for unemployment after breast cancer. Other risk factors for unemployment included low socioeconomic status and demography, while adjuvant therapy did not increase the risk of unemployment. Duration of unemployment before breast cancer was the most important determinant of unemployment after breast cancer treatment. This allows identification of a particularly vulnerable group of patients in need of rehabilitation.

  16. Interrelationships of Prenatal and Postnatal Growth, Hormones, Diet, and Breast Cancer

    National Research Council Canada - National Science Library

    Sanderson, Maureen

    2006-01-01

    .... Based on these interrelationships, we hypothesized that insulin resistance would be positively associated with breast cancer, and that genetic susceptibility, and adolescent/adult diet and physical...

  17. Label-free recognition of drug resistance via impedimetric screening of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Bilge Eker

    Full Text Available We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX from their parental cells (MCF-7 WT via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra . Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

  18. Breast Cancer Basics and You

    Science.gov (United States)

    ... page please turn JavaScript on. Feature: Screening For Breast Cancer Breast Cancer Basics and You Past Issues / Summer 2014 Table ... more than 232,670 new cases of female breast cancer in the United States in 2014. More than ...

  19. Retrospective observation on contribution and limitations of screening for breast cancer with mammography in Korea: detection rate of breast cancer and incidence rate of interval cancer of the breast.

    Science.gov (United States)

    Lee, Kunsei; Kim, Hyeongsu; Lee, Jung Hyun; Jeong, Hyoseon; Shin, Soon Ae; Han, Taehwa; Seo, Young Lan; Yoo, Youngbum; Nam, Sang Eun; Park, Jong Heon; Park, Yoo Mi

    2016-11-18

    The purpose of this study was to determine the benefits and limitations of screening for breast cancer using mammography. Descriptive design with follow-up was used in the study. Data from breast cancer screening and health insurance claim data were used. The study population consisted of all participants in breast cancer screening from 2009 to 2014. Crude detection rate, positive predictive value and sensitivity and specificity of breast cancer screening and, incidence rate of interval cancer of the breast were calculated. The crude detection rate of breast cancer screening per 100,000 participants increased from 126.3 in 2009 to 182.1 in 2014. The positive predictive value of breast cancer screening per 100,000 positives increased from 741.2 in 2009 to 1,367.9 in 2014. The incidence rate of interval cancer of the breast per 100,000 negatives increased from 51.7 in 2009 to 76.3 in 2014. The sensitivities of screening for breast cancer were 74.6% in 2009 and 75.1% in 2014 and the specificities were 83.1% in 2009 and 85.7% in 2014. To increase the detection rate of breast cancer by breast cancer screening using mammography, the participation rate should be higher and an environment where accurate mammography and reading can be performed and reinforcement of quality control are required. To reduce the incidence rate of interval cancer of the breast, it will be necessary to educate women after their 20s to perform self-examination of the breast once a month regardless of participation in screening for breast cancer.

  20. Pharmacogenetics and breast cancer management: current status and perspectives.

    Science.gov (United States)

    Ciccolini, Joseph; Fanciullino, Raphaelle; Serdjebi, Cindy; Milano, Gérard

    2015-05-01

    Breast cancer has benefited from a number of innovative therapeutics over the last decade. Cytotoxics, hormone therapy, targeted therapies and biologics can now be given to ensure optimal management of patients. As life expectancy of breast cancer patients has been significantly stretched and that several lines of treatment are now made available, determining the best drug or drug combinations to be primarily given and the best dosing and scheduling for each patient is critical for ensuring an optimal toxicity/efficacy balance. Defining patient's characteristics at the tumor level (pharmacogenomics) and the constitutional level (pharmacogenetics) is a rising trend in oncology. This review covers the latest strategies based upon the search of relevant biomarkers for efficacy, resistance and toxicity to be undertaken at the bedside to shift towards precision medicine in breast cancer patients. In the expanding era of bioguided medicine, identifying relevant and clinically validated biomarkers from the plethora of published material remains an uneasy task. Sorting the variety of genetic and molecular markers that have been investigated over the last decade on their level of evidence and addressing the issue of drug exposure should help to improve the management of breast cancer therapy.

  1. Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer

    DEFF Research Database (Denmark)

    Szallasi, Zoltan Imre; Li, Yang; Zou, Lihua

    2010-01-01

    Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific...... chemotherapy drugs is a challenge but is necessary to improve outcomes. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed...... that 8q22 amplification and overexpression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines and are permissive for metastatic recurrence. Overexpression of these two genes may predict anthracycline resistance and influence selection of chemotherapy....

  2. Awareness of Breast Cancer and Breast Self Examination Among ...

    African Journals Online (AJOL)

    Background: Breast cancer is the commonest malignancy affecting women in Nigeria. Regular breast self examination reduces morbidity and mortality from this disease. Objective: To assess the knowledge of breast cancer, breast self examination and practice amongst secondary school teachers in Enugu , Nigeria.

  3. Early breast cancer

    International Nuclear Information System (INIS)

    Dongen, J.A. van

    1989-01-01

    The therapy of early breast cancer has been changing during the last decennium. It requires a multi-disciplinary approach and in each of these disciplines improvements have been implemented. The result is that treatment schedules can now be adapted to specific subgroups. In this review early breast cancer is defined as operable disease, using the criteria set out by Haagensen. Emphasis is given to describing the new developments in prognostic criteria, since these form the basis for creating subgroups for specific treatment schedules. Distinction is made between the factors relating to growth rate and those relating to metastatic potential. Data on screening promises a beneficial effect of the implementation of screening in national health care programs. Important shifts are seen in treatment schedules; the place of postoperative radiotherapy after classic ablative treatment is being challenged, whereas it plays a major role in the new breast conserving therapy schedules. The data mentioned in the review suggest that a large proportion of 'operable' cases can be treated with breast conservation but details in the technique of breast conserving therapy are still under investigation. They form a major part of the coming prospective studies in breast cancer. Improvements in reconstruction techniques, creating better cosmetic results, make reconstruction more competitive with breast conserving therapy. The use of chemotherapy and endocrine manipulation in early breast cancer has now been clearly confirmed by the overview technique by the Peto-group, thanks to all efforts of individual trialists together. (orig.)

  4. Chemo Resistance of Breast Cancer Stem Cells

    National Research Council Canada - National Science Library

    Wicha, Max S

    2006-01-01

    .... Development of this new tool will greatly facilitate future studies. Preliminary results both in xenograft models as well as in neoadjuvant trial are providing strong support for our hypothesis for resistance of cancer cells to chemotherapy...

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

    Science.gov (United States)

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

    2015-01-01

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

  6. CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer-Specific Death, and Increased Risk of a Second Breast Cancer

    DEFF Research Database (Denmark)

    Weischer, Maren; Nordestgaard, Børge G; Pharoah, Paul

    2012-01-01

    PURPOSE We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. PATIENTS AND METHODS From 22 studies participating in the Breast Cancer Assoc...

  7. Breast cancer subtype distribution is different in normal weight, overweight, and obese women.

    Science.gov (United States)

    Gershuni, Victoria; Li, Yun R; Williams, Austin D; So, Alycia; Steel, Laura; Carrigan, Elena; Tchou, Julia

    2017-06-01

    Obesity is associated with tumor promoting pathways related to insulin resistance and chronic low-grade inflammation which have been linked to various disease states, including cancer. Many studies have focused on the relationship between obesity and increased estrogen production, which contributes to the pathogenesis of estrogen receptor-positive breast cancers. The link between obesity and other breast cancer subtypes, such as triple-negative breast cancer (TNBC) and Her2/neu+ (Her2+) breast cancer, is less clear. We hypothesize that obesity may be associated with the pathogenesis of specific breast cancer subtypes resulting in a different subtype distribution than normal weight women. A single-institution, retrospective analysis of tumor characteristics of 848 patients diagnosed with primary operable breast cancer between 2000 and 2013 was performed to evaluate the association between BMI and clinical outcome. Patients were grouped based on their BMI at time of diagnosis stratified into three subgroups: normal weight (BMI = 18-24.9), overweight (BMI = 25-29.9), and obese (BMI > 30). The distribution of breast cancer subtypes across the three BMI subgroups was compared. Obese and overweight women were more likely to present with TNBC and normal weight women with Her2+ breast cancer (p = 0.008). We demonstrated, for the first time, that breast cancer subtype distribution varied significantly according to BMI status. Our results suggested that obesity might activate molecular pathways other than the well-known obesity/estrogen circuit in the pathogenesis of breast cancer. Future studies are needed to understand the molecular mechanisms that drive the variation in subtype distribution across BMI subgroups.

  8. Osteopontin splice variants are differential predictors of breast cancer treatment responses

    OpenAIRE

    Zduniak, Krzysztof; Agrawal, Anil; Agrawal, Siddarth; Hossain, Md Monir; Ziolkowski, Piotr; Weber, Georg F.

    2016-01-01

    Background Osteopontin is a marker for breast cancer progression, which in previous studies has also been associated with resistance to certain anti-cancer therapies. It is not known which splice variants may mediate treatment resistance. Methods Here we analyze the association of osteopontin variant expression before treatment, differentiated according to immunohistochemistry with antibodies to exon 4 and to the osteopontin-c splice junction respectively, with the ensuing therapy responses i...

  9. Cutaneous manifestations of breast cancer

    OpenAIRE

    Agnieszka B. Owczarczyk-Saczonek; Dawid Sigorski; Paweł Różanowski; Agnieszka Markiewicz; Waldemar J. Placek

    2017-01-01

    Breast cancer is the most common malignant neoplasm among women in Poland and in the European Union. According to most recent data of the Polish National Cancer Registry, in 2014 breast cancer was diagnosed in over 17,000 women. Based on the National Health Fund records, it is estimated that there are about 55,000–60,000 women in Poland who have a history of breast cancer diagnosis and are potentially at a risk of relapse. The most common sign of breast cancer is the presence of a nodule, how...

  10. Targeting HER 1 and 2 in breast cancer with lapatinib

    Directory of Open Access Journals (Sweden)

    Gerald M. Higa

    2011-12-01

    Full Text Available Numerous clinical trials support the biological relevance of the HER2 oncoprotein in breast cancer. In spite of improved outcomes, overexpression of the receptor is associated with increased risks of disease relapse, even in patients with early, and potentially curable, disease. Until recently, development of resistance to trastuzumab left patients with no therapeutic option other than specifically targeted HER2. This paper provides an in-depth review of lapatinib, a dual HER kinase inhibitor, as well as some insight into three HER family members, in breast cancer.

  11. Rat models of 17β-estradiol-induced mammary cancer reveal novel insights into breast cancer etiology and prevention.

    Science.gov (United States)

    Shull, James D; Dennison, Kirsten L; Chack, Aaron C; Trentham-Dietz, Amy

    2018-03-01

    Numerous laboratory and epidemiologic studies strongly implicate endogenous and exogenous estrogens in the etiology of breast cancer. Data summarized herein suggest that the ACI rat model of 17β-estradiol (E2)-induced mammary cancer is unique among rodent models in the extent to which it faithfully reflects the etiology and biology of luminal types of breast cancer, which together constitute ~70% of all breast cancers. E2 drives cancer development in this model through mechanisms that are largely dependent upon estrogen receptors and require progesterone and its receptors. Moreover, mammary cancer development appears to be associated with generation of oxidative stress and can be modified by multiple dietary factors, several of which may attenuate the actions of reactive oxygen species. Studies of susceptible ACI rats and resistant COP or BN rats provide novel insights into the genetic bases of susceptibility and the biological processes regulated by genetic determinants of susceptibility. This review summarizes research progress resulting from use of these physiologically relevant rat models to advance understanding of breast cancer etiology and prevention.

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

    Science.gov (United States)

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

    2014-01-01

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

  13. Therapeutic Potential of a Novel Smac/DIABLO in Breast Cancer

    National Research Council Canada - National Science Library

    Srivastava, Rakesh K

    2005-01-01

    ... potential of tamoxifen, doxorubicin and paclitaxel. Overexpression of Smac/DIABLO gene or Smac peptide enhances the apoptosis-inducing potential of tamoxifen, doxorubicin and paclitaxel, and sentitizes TRAiL-resistant breast cancer cell lines...

  14. Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab.

    Science.gov (United States)

    Sharieh, Elham Abu; Awidi, Abdulla S; Ahram, Mamoun; Zihlif, Malek A

    2016-01-10

    Development of resistance against cancer therapeutic agents is a common problem in cancer management. Trastuzumab resistance is one of the challenges in management of HER-2-positive breast cancer patients resulting in breast cancer progression, metastasis, and patient poor outcome. The aim of this study is to determine the alteration in gene expression in response to Trastuzumab resistance after long-term exposure to Trastuzumab. The Trastuzumab-resistant MDA-MB-453 (MDA-MB-453/TR) cell line was developed by exposing cells to 10 μM Trastuzumab continuously for 6 months. Sensitivity toward Trastuzumab was tested using cell viability assays. The acquisition of an epithelial-to mesenchymal transition (EMT) phenotype was also observed in parallel with the development of resistance. Based on the real-time-based PCR array technology, several genes were altered affecting multiple networks. The most up-regulated genes were TGF-β1 and EGF, and IGFBP-3. These genes are known to have a critical role in Trastuzumab resistance in breast cancer cell lines and/or in the acquisition of EMT. They are also recognized for their role in cancer progression and metastasis. These alterations indicate that the development of Trastuzumab resistance is multifactorial and involves a development of a mesenchymal like phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. THE MAMMOGRAPHIC CALCIFICATIONS IN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    Tang Ruiying; Liu Jingxian; Gaowen

    1998-01-01

    Objective: This study was performed to exam the relativeship between mammographic calcifications and breast cancer. Methods: All of the 184 patients with breast diseases underwent mammography before either an open biopsy or a mastectomy. The presence,morphology, and distribution of calcifications visualized on mammograms for breast cancer were compared with the controls who remained cancer free. Statistical comparisons were made by using the x2 test. Results:Of the 184 patients with breast diaeases, 93 malignant and 91 benign lesions were histologically confirmed.Calcifications were visualized on mammograms in 60(64%) of 93 breast cancers and 26 (28%) of 91 non breast cancers. The estimated odds ratio (OR) of breast cancer was 4.5 in women with calcifications seen on mammograms, compared with those having none (P<0.01). Of the 60 breast carcinomas having mammographic calcifications, 28 (47%) were infiltrating ductal carcinomas.There were only 8 (24%) cases with infiltrating ductal cancers in the group of without calcifications seen on the mammograms (P<0.05). Conclusion: Our finding suggests that mammographic calcification appears to be a risk factor for breast cancer. The granular and linear cast type calcification provide clues to the presence of breast cancer, especially when the carcinomas without associated masses were seen on mammograms.

  16. Metastasis of breast cancer cells to the bone, lung, and lymph nodes promotes resistance to ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Hara, Takamitsu [Gunma Prefectural College of Health Sciences, Department of Radiological Technology, School of Radiological Technology, Gunma, Maebashi (Japan); Iwadate, Manabu [Fukushima Medical University, Department of Thyroid and Endocrinology, School of Medicine, Fukushima (Japan); Tachibana, Kazunoshin [Fukushima Medical University, Department of Breast Surgery, School of Medicine, Fukushima (Japan); Waguri, Satoshi [Fukushima Medical University, Department of Anatomy and Histology, School of Medicine, Fukushima (Japan); Takenoshita, Seiichi [Fukushima Medical University, Advanced Clinical Research Center, Fukushima Global Medical Science Center, School of Medicine, Fukushima (Japan); Hamada, Nobuyuki [Central Research Institute of Electric Power Industry (CRIEPI), Radiation Safety Research Center, Nuclear Technology Research Laboratory, Tokyo, Komae (Japan)

    2017-10-15

    Metastasis represents the leading cause of breast cancer deaths, necessitating strategies for its treatment. Although radiotherapy is employed for both primary and metastatic breast cancers, the difference in their ionizing radiation response remains incompletely understood. This study is the first to compare the radioresponse of a breast cancer cell line with its metastatic variants and report that such metastatic variants are more radioresistant. A luciferase expressing cell line was established from human basal-like breast adenocarcinoma MDA-MB-231 and underwent in vivo selections, whereby a cycle of inoculations into the left cardiac ventricle or the mammary fat pad of athymic nude mice, isolation of metastases to the bone, lung and lymph nodes visualized with bioluminescence imaging, and expansion of obtained cells was repeated twice or three times. The established metastatic cell lines were assessed for cell proliferation, wound healing, invasion, clonogenic survival, and apoptosis. The established metastatic cell lines possessed an increased proliferative potential in vivo and were more chemotactic, invasive, and resistant to X-ray-induced clonogenic inactivation and apoptosis in vitro. Breast cancer metastasis to the bone, lung, and lymph nodes promotes radioresistance. (orig.) [German] Metastasierung ist die Hauptursache fuer den toedlichen Verlauf von Brustkrebserkrankungen. Darauf muessen spezifische Behandlungsstrategien ausgerichtet werden. Sowohl primaere als auch metastatische Brustkrebsarten koennen mit einer Strahlentherapie behandelt werden, allerdings sind die Unterschiede in der Reaktion auf ionisierende Strahlung bis heute nicht vollstaendig verstanden. In dieser Studie wird zum ersten Mal die Strahlenantwort einer Brustkrebszelllinie mit der ihrer metastatischen Varianten verglichen und die erhoehte Strahlenresistenz der metastatischen Varianten gezeigt. Eine Luciferase-exprimierende Zelllinie wurde aus humanen basaloiden Brustadenokarzinomen

  17. Human papilloma viruses (HPV and breast cancer.

    Directory of Open Access Journals (Sweden)

    James Sutherland Lawson

    2015-12-01

    Full Text Available Purpose: Human papillomaviruses (HPV may have a role in some breast cancers. The purpose of this study is to fill important gaps in the evidence. These gaps are: (i confirmation of the presence of high risk for cancer HPVs in breast cancers, (ii evidence of HPV infections in benign breast tissues prior to the development of HPV positive breast cancer in the same patients, (iii evidence that HPVs are biologically active and not harmless passengers in breast cancer.Methods: RNA-seq data from The Cancer Genome Atlas (TCGA was used to identify HPV RNA sequences in breast cancers. We also conducted a retrospective cohort study based on polymerase chain reaction (PCR analyses to identify HPVs in archival specimens from Australian women with benign breast biopsies who later developed breast cancer. To assess whether HPVs in breast cancer were biologically active, the expression of the oncogenic protein HPV E7 was assessed by immunohistochemistry (IHC.Results: Thirty (3.5% low risk and 20 (2.3% high risk HPV types were identified in 855 breast cancers from the TCGA data base. The high risk types were HPV 18 (48%, HPV 113 (24%, HPV 16 (10%, HPV 52 (10%. Data from the PCR cohort study, indicated that HPV type 18 was the most common type identified in breast cancer specimens (55% of 40 breast cancer specimens followed by HPV 16 (13%. The same HPV type was identified in both the benign and subsequent breast cancer in 15 patients. HPV E7 proteins were identified in 72% of benign breast specimens and 59% of invasive breast cancer specimens.Conclusions: There were 4 observations of particular interest: (i confirmation by both NGS and PCR of the presence of high risk HPV gene sequences in breast cancers, (ii a correlation between high risk HPV in benign breast specimens and subsequent HPV positive breast cancer in the same patient, (iii HPVs in breast cancer are likely to be biologically active (as shown by transcription of HPV DNA to RNA plus the expression of

  18. Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation.

    Science.gov (United States)

    Lewis, Joan S; Meeke, Kathleen; Osipo, Clodia; Ross, Eric A; Kidawi, Noman; Li, Tianyu; Bell, Eric; Chandel, Navdeep S; Jordan, V Craig

    2005-12-07

    We previously developed an estrogen receptor (ER)-positive breast cancer cell line (MCF-7:5C) that is resistant to long-term estrogen deprivation and undergoes rapid and complete apoptosis in the presence of physiologic concentrations of 17beta-estradiol. Here, we investigated the role of the mitochondrial apoptotic pathway in this process. Apoptosis in MCF-7:5C cells treated with estradiol, fulvestrant, or vehicle (control) was investigated by annexin V-propidium iodide double staining and 4',6-diamidino-2-phenylindole (DAPI) staining. Apoptosis was also analyzed in MCF-7:5C cells transiently transfected with small interfering RNAs (siRNAs) to apoptotic pathway components. Expression of apoptotic pathway intermediates was measured by western blot analysis. Mitochondrial transmembrane potential (psim) was determined by rhodamine-123 retention assay. Mitochondrial pathway activity was determined by cytochrome c release and cleavage of poly(ADP-ribose) polymerase (PARP) protein. Tumorigenesis was studied in ovariectomized athymic mice that were injected with MCF-7:5C cells. Differences between the treatment groups and control group were determined by two-sample t test or one-factor analysis of variance. All statistical tests were two-sided. MCF-7:5C cells treated with estradiol underwent apoptosis and showed increased expression of proapoptotic proteins, decreased psim, enhanced cytochrome c release, and PARP cleavage compared with cells treated with fulvestrant or vehicle. Blockade of Bax, Bim, and p53 mRNA expression by siRNA reduced estradiol-induced apoptosis relative to control by 76% [95% confidence interval (CI) = 73% to 79%, P estradiol-induced apoptosis in long-term estrogen-deprived breast cancer cells. Physiologic concentrations of estradiol could potentially be used to induce apoptosis and tumor regression in tumors that have developed resistance to aromatase inhibitors.

  19. Risk of treatment-related esophageal cancer among breast cancer survivors

    DEFF Research Database (Denmark)

    Morton, L M; Gilbert, E S; Hall, P

    2012-01-01

    Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use.......Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use....

  20. Evidence that breast tissue stiffness is associated with risk of breast cancer.

    Science.gov (United States)

    Boyd, Norman F; Li, Qing; Melnichouk, Olga; Huszti, Ella; Martin, Lisa J; Gunasekara, Anoma; Mawdsley, Gord; Yaffe, Martin J; Minkin, Salomon

    2014-01-01

    Evidence from animal models shows that tissue stiffness increases the invasion and progression of cancers, including mammary cancer. We here use measurements of the volume and the projected area of the compressed breast during mammography to derive estimates of breast tissue stiffness and examine the relationship of stiffness to risk of breast cancer. Mammograms were used to measure the volume and projected areas of total and radiologically dense breast tissue in the unaffected breasts of 362 women with newly diagnosed breast cancer (cases) and 656 women of the same age who did not have breast cancer (controls). Measures of breast tissue volume and the projected area of the compressed breast during mammography were used to calculate the deformation of the breast during compression and, with the recorded compression force, to estimate the stiffness of breast tissue. Stiffness was compared in cases and controls, and associations with breast cancer risk examined after adjustment for other risk factors. After adjustment for percent mammographic density by area measurements, and other risk factors, our estimate of breast tissue stiffness was significantly associated with breast cancer (odds ratio = 1.21, 95% confidence interval = 1.03, 1.43, p = 0.02) and improved breast cancer risk prediction in models with percent mammographic density, by both area and volume measurements. An estimate of breast tissue stiffness was associated with breast cancer risk and improved risk prediction based on mammographic measures and other risk factors. Stiffness may provide an additional mechanism by which breast tissue composition is associated with risk of breast cancer and merits examination using more direct methods of measurement.

  1. Combining quantitative and qualitative breast density measures to assess breast cancer risk.

    Science.gov (United States)

    Kerlikowske, Karla; Ma, Lin; Scott, Christopher G; Mahmoudzadeh, Amir P; Jensen, Matthew R; Sprague, Brian L; Henderson, Louise M; Pankratz, V Shane; Cummings, Steven R; Miglioretti, Diana L; Vachon, Celine M; Shepherd, John A

    2017-08-22

    Accurately identifying women with dense breasts (Breast Imaging Reporting and Data System [BI-RADS] heterogeneously or extremely dense) who are at high breast cancer risk will facilitate discussions of supplemental imaging and primary prevention. We examined the independent contribution of dense breast volume and BI-RADS breast density to predict invasive breast cancer and whether dense breast volume combined with Breast Cancer Surveillance Consortium (BCSC) risk model factors (age, race/ethnicity, family history of breast cancer, history of breast biopsy, and BI-RADS breast density) improves identifying women with dense breasts at high breast cancer risk. We conducted a case-control study of 1720 women with invasive cancer and 3686 control subjects. We calculated ORs and 95% CIs for the effect of BI-RADS breast density and Volpara™ automated dense breast volume on invasive cancer risk, adjusting for other BCSC risk model factors plus body mass index (BMI), and we compared C-statistics between models. We calculated BCSC 5-year breast cancer risk, incorporating the adjusted ORs associated with dense breast volume. Compared with women with BI-RADS scattered fibroglandular densities and second-quartile dense breast volume, women with BI-RADS extremely dense breasts and third- or fourth-quartile dense breast volume (75% of women with extremely dense breasts) had high breast cancer risk (OR 2.87, 95% CI 1.84-4.47, and OR 2.56, 95% CI 1.87-3.52, respectively), whereas women with extremely dense breasts and first- or second-quartile dense breast volume were not at significantly increased breast cancer risk (OR 1.53, 95% CI 0.75-3.09, and OR 1.50, 95% CI 0.82-2.73, respectively). Adding continuous dense breast volume to a model with BCSC risk model factors and BMI increased discriminatory accuracy compared with a model with only BCSC risk model factors (C-statistic 0.639, 95% CI 0.623-0.654, vs. C-statistic 0.614, 95% CI 0.598-0.630, respectively; P breasts and fourth

  2. DEGRO practical guidelines. Radiotherapy of breast cancer I. Radiotherapy following breast conserving therapy for invasive breast cancer

    International Nuclear Information System (INIS)

    Sedlmayer, F.

    2013-01-01

    Background and purpose: The aim of the present paper is to update the practical guidelines for postoperative adjuvant radiotherapy of breast cancer published in 2007 by the breast cancer expert panel of the German Society for Radiooncology (Deutsche Gesellschaft fuer Radioonkologie, DEGRO). The present recommendations are based on a revision of the German interdisciplinary S-3 guidelines published in July 2012. Methods: A comprehensive survey of the literature concerning radiotherapy following breast conserving therapy (BCT) was performed using the search terms 'breast cancer', 'radiotherapy', and 'breast conserving therapy'. Data from lately published meta-analyses, recent randomized trials, and guidelines of international breast cancer societies, yielding new aspects compared to 2007, provided the basis for defining recommendations according to the criteria of evidence-based medicine. In addition to the more general statements of the DKG (Deutsche Krebsgesellschaft), this paper addresses indications, target definition, dosage, and technique of radiotherapy of the breast after conservative surgery for invasive breast cancer. Results: Among numerous reports on the effect of radiotherapy during BCT published since the last recommendations, the recent EBCTCG report builds the largest meta-analysis so far available. In a 15 year follow-up on 10,801 patients, whole breast irradiation (WBI) halves the average annual rate of disease recurrence (RR 0.52, 0.48-0.56) and reduces the annual breast cancer death rate by about one sixth (RR 0.82, 0.75-0.90), with a similar proportional, but different absolute benefit in prognostic subgroups (EBCTCG 2011). Furthermore, there is growing evidence that risk-adapted dose augmentation strategies to the tumor bed as well as the implementation of high precision RT techniques (e.g., intraoperative radiotherapy) contribute substantially to a further reduction of local relapse rates. A main focus of ongoing research lies in partial breast

  3. Awareness of Breast Cancer and Practice of Breast Self ...

    African Journals Online (AJOL)

    Background and Objective: Breast cancer is the commonest cancer among women in globally and in Nigeria. In Nigeria, cases of breast cancer cases have been prevalent for three decades and more than 90% of cases can be detected by women themselves through breast self – examination. The objective of this study ...

  4. Obesity and Breast Cancer.

    Science.gov (United States)

    Fortner, Renée T; Katzke, Verena; Kühn, Tilman; Kaaks, Rudolf

    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.

  5. [Management of breast cancer in a woman with breast implants].

    Science.gov (United States)

    Remacle, S; Lifrange, E; Nizet, J-L

    2015-01-01

    The incidence of breast cancer, currently one woman on eight, also concerns patients who underwent augmentation surgery. Breast implants have already been the subject of numerous publications concerning the risk of inducing breast cancer or of delaying its diagnosis; however, no significant causal relationship has been established. The purpose of this article is to assess the diagnostic and therapeutic consequences when breast cancer is identified in a patient with breast implants.

  6. Positron emission tomography of tumour [{sup 18}F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy

    Energy Technology Data Exchange (ETDEWEB)

    Kruchten, Michel van; Schroeder, Carolien P.; Vries, Elisabeth G.E. de; Hospers, Geke A.P. [University of Groningen, Department of Medical Oncology, University Medical Centre Groningen (Netherlands); Glaudemans, Andor W.J.M.; Vries, Erik F.J. de [University of Groningen, Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen (Netherlands)

    2015-10-15

    Whereas anti-oestrogen therapy is widely applied to treat oestrogen receptor (ER) positive breast cancer, paradoxically, oestrogens can also induce tumour regression. Up-regulation of ER expression is a marker for oestrogen hypersensitivity. We, therefore, performed an exploratory study to evaluate positron emission tomography (PET) with the tracer 16α-[{sup 18}F]fluoro-17β-oestradiol ({sup 18}F-FES) as potential marker to select breast cancer patients for oestradiol therapy. Eligible patients had acquired endocrine-resistant metastatic breast cancer that progressed after ≥2 lines of endocrine therapy. All patients had prior ER-positive histology. Treatment consisted of oestradiol 2 mg, three times daily, orally. Patients underwent {sup 18}F-FES-PET/CT imaging at baseline. Tumour {sup 18}F-FES-uptake was quantified for a maximum of 20 lesions and expressed as maximum standardised uptake value (SUV{sub max}). CT-scan was repeated every 3 months to evaluate treatment response. Clinical benefit was defined as time to radiologic or clinical progression ≥24 weeks. {sup 18}F-FES uptake, quantified for 255 lesions in 19 patients, varied greatly between lesions (median 2.8; range 0.6-24.3) and between patients (median 2.5; range 1.1-15.5). Seven (37 %) patients experienced clinical benefit of oestrogen therapy, eight progressed (PD), and four were non-evaluable due to side effects. The positive and negative predictive value (PPV/NPV) of {sup 18}F-FES-PET for response to treatment were 60 % (95 % CI: 31-83 %) and 80 % (95 % CI: 38-96 %), respectively, using SUV{sub max} >1.5. {sup 18}F-FES-PET may aid identification of patients with acquired antihormone resistant breast cancer that are unlikely to benefit from oestradiol therapy. (orig.)

  7. Levels of estrogen, carcinoembryonic antigen and cancer antigen of breast in breast cancer patients

    International Nuclear Information System (INIS)

    Abdelhadi, H. A.

    2005-09-01

    This study was conducted during the period from february 2004 to July 2004; with the objective of measuring the levels of estrogen (E2), carcinoembryonic antigen (CEA) and cancer antigen of breast (CA-15.3) so as to facilitate the early diagnosis of breast cancer and determine the involvement of these parameters as risk factors for breast cancer. Ninety blood samples were collected from Sudanese females, divided into two groups; control group and patient groups. The patients group was sixty Sudanese females visiting the Radio Isotope Center, Khartoum (RICK) and they were confirmed as breast cancer patient by histopathology. The levels of the above mentioned parameters were determined by using radioimmunoassay technique. The results showed that, no significant (p=0.05) difference between the levels of the estrogen in patients compared to the control, on the other hand there was non significant (p>0.05) elevation in CEA levels in the patients with breast cancer compared to the control. The level of CA15.3 was significantly (p<0.0001) higher in the breast cancer patients compared to the control.(Author)

  8. Coffee induces breast cancer resistance protein expression in Caco-2 cells.

    Science.gov (United States)

    Isshiki, Marina; Umezawa, Kazuo; Tamura, Hiroomi

    2011-01-01

    Coffee is a beverage that is consumed world-wide on a daily basis and is known to induce a series of metabolic and pharmacological effects, especially in the digestive tract. However, little is known concerning the effects of coffee on transporters in the gastrointestinal tract. To elucidate the effect of coffee on intestinal transporters, we investigated its effect on expression of the breast cancer resistance protein (BCRP/ABCG2) in a human colorectal cancer cell line, Caco-2. Coffee induced BCRP gene expression in Caco-2 cells in a coffee-dose dependent manner. Coffee treatment of Caco-2 cells also increased the level of BCRP protein, which corresponded to induction of gene expression, and also increased cellular efflux activity, as judged by Hoechst33342 accumulation. None of the major constituents of coffee tested could induce BCRP gene expression. The constituent of coffee that mediated this induction was extractable with ethyl acetate and was produced during the roasting process. Dehydromethylepoxyquinomicin (DHMEQ), an inhibitor of nuclear factor (NF)-κB, inhibited coffee-mediated induction of BCRP gene expression, suggesting involvement of NF-κB in this induction. Our data suggest that daily consumption of coffee might induce BCRP expression in the gastrointestinal tract and may affect the bioavailability of BCRP substrates.

  9. Docosahexaenoic Acid in Preventing Recurrence in Breast Cancer Survivors

    Science.gov (United States)

    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

  10. Evaluation of diagnosis of small breast cancer with high frequency and color doppler ultrasound

    International Nuclear Information System (INIS)

    Xia Guobing; Hu Chunhong; Jing Qiulong

    2008-01-01

    Objective: To probe the features of high frequency ultrasonography (HFU) and color Doppler ultrasound (CDU) in the case of small breast cancers in order to evaluate the diagnostic value for small breast cancer with CDU. Methods: The features of HFU and CDU were respective analyzed in 67 small breast masses, the biggest diameter of which was under 2cm identified with pathology. Results Partially characteristic changes of small breast cancers were displayed, and micro-calcification within the mass was an important characteristic, in addition, the Resistant Index (RI) ≥ 0.70 on Pulsed Doppler (PD) and the grade of blood flow on Color Doppler Flow Imaging (CDFI)≥T2 implied much more positive malignancy prediction. Conclusion: HFU integrated with CDU can be used for the early and accurate diagnosis of the small breast cancer. (authors)

  11. Association between breast cancer, breast density, and body adiposity evaluated by MRI

    International Nuclear Information System (INIS)

    Zhu, Wenlian; Huang, Peng; Macura, Katarzyna J.; Artemov, Dmitri

    2016-01-01

    Despite the lack of reliable methods with which to measure breast density from 2D mammograms, numerous studies have demonstrated a positive association between breast cancer and breast density. The goal of this study was to study the association between breast cancer and body adiposity, as well as breast density quantitatively assessed from 3D MRI breast images. Breast density was calculated from 3D T1-weighted MRI images. The thickness of the upper abdominal adipose layer was used as a surrogate marker for body adiposity. We evaluated the correlation between breast density, age, body adiposity, and breast cancer. Breast density was calculated for 410 patients with unilateral invasive breast cancer, 73 patients with ductal carcinoma in situ (DCIS), and 361 controls without breast cancer. Breast density was inversely related to age and the thickness of the upper abdominal adipose layer. Breast cancer was only positively associated with body adiposity and age. Age and body adiposity are predictive of breast density. Breast cancer was not associated with breast density; however, it was associated with the thickness of the upper abdominal adipose layer, a surrogate marker for body adiposity. Our results based on a limited number of patients warrant further investigations. (orig.)

  12. Primary tumor levels of tissue inhibitor of metalloproteinases-1 are predictive of resistance to chemotherapy in patients with metastatic breast cancer

    DEFF Research Database (Denmark)

    Rasmussen, Anne-Sofie Schrohl; Meijer-van Gelder, Marion E.; Holten-Andersen, Mads N.

    2006-01-01

    /methotrexate/5-fluorouracil and anthracycline-based chemotherapy (P = 0.01; odds ratio, 2.0; 95% confidence interval, 1.1-3.3). In a multivariate model, including lymph node status, steroid hormone receptor status, menopausal status, dominant metastases site, type of chemotherapy, and disease-free interval, TIMP......PURPOSE: Only about 50% of metastatic breast cancer patients benefit from cytotoxic chemotherapy. Today, no validated markers exist for prediction of chemotherapy sensitivity/resistance in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against...... tumor expression levels of TIMP-1 protein and objective response to first-line chemotherapy in 173 patients with metastatic breast cancer. RESULTS: When analyzed as a continuous log-transformed variable, increasing TIMP-1 levels were significantly associated with lack of response to cyclophosphamide...

  13. Getting free of breast cancer

    DEFF Research Database (Denmark)

    Halttunen, Arja; Hietanen, P; Jallinoja, P

    1992-01-01

    Twenty-two breast cancer patients who were relapse-free and had no need for cancer-related treatment were interviewed 8 years after mastectomy in order to evaluate their feelings of getting free of breast cancer and the meaning of breast cancer in their lives. The study is a part of an intervention...... and follow-up study of 57 breast cancer patients. Half of the 22 patients still had frequent or occasional thoughts of recurrence and over two-thirds still thought they had not been 'cured' of cancer. More than half of the patients admitted that going through breast cancer had made them more mature. Women...... who had less thoughts of recurrence belonged to a group that had gone through an eight-week group psychotherapy intervention, were less depressed and had more other illnesses. Women who felt 'cured' had less limitations and restrictions due to cancer and belonged more often to higher social classes...

  14. Micropapillary Lung Cancer with Breast Metastasis Simulating Primary Breast Cancer due to Architectural Distortion on Images

    Energy Technology Data Exchange (ETDEWEB)

    Ko, Kyung Ran; Hong, Eun Kyung; Lee, See Yeon [Center for Breast Cancer, National Cancer Center, Goyang (Korea, Republic of); Ro, Jae Yoon [The Methodist Hospital, Weill Medical College of Cornell University, Houston (United States)

    2012-03-15

    A 47-year-old Korean woman with right middle lobe lung adenocarcinoma, malignant pleural effusion, and multiple lymph node and bone metastases, after three months of lung cancer diagnosis, presented with a palpable right breast mass. Images of the right breast demonstrated architectural distortion that strongly suggested primary breast cancer. Breast biopsy revealed metastatic lung cancer with a negative result for estrogen receptor (ER), progesterone receptor (PR) and mammaglobin, and a positive result for thyroid transcription factor-1 (TTF-1). We present a case of breast metastasis from a case of lung cancer with an extensive micropapillary component, which was initially misinterpreted as a primary breast cancer due to unusual image findings with architectural distortion.

  15. Resolving breast cancer heterogeneity by searching reliable protein cancer biomarkers in the breast fluid secretome

    International Nuclear Information System (INIS)

    Mannello, Ferdinando; Ligi, Daniela

    2013-01-01

    One of the major goals in cancer research is to find and evaluate the early presence of biomarkers in human fluids and tissues. To resolve the complex cell heterogeneity of a tumor mass, it will be useful to characterize the intricate biomolecular composition of tumor microenvironment (the so called cancer secretome), validating secreted proteins as early biomarkers of cancer initiation and progression. This approach is not broadly applicable because of the paucity of well validated and FDA-approved biomarkers and because most of the candidate biomarkers are mainly organ-specific rather than tumor-specific. For these reasons, there is an urgent need to identify and validate a panel of biomarker combinations for early detection of human tumors. This is especially important for breast cancer, the cancer spread most worldwide among women. It is well known that patients with early diagnosed breast cancer live longer, require less extensive treatment and fare better than patients with more aggressive and/or advanced disease. In the frame of searching breast cancer biomarkers (especially using nipple aspirate fluid mirroring breast microenvironment), studies have highlighted an optimal combination of well-known biomarkers: uPA + PAI-1 + TF. When individually investigated they did not show perfect accuracy in predicting the presence of breast cancer, whereas the triple combination has been demonstrated to be highly predictive of pre-cancer and/or cancerous conditions, approaching 97-100% accuracy. Despite the heterogeneous composition of breast cancer and the difficulties to find specific breast cancer biomolecules, the noninvasive analysis of the nipple aspirate fluid secretome may significantly improve the discovery of promising biomarkers, helping also the differentiation among benign and invasive breast diseases, opening new frontiers in early oncoproteomics

  16. Clinical implications of recent studies using mTOR inhibitors to treat advanced hormone receptor-positive breast cancer

    International Nuclear Information System (INIS)

    Arena, Francis

    2014-01-01

    Breast cancer is a leading cause of cancer-related death worldwide. Approximately 75% of breast cancer is hormone receptor-positive (HR + ) and is managed with endocrine therapies. However, relapse or disease progression caused by primary or acquired endocrine resistance is frequent. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)-mediated signaling is one of the molecular mechanisms leading to endocrine resistance. mTOR inhibitors that target the PI3K/Akt/mTOR pathway are the first of the targeted therapies to be evaluated in clinical trials to overcome endocrine resistance. Although the clinical trial with temsirolimus, an mTOR inhibitor, did not show any benefit when compared with endocrine therapy alone, a Phase II clinical trial with sirolimus has been promising. Recently, everolimus was approved in combination with exemestane by the US Food and Drug Administration for treating postmenopausal women with advanced HR + breast cancer, based on the results of a Phase III trial. Therefore, everolimus represents the first and only targeted agent approved for combating endocrine resistance

  17. Racial and Socioeconomic Disparities Are More Pronounced in Inflammatory Breast Cancer Than Other Breast Cancers

    Directory of Open Access Journals (Sweden)

    Ryan A. Denu

    2017-01-01

    Full Text Available Inflammatory breast cancer (IBC is a rare yet aggressive form of breast cancer. We examined differences in patient demographics and outcomes in IBC compared to locally advanced breast cancer (LABC and all other breast cancer patients from the Breast and Prostate Cancer Data Quality and Patterns of Care Study (POC-BP, containing information from cancer registries in seven states. Out of 7,624 cases of invasive carcinoma, IBC and LABC accounted for 2.2% (N=170 and 4.9% (N=375, respectively. IBC patients were more likely to have a higher number (P=0.03 and severity (P=0.01 of comorbidities than other breast cancer patients. Among IBC patients, a higher percentage of patients with metastatic disease versus nonmetastatic disease were black, on Medicaid, and from areas of higher poverty and more urban areas. Black and Hispanic IBC patients had worse overall and breast cancer-specific survival than white patients; moreover, IBC patients with Medicaid, patients from urban areas, and patients from areas of higher poverty and lower education had worse outcomes. These data highlight the effects of disparities in race and socioeconomic status on the incidence of IBC as well as IBC outcomes. Further work is needed to reveal the causes behind these disparities and methods to improve IBC outcomes.

  18. Light deficiency confers breast cancer risk by endocrine disorders.

    Science.gov (United States)

    Suba, Zsuzsanna

    2012-09-01

    North-America and northern European countries exhibit the highest incidence rate of breast cancer, whereas women in southern regions are relatively protected. Immigrants from low cancer incidence regions to high-incidence areas might exhibit similarly higher or excessive cancer risk as compared with the inhabitants of their adoptive country. Additional cancer risk may be conferred by incongruence between their biological characteristics and foreign environment. Many studies established the racial/ethnic disparities in the risk and nature of female breast cancer in United States between African-American and Caucasian women. Mammary tumors in black women are diagnosed at earlier age, and are associated with higher rate of mortality as compared with cancers of white cases. Results of studies on these ethnic/racial differences in breast cancer incidence suggest that excessive pigmentation of dark skinned women results in a relative light-deficiency. Poor light exposure may explain the deleterious metabolic and hormonal alterations; such as insulin resistance, deficiencies of estrogen, thyroxin and vitamin-D conferring excessive cancer risk. The more northern the location of an adoptive country the higher the cancer risk for dark skinned immigrants. Recognition of the deleterious systemic effects of darkness and excessive melatonin synthesis enables cancer protection treatment for people living in light-deficient environment. Recent patents provide new methods for the prevention of hormonal and metabolic abnormities.

  19. Expression and Significance of CYR61 Expression in Breast Cancer Tumor Specimens

    National Research Council Canada - National Science Library

    Lupu, Ruth

    2002-01-01

    Breast cancer often progresses from an estrogen (ER)-dependent, non-metastatic, antiestrogen-sensitive phenotype to an ER-independent, antiestrogen-resistant, highly invasive, and metastatic phenotype...

  20. Understanding and potentially reducing second breast cancer

    International Nuclear Information System (INIS)

    Brenner, D.

    2011-01-01

    Full text: Long term survival after breast cancer diagnosis has increased markedly in the last decade: 15-year relative survival after breast cancer diagnosis is now 75% in the US. Associated with these excellent survival prospects, however, long term studies suggest that contralateral second breast cancer rates are in the range from 10 to 15% at 15 years post treatment, and are still higher for BRCA1/2 carriers, as well as for still longer term survivors. These second cancer risks are much higher than those for a comparable healthy woman to develop a first breast cancer. It follows that women with breast cancer are highly prone to develop a second breast cancer. We propose here a new option for reducing the disturbingly high risk of a contralateral second breast cancer. in patients with both estrogen positive and negative primary breast cancer: prophylactic mammary irradiation (PMI) of the contralateral breast. The rationale behind PMI is evidence that standard post-Iumpectomy radiotherapy of the affected (ipsilateral) breast substantially reduces the long-term genetically-based second cancer risk in the ipsilateral breast, by killing the existing premalignant cells in that breast. This suggests that there are relatively few premalignant cells in the breast (hundreds or thousands, not millions), so even a fairly modest radiation cell-kill level across the whole breast would be expected to kill essentially all of them. If this is so, then a modest radiation dose-much lower than that to the affected breast--delivered uniformly to the whole contralateral breast, and typically delivered at the same time as the radiotherapy of the ipsilateral breast, would have the potential to markedly reduce second-cancer risks in the contralateral breast by killing essentially all the pre-malignant cells in that breast while causing only a very low level of radiation-induced sequelae. Therefore we hypothesize that low-dose prophylactic mammary irradiation of the contralateral breast

  1. COPING MECHANISM OF CAREER WOMEN WITH BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Rosnani Rosnani

    2017-06-01

    Full Text Available Introduction: Patients with cancer may experience psychological disorders such as depression, anxiety, anger, helplessness, and unappreciated, so in certain situations require defense mechanisms (coping mechanism to oppose or resist feelings of anxiety, fear or stress that haunt her. The aim of this study was to know the coping mechanism of career women with breast cancer reviewed by phenomenology in Palembang 2016. Method: Type of this study was a qualitative study with a phenomenological approach. Total samples were 8 participants with inclusion criteria: career women, productive age range, health physic and physiologic. Independent variable was a coping mechanism, and the dependent variable was breast cancer. The instrument used the voice recorder, and interview guides. Data analyze used verbatim transcript with credibility, dependability, and confirmability. Result: The results showed that working women who have breast cancer have a coping strategy that is adjusted to the psychological condition and physical reactions of the therapy in progress. Psychologically, the coping mechanism is in the form of rejecting, drawing closer to Allah SWT, seeking the opinion of other health workers, discussing conditions with spouse and family, seeking alternative treatment and asking for doctor's direction. The coping mechanism of the body's reaction to therapy is done by taking medicine according to the rules and remember Allah SWT. Conclusions: Need the support of the coping mechanism in patients with breast cancer and nursing care approach with the pattern of coping mechanisms with the involvement of the family.

  2. beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts

    International Nuclear Information System (INIS)

    Park, Catherine C.; Park, Catherine C.; Zhang, Hui J.; Yao, Evelyn S.; Park, Chong J.; Bissell, Mina J.

    2008-01-01

    β1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of β1 integrin signaling. We showed previously that β1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and β1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo

  3. beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Park, Catherine C.; Park, Catherine C.; Zhang, Hui J.; Yao, Evelyn S.; Park, Chong J.; Bissell, Mina J.

    2008-06-02

    {beta}1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of {beta}1 integrin signaling. We showed previously that {beta}1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and {beta}1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo.

  4. Hormones and breast cancer: can we use them in ways that could reduce the risk?

    Directory of Open Access Journals (Sweden)

    Khalid Mahmud

    2011-12-01

    Full Text Available Many hormones promote or inhibit breast cancer in different ways. These effects and the mechanisms involved are reviewed in order to suggest a potentially safer use of hormones. Natural estrogens, administered transdermally, and natural progesterone may be the safest combination of female hormones. Increased intake of cruciferous vegetables could provide additional safety by improving 2-hydoxyestrone and diminishing 16 alphahydroxyestrone. Testosterone and dehydroepiandrosterone (DHEA may directly inhibit breast cancer, but could potentially stimulate it by being aromatized into estrogen in the breast. Modest doses with blood level monitoring appear logical. Melatonin and oxytocin are inhibitory to breast and other cancers. Insulin is a growth factor for breast cancer. Managing insulin resistance before the onset of diabetes could reduce the risk. Tri-iodothyronine (T3 has multiple anti-breast cancer effects. Synthroid may not increase T3 levels adequately. Human growth hormone does not appear to increase risk; but it should not be given for performance enhancement.

  5. New agents for the management of resistant metastatic breast cancer.

    Science.gov (United States)

    Anampa, Jesus; Sparano, Joseph A

    2017-12-01

    Metastatic breast cancer (MBC) is an incurable disease and treatment is directed towards symptom palliation and survival prolongation. Treatment selection in patients is based on tumor biology, age, comorbidities, performance status, tumor burden, and prior treatment history. Areas covered: This present review summarizes the recent treatment strategies in the management of MBC, highlighting regimens after first-line therapy. Topics discussed include new strategies for endocrine therapy, anti-HER2 therapy, and promising strategies for the management of triple negative breast cancer. Expert opinion: MBC is a heterogeneous entity and despite recent advances, there is significant room for improvement of treatment beyond first-line therapies. Combination regimens that can maximize clinical efficacy while minimizing toxicities are required. Current investigation approaches in advanced stages of clinical development include immunoconjugates, immune checkpoint blockade, novel cyclin-dependent-kinase inhibitors, and PARP inhibitors for MBC associated with germline BRCA mutations. We recommend that every patient with MBC should be evaluated for clinical trial options.

  6. Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival.

    Science.gov (United States)

    Pai, Vaibhav P; Marshall, Aaron M; Hernandez, Laura L; Buckley, Arthur R; Horseman, Nelson D

    2009-01-01

    The breast microenvironment can either retard or accelerate the events associated with progression of latent cancers. However, the actions of local physiological mediators in the context of breast cancers are poorly understood. Serotonin (5-HT) is a critical local regulator of epithelial homeostasis in the breast and other organs. Herein, we report complex alterations in the intrinsic mammary gland serotonin system of human breast cancers. Serotonin biosynthetic capacity was analyzed in human breast tumor tissue microarrays using immunohistochemistry for tryptophan hydroxylase 1 (TPH1). Serotonin receptors (5-HT1-7) were analyzed in human breast tumors using the Oncomine database. Serotonin receptor expression, signal transduction, and 5-HT effects on breast cancer cell phenotype were compared in non-transformed and transformed human breast cells. In the context of the normal mammary gland, 5-HT acts as a physiological regulator of lactation and involution, in part by favoring growth arrest and cell death. This tightly regulated 5-HT system is subverted in multiple ways in human breast cancers. Specifically, TPH1 expression undergoes a non-linear change during progression, with increased expression during malignant progression. Correspondingly, the tightly regulated pattern of 5-HT receptors becomes dysregulated in human breast cancer cells, resulting in both ectopic expression of some isoforms and suppression of others. The receptor expression change is accompanied by altered downstream signaling of 5-HT receptors in human breast cancer cells, resulting in resistance to 5-HT-induced apoptosis, and stimulated proliferation. Our data constitutes the first report of direct involvement of 5-HT in human breast cancer. Increased 5-HT biosynthetic capacity accompanied by multiple changes in 5-HT receptor expression and signaling favor malignant progression of human breast cancer cells (for example, stimulated proliferation, inappropriate cell survival). This occurs

  7. Epithelial-mesenchymal Transition---A Hallmark of Breast Cancer Metastasis.

    Science.gov (United States)

    Wang, Yifan; Zhou, Binhua P

    2013-03-01

    Epithelial-mesenchymal transition (EMT) is a highly conserved cellular program that converts polarized, immotile epithelial cells to migratory mesenchymal cells. In addition, EMT was initially recognized as a key step for morphogenesis during embryonic development. Emerging evidences indicate that this important developmental program promotes metastasis, drug resistance, and tumor recurrence, features that are associated with a poor clinical outcome for patients with breast cancer. Therefore, better understanding of regulation and signaling pathways in EMT is essential to develop novel targeted therapeutics. In this review, we present updated developments underlying EMT in tumor progression and metastasis, and discuss the challenges remaining in breast cancer research.

  8. Heat Shock Protein 90 (Hsp90 Expression and Breast Cancer

    Directory of Open Access Journals (Sweden)

    Christos A. Papadimitriou

    2012-09-01

    Full Text Available Hsp90 is an abundant protein in mammalian cells. It forms several discrete complexes, each containing distinct groups of co-chaperones that assist protein folding and refolding during stress, protein transport and degradation. It interacts with a variety of proteins that play key roles in breast neoplasia including estrogen receptors, tumor suppressor p53 protein, angiogenesis transcription factor HIF-1alpha, antiapoptotic kinase Akt, Raf-1 MAP kinase and a variety of receptor tyrosine kinases of the erbB family. Elevated Hsp90 expression has been documented in breast ductal carcinomas contributing to the proliferative activity of breast cancer cells; whilst a significantly decreased Hsp90 expression has been shown in infiltrative lobular carcinomas and lobular neoplasia. Hsp90 overexpression has been proposed as a component of a mechanism through which breast cancer cells become resistant to various stress stimuli. Therefore, pharmacological inhibition of HSPs can provide therapeutic opportunities in the field of cancer treatment. 17-allylamino,17-demethoxygeldanamycin is the first Hsp90 inhibitor that has clinically been investigated in phase II trial, yielding promising results in patients with HER2-overexpressing metastatic breast cancer, whilst other Hsp90 inhibitors (retaspimycin HCL, NVP-AUY922, NVP-BEP800, CNF2024/BIIB021, SNX-5422, STA-9090, etc. are currently under evaluation.

  9. PET scan for breast cancer

    Science.gov (United States)

    ... radioactive substance (called a tracer) to look for breast cancer. This tracer can help identify areas of cancer ... only after a woman has been diagnosed with breast cancer. It is done to see if the cancer ...

  10. Breast cancer and breast health awareness as an evolving health promotion concept

    International Nuclear Information System (INIS)

    Plesnicar, A.; Kralj, B.; Kovac, V.

    2004-01-01

    Background. Breast cancer is the most frequent malignant disease in the majority of developed countries. In the last few years the introduction of mammography screening programmes has resulted in an improved survival of breast cancer patients. However, the incidence of the disease in these countries is still on the increase. Present focus on secondary breast cancer prevention activities, consisting of early detection and treatment, cannot ensure a decrease of breast cancer incidence. Improved breast health awareness could therefore represent a part of specific health promotion activities aimed at decreasing the incidence of breast cancer. Conclusions. In developed countries breast cancer is a significant health care issue. Secondary breast cancer prevention activities should therefore be complemented by specific health promotion activities in order to reduce its incidence in the future. Primary breast cancer prevention would include health promotion activities aimed at enhancement of the individual as well as collective breast health awareness. Properly enlightened members of the influential population groups could attain appropriate changes in the fields of legislation, taxation, customs and commercial regulations that would enable women to control their own breast health. (author)

  11. Immunophenotyping of hereditary breast cancer

    NARCIS (Netherlands)

    van der Groep, P.

    2009-01-01

    Hereditary breast cancer runs in families where several family members in different generations are affected. Most of these breast cancers are caused by mutations in the high penetrance genes BRCA1 and BRCA2 which account for about 5% of all breast cancers. However, mutations in BRCA1 and BRCA2 may

  12. Radiofrequency Tagged Surgery in Treating Patients With Breast Cancer

    Science.gov (United States)

    2018-06-18

    Positive Axillary Lymph Node; Stage 0 Breast Cancer AJCC v6 and v7; Stage I Breast Cancer AJCC v7; Stage IA Breast Cancer AJCC v7; Stage IB Breast Cancer AJCC v7; Stage II Breast Cancer AJCC v6 and v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7

  13. Management of fertility preservation in young breast cancer patients in a large breast cancer centre.

    Science.gov (United States)

    Lawrenz, B; Neunhoeffer, E; Henes, M; Lessmann-Bechle, S; Krämer, B; Fehm, Tanja

    2010-11-01

    The increase of breast cancer in young women under 40 years and the increasing age of women at the time of the birth of their first child underlines the importance to implement counselling for fertility-preserving strategies in the management of breast cancer care. We present the fertility-preserving procedures performed after routine counselling for primary breast cancer patients in a large certified breast cancer centre. Since November 2006, patients aged below 40 years with histologically confirmed breast cancer are routinely counselled on fertility-preserving possibilities before breast surgery and chemotherapy in the fertility centre of the University Women's Hospital in Tuebingen. The recommendations are based on the treatment recommendations of the network FertiPROTEKT. During the last 40 months, 56 primary breast cancer patients were counselled. Forty-one of these patients were hormone receptor positive. Thirty-four patients (63%) underwent fertility-preserving strategies. The majority of the patients (n = 22) decided on ovarian tissue cryopreservation. GnRH protection was performed in 14 patients. In 12 patients an ovarian stimulation protocol was initiated to cryopreserve fertilized or unfertilized oocytes. A combination of different fertility-preserving methods was performed in 12 patients. The preservation of ovarian function and fertility are of great importance to young breast cancer patients. Counselling on fertility-preserving strategies is therefore critical in these patients and should be routinely performed.

  14. Statins and breast cancer prognosis

    DEFF Research Database (Denmark)

    Ahern, Thomas P; Lash, Timothy L; Damkier, Per

    2014-01-01

    Much preclinical and epidemiological evidence supports the anticancer effects of statins. Epidemiological evidence does not suggest an association between statin use and reduced incidence of breast cancer, but does support a protective effect of statins-especially simvastatin-on breast cancer...... recurrence. Here, we argue that the existing evidence base is sufficient to justify a clinical trial of breast cancer adjuvant therapy with statins and we advocate for such a trial to be initiated without delay. If a protective effect of statins on breast cancer recurrence is supported by trial evidence......, then the indications for a safe, well tolerated, and inexpensive treatment can be expanded to improve outcomes for breast cancer survivors. We discuss several trial design opportunities-including candidate predictive biomarkers of statin safety and efficacy-and off er solutions to the key challenges involved...

  15. Decline in breast cancer mortality

    DEFF Research Database (Denmark)

    Njor, Sisse Helle; Schwartz, Walter; Blichert-Toft, Mogens

    2015-01-01

    OBJECTIVES: When estimating the decline in breast cancer mortality attributable to screening, the challenge is to provide valid comparison groups and to distinguish the screening effect from other effects. In Funen, Denmark, multidisciplinary breast cancer management teams started before screening...... was introduced; both activities came later in the rest of Denmark. Because Denmark had national protocols for breast cancer treatment, but hardly any opportunistic screening, Funen formed a "natural experiment", providing valid comparison groups and enabling the separation of the effect of screening from other...... factors. METHODS: Using Poisson regression we compared the observed breast cancer mortality rate in Funen after implementation of screening with the expected rate without screening. The latter was estimated from breast cancer mortality in the rest of Denmark controlled for historical differences between...

  16. Unemployment among breast cancer survivors

    DEFF Research Database (Denmark)

    Carlsen, Kathrine; Ewertz, Marianne; Dalton, Susanne Oksbjerg

    2014-01-01

    AIM: Though about 20% of working age breast cancer survivors do not return to work after treatment, few studies have addressed risk factors for unemployment. The majority of studies on occupational consequences of breast cancer focus on non-employment, which is a mixture of sickness absence......, unemployment, retirement pensions and other reasons for not working. Unemployment in combination with breast cancer may represent a particular challenge for these women. The aim of the present study is therefore to analyze the risk for unemployment in the years following diagnosis and treatment for breast...... cancer. METHOD: This study included 14,750 women diagnosed with breast cancer in Denmark 2001-2009 identified through a population-based clinical database and linked with information from Danish administrative population based registers for information on labour market affiliation, socio...

  17. Breast cancer in atomic bomb survivors

    International Nuclear Information System (INIS)

    Tokunga, M.; Land, C.E.; Tokuoka, S.

    1986-01-01

    Thirty eight years after the atomic bombings, studies of the Radiation Effects Research Foundation (RERF) on the extended Life Span Study (LSS) sample have continued to provide important information on radiation carcinogenesis. The third breast cancer survey among this sample revealed 564 cases during the period 1950-80, of which 412 were reviewed microscopically. The following statements reflect the conclusions from the current investigation; 1) the relationship between radiation dose and breast cancer incidence was consistent with linearity and did not differ markedly between the Hiroshima and Nagasaki survivors, 2) a dose-related breast cancer risk was observed among women who were in their first decade of life at the time of exposure, 3) the relative risk of radiationinduced breast cancer decreased with increasing age at exposure, 4) the pattern over time of age-specific breast cancer incidence is similar for exposed and control women (that is, exposed women have more breast cancer than control women but the excess risk closely follows normal risk as expressed by age-specific population rates), and 5) radiation-induced breast cancer appears to be morphologically similar to other breast cancer

  18. Breast cancer in atomic bomb survivors

    International Nuclear Information System (INIS)

    Tokunaga, Masayoshi; Tokuoka, Shoji; Land, C.E.

    1986-01-01

    Thirty eight years after the atomic bombings, studies of the Radiation Effects Research Foundation (RERF) on the extended Life Span Study (LSS) sample have continued to provide important information on radiation carcinogenesis. The third breast cancer survey among this sample revealed 564 cases during the period 1950 - 80, of which 412 were reviewed microscopically. The following statements reflect the conclusions from the current investigation; 1) the relationship between radiation dose and breast cancer incidence was consistent with linearity and did not differ markedly between the Hiroshima and Nagasaki survivors, 2) a dose-related breast cancer risk was observed among women who were in their first decade of life at the time of exposure, 3) the relative risk of radiation-induced breast cancer decreased with increasing age at exposure, 4) the pattern over time of age-specific breast cancer incidence is similar for exposed and control women (that is, exposed women have more breast cancer than control women but the excess risk closely follows normal risk as expressed by age-specific population rates), and 5) radiation-induced breast cancer appears to be morphologically similar to other breast cancer. (author)

  19. Women's perceived benefits of exercise during and after breast cancer treatment.

    Science.gov (United States)

    Bulmer, Sandra Minor; Howell, Jeremy; Ackerman, Louise; Fedric, Regan

    2012-01-01

    Empirical data support the benefits of physical activity for women who have been diagnosed with breast cancer. However, the experience of exercising during or after breast cancer treatment has not been fully documented. The purpose of the researchers in this study was to provide an in-depth description of women's experiences with exercising during or after their breast cancer treatments, specifically, their perceptions of the benefits they experienced as a result of participation in an individualized exercise program that included cardiovascular and resistance activities. Forty-five women who had been diagnosed with breast cancer within the previous two years were recruited from two oncology practices after electing to enroll in an exercise program. Data were collected between September 2006 and August 2007 through in-depth interviews at various stages in the exercise program and analyzed simultaneously using thematic analysis methods. Whether in treatment or post-treatment, women attributed psychological, physical, and social benefits to their participation in the exercise program. Participants credited the program with helping them to feel better, regain control over their bodies and their lives, manage their emotions, and prepare them to live healthfully going forward. These results provide insight into the specific ways women experience exercise during and after their breast cancer treatments.

  20. Screen-detected versus interval cancers: Effect of imaging modality and breast density in the Flemish Breast Cancer Screening Programme.

    Science.gov (United States)

    Timmermans, Lore; Bleyen, Luc; Bacher, Klaus; Van Herck, Koen; Lemmens, Kim; Van Ongeval, Chantal; Van Steen, Andre; Martens, Patrick; De Brabander, Isabel; Goossens, Mathieu; Thierens, Hubert

    2017-09-01

    To investigate if direct radiography (DR) performs better than screen-film mammography (SF) and computed radiography (CR) in dense breasts in a decentralized organised Breast Cancer Screening Programme. To this end, screen-detected versus interval cancers were studied in different BI-RADS density classes for these imaging modalities. The study cohort consisted of 351,532 women who participated in the Flemish Breast Cancer Screening Programme in 2009 and 2010. Information on screen-detected and interval cancers, breast density scores of radiologist second readers, and imaging modality was obtained by linkage of the databases of the Centre of Cancer Detection and the Belgian Cancer Registry. Overall, 67% of occurring breast cancers are screen detected and 33% are interval cancers, with DR performing better than SF and CR. The interval cancer rate increases gradually with breast density, regardless of modality. In the high-density class, the interval cancer rate exceeds the cancer detection rate for SF and CR, but not for DR. DR is superior to SF and CR with respect to cancer detection rates for high-density breasts. To reduce the high interval cancer rate in dense breasts, use of an additional imaging technique in screening can be taken into consideration. • Interval cancer rate increases gradually with breast density, regardless of modality. • Cancer detection rate in high-density breasts is superior in DR. • IC rate exceeds CDR for SF and CR in high-density breasts. • DR performs better in high-density breasts for third readings and false-positives.

  1. Imaging Management of Breast Density, a Controversial Risk Factor for Breast Cancer.

    Science.gov (United States)

    Falcon, Shannon; Williams, Angela; Weinfurtner, Jared; Drukteinis, Jennifer S

    2017-04-01

    Breast density is well recognized as an independent risk factor for the development of breast cancer. However, the magnitude of risk is controversial. As the public becomes increasingly aware of breast density as a risk factor, legislation and notification laws in relation to breast density have become common throughout the United States. Awareness of breast density as a risk factor for breast cancer presents new challenges for the clinician in the approach to the management and screening of women with dense breasts. The evidence and controversy surrounding breast density as a risk factor for the development of breast cancer are discussed. Common supplemental screening modalities for breast cancer are also discussed, including tomosynthesis, ultrasonography, and magnetic resonance imaging. A management strategy for screening women with dense breasts is also presented. The American College of Radiology recognizes breast density as a controversial risk factor for breast cancer, whereas the American Congress of Obstetricians and Gynecologists recognizes breast density as a modest risk factor. Neither organization recommends the routine use of supplemental screening in women with dense breasts without considering additional patient-related risk factors. Breast density is a poorly understood and controversial risk factor for the development of breast cancer. Mammography is a screening modality proven to reduce breast cancer-related mortality rates and is the single most appropriate tool for population-based screening. Use of supplemental screening modalities should be tailored to individual risk assessment.

  2. Delayed breast reconstruction with implants after invasive breast cancer does not impair prognosis

    DEFF Research Database (Denmark)

    Holmich, L.R.; During, M.; Henriksen, T.F.

    2008-01-01

    We investigated if delayed breast implant reconstruction after breast cancer impairs prognosis. Using data from the Danish Breast Cancer Cooperative Group register, we identified all women......We investigated if delayed breast implant reconstruction after breast cancer impairs prognosis. Using data from the Danish Breast Cancer Cooperative Group register, we identified all women...

  3. Iodide transport and breast cancer.

    Science.gov (United States)

    Poole, Vikki L; McCabe, Christopher J

    2015-10-01

    Breast cancer is the second most common cancer worldwide and the leading cause of cancer death in women, with incidence rates that continue to rise. The heterogeneity of the disease makes breast cancer exceptionally difficult to treat, particularly for those patients with triple-negative disease. To address the therapeutic complexity of these tumours, new strategies for diagnosis and treatment are urgently required. The ability of lactating and malignant breast cells to uptake and transport iodide has led to the hypothesis that radioiodide therapy could be a potentially viable treatment for many breast cancer patients. Understanding how iodide is transported, and the factors regulating the expression and function of the proteins responsible for iodide transport, is critical for translating this hypothesis into reality. This review covers the three known iodide transporters - the sodium iodide symporter, pendrin and the sodium-coupled monocarboxylate transporter - and their role in iodide transport in breast cells, along with efforts to manipulate them to increase the potential for radioiodide therapy as a treatment for breast cancer. © 2015 Society for Endocrinology.

  4. Interleukin-19 in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ying-Yin Chen

    2013-01-01

    Full Text Available Inflammatory cytokines within the tumor microenvironment are linked to progression in breast cancer. Interleukin- (IL- 19, part of the IL-10 family, contributes to a range of diseases and disorders, such as asthma, endotoxic shock, uremia, psoriasis, and rheumatoid arthritis. IL-19 is expressed in several types of tumor cells, especially in squamous cell carcinoma of the skin, tongue, esophagus, and lung and invasive duct carcinoma of the breast. In breast cancer, IL-19 expression is correlated with increased mitotic figures, advanced tumor stage, higher metastasis, and poor survival. The mechanisms of IL-19 in breast cancer have recently been explored both in vitro and in vivo. IL-19 has an autocrine effect in breast cancer cells. It directly promotes proliferation and migration and indirectly provides a microenvironment for tumor progression, which suggests that IL-19 is a prognostic marker in breast cancer and that antagonizing IL-19 may have therapeutic potential.

  5. RAD51B in Familial Breast Cancer

    OpenAIRE

    Pelttari, L.M.; Khan, S.; et al.,

    2016-01-01

    Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737\\ud and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast\\ud cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer\\ud predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the\\ud coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for\\ud identifi...

  6. RAD51B in familial breast cancer

    OpenAIRE

    Pelttari, LM; Khan, S; Vuorela, M; Kiiski, JI; Vilske, S; Nevanlinna, V; Ranta, S; Schleutker, J; Winqvist, R; Kallioniemi, A; Dörk, T; Bogdanova, NV; Figueroa, J; Pharoah, PDP; Schmidt, MK

    2016-01-01

    Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possi...

  7. Breast Cancer After Chest Radiation Therapy for Childhood Cancer

    Science.gov (United States)

    Moskowitz, Chaya S.; Chou, Joanne F.; Wolden, Suzanne L.; Bernstein, Jonine L.; Malhotra, Jyoti; Friedman, Danielle Novetsky; Mubdi, Nidha Z.; Leisenring, Wendy M.; Stovall, Marilyn; Hammond, Sue; Smith, Susan A.; Henderson, Tara O.; Boice, John D.; Hudson, Melissa M.; Diller, Lisa R.; Bhatia, Smita; Kenney, Lisa B.; Neglia, Joseph P.; Begg, Colin B.; Robison, Leslie L.; Oeffinger, Kevin C.

    2014-01-01

    Purpose The risk of breast cancer is high in women treated for a childhood cancer with chest irradiation. We sought to examine variations in risk resulting from irradiation field and radiation dose. Patients and Methods We evaluated cumulative breast cancer risk in 1,230 female childhood cancer survivors treated with chest irradiation who were participants in the CCSS (Childhood Cancer Survivor Study). Results Childhood cancer survivors treated with lower delivered doses of radiation (median, 14 Gy; range, 2 to 20 Gy) to a large volume (whole-lung field) had a high risk of breast cancer (standardized incidence ratio [SIR], 43.6; 95% CI, 27.2 to 70.3), as did survivors treated with high doses of delivered radiation (median, 40 Gy) to the mantle field (SIR, 24.2; 95% CI, 20.7 to 28.3). The cumulative incidence of breast cancer by age 50 years was 30% (95% CI, 25 to 34), with a 35% incidence among Hodgkin lymphoma survivors (95% CI, 29 to 40). Breast cancer–specific mortality at 5 and 10 years was 12% (95% CI, 8 to 18) and 19% (95% CI, 13 to 25), respectively. Conclusion Among women treated for childhood cancer with chest radiation therapy, those treated with whole-lung irradiation have a greater risk of breast cancer than previously recognized, demonstrating the importance of radiation volume. Importantly, mortality associated with breast cancer after childhood cancer is substantial. PMID:24752044

  8. Breast cancer: surgery at the South egypt cancer institute.

    Science.gov (United States)

    Salem, Ahmed A S; Salem, Mohamed Abou Elmagd; Abbass, Hamza

    2010-09-30

    Breast cancer is the most frequent malignant tumor in women worldwide. In Egypt, it is the most common cancer among women, representing 18.9% of total cancer cases (35.1% in women and 2.2% in men) among the Egypt National Cancer Institute's (NCI) series of 10,556 patients during the year 2001, with an age-adjusted rate of 49.6 per 100,000 people. In this study, the data of all breast cancer patients presented to the surgical department of the South Egypt cancer Institute (SECI) hospital during the period from Janurary 2001 to December 2008 were reviewed .We report the progress of the availability of breast cancer management and evaluation of the quality of care delivered to breast cancer patients. The total number of patients with a breast lump presented to the SECI during the study period was 1,463 patients (32 males and 1431 females); 616 patients from the total number were admitted at the surgical department .There was a decline in advanced cases. Since 2001, facilities for all lines of comprehensive management have been made accessible for all patients. We found that better management could lead to earlier presentation, and better overall outcome in breast cancer patients.The incidence is steadily increasing with a tendency for breast cancer to occur in younger age groups and with advanced stages.

  9. Breast Cancer: Surgery at the South Egypt Cancer Institute

    Directory of Open Access Journals (Sweden)

    Ahmed A.S. Salem

    2010-09-01

    Full Text Available Breast cancer is the most frequent malignant tumor in women worldwide. In Egypt, it is the most common cancer among women, representing 18.9% of total cancer cases (35.1% in women and 2.2% in men among the Egypt National Cancer Institute’s (NCI series of 10,556 patients during the year 2001, with an age-adjusted rate of 49.6 per 100,000 people. In this study, the data of all breast cancer patients presented to the surgical department of the South Egypt cancer Institute (SECI hospital during the period from Janurary 2001 to December 2008 were reviewed .We report the progress of the availability of breast cancer management and evaluation of the quality of care delivered to breast cancer patients. The total number of patients with a breast lump presented to the SECI during the study period was 1,463 patients (32 males and 1431 females; 616 patients from the total number were admitted at the surgical department .There was a decline in advanced cases. Since 2001, facilities for all lines of comprehensive management have been made accessible for all patients. We found that better management could lead to earlier presentation, and better overall outcome in breast cancer patients.The incidence is steadily increasing with a tendency for breast cancer to occur in younger age groups and with advanced stages.

  10. Preeclampsia and breast cancer

    DEFF Research Database (Denmark)

    Pacheco, Nadja Livia Pekkola; Andersen, Anne-Marie Nybo; Kamper-Jørgensen, Mads

    2015-01-01

    BACKGROUND: In parous women preeclampsia has been associated with reduced risk of developing breast cancer. Characteristics of births following preeclamptic pregnancies may help understand mechanisms involved in the breast cancer risk reduction inferred by preeclampsia. METHODS: We conducted...... a register-based cohort study of all Danish women giving birth during 1978-2010 (n = 778,701). The association between preeclampsia and breast cancer was evaluated overall and according to birth characteristics by means of incidence rate ratios (IRR) estimated in Poisson regression models. RESULTS: Compared...... with women with non-preeclamptic pregnancies only, women with one or more preeclamptic pregnancies were 19% significantly less likely to develop breast cancer (IRR = 0.81 [95% CI 0.72-0.93]). We found some indication of greater risk reduction in women with term births, one or more previous births...

  11. CDC Vital Signs: Breast Cancer

    Science.gov (United States)

    ... 2.65 MB] Read the MMWR Science Clips Breast Cancer Black Women Have Higher Death Rates from Breast ... of Page U.S. State Info Number of Additional Breast Cancer Deaths Among Black Women, By State SOURCE: National ...

  12. Reproductive History and Breast Cancer Risk

    Science.gov (United States)

    ... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... 4 ). This risk reduction is limited to hormone receptor –positive breast cancer; age at first full-term ...

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

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  14. Epigenetic suppression of neprilysin regulates breast cancer invasion.

    Science.gov (United States)

    Stephen, H M; Khoury, R J; Majmudar, P R; Blaylock, T; Hawkins, K; Salama, M S; Scott, M D; Cosminsky, B; Utreja, N K; Britt, J; Conway, R E

    2016-03-07

    In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT-PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer

  15. BREAST RECONSTRUCTIONS AFTER BREAST CANCER TREATING

    Directory of Open Access Journals (Sweden)

    Erik Vrabič

    2018-02-01

    Full Text Available Background. Breasts are an important symbol of physical beauty, feminity, mothering and sexual desire through the entire history of mankind. Lost of the whole or part of the breast is functional and aesthetic disturbance for woman. It is understandable, that the woman, who is concerned over breast loss, is as appropriate as another person´s concern over the loss of a limb or other body part. Before the 1960, breast reconstruction was considered as a dangerous procedure and it was almost prohibited. Considering the psychological importance of the breast in modern society, the possibility of breast reconstruction for the woman about to undergo a mastectomy is a comforting alternative. We can perform breast reconstruction with autologous tissue (autologous reconstruction, with breast implants and combination of both methods. For autologous reconstruction we can use local tissue (local flaps, or tissue from distant parts of the body (free vascular tissue transfer. Tissue expansion must be performed first, in many cases of breast reconstructions with breast implants. Conclusions. Possibility of breast reconstruction made a big progress last 3 decades. Today we are able to reconstruct almost every defect of the breast and the entire breast. Breast reconstruction rise the quality of life for breast cancer patients. Breast reconstruction is a team work of experts from many medicine specialites. In Slovenia we can offer breast reconstruction for breast cancer patients in Ljubljana, where plastic surgeons from Clinical Department for Plastic Surgery and Burns cooperate with oncologic surgeons. Ten years ago a similar cooperation between plastic surgeons and surgeons of the Centre for Breast Diseases was established in Maribor.

  16. A targeted proteomics approach to the quantitative analysis of ERK/Bcl-2-mediated anti-apoptosis and multi-drug resistance in breast cancer.

    Science.gov (United States)

    Yang, Ting; Xu, Feifei; Sheng, Yuan; Zhang, Wen; Chen, Yun

    2016-10-01

    Apoptosis suppression caused by overexpression of anti-apoptotic proteins is a central factor to the acquisition of multi-drug resistance (MDR) in breast cancer. As a highly conserved anti-apoptotic protein, Bcl-2 can initiate an anti-apoptosis response via an ERK1/2-mediated pathway. However, the details therein are still far from completely understood and a quantitative description of the associated proteins in the biological context may provide more insights into this process. Following our previous attempts in the quantitative analysis of MDR mechanisms, liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted proteomics was continually employed here to describe ERK/Bcl-2-mediated anti-apoptosis. A targeted proteomics assay was developed and validated first for the simultaneous quantification of ERK1/2 and Bcl-2. In particular, ERK isoforms (i.e., ERK1 and ERK2) and their differential phosphorylated forms including isobaric ones were distinguished. Using this assay, differential protein levels and site-specific phosphorylation stoichiometry were observed in parental drug-sensitive MCF-7/WT cancer cells and drug-resistant MCF-7/ADR cancer cells and breast tissue samples from two groups of patients who were either suspected or diagnosed to have drug resistance. In addition, quantitative analysis of the time course of both ERK1/2 and Bcl-2 in doxorubicin (DOX)-treated MCF-7/WT cells confirmed these findings. Overall, we propose that targeted proteomics can be used generally to resolve more complex cellular events.

  17. Adherence to Guidelines for Breast Surveillance in Breast Cancer Survivors.

    Science.gov (United States)

    Ruddy, Kathryn J; Sangaralingham, Lindsey; Freedman, Rachel A; Mougalian, Sarah; Neuman, Heather; Greenberg, Caprice; Jemal, Ahmedin; Duma, Narjust; Haddad, Tufia C; Lemaine, Valerie; Ghosh, Karthik; Hieken, Tina J; Hunt, Katie; Vachon, Celine; Gross, Cary; Shah, Nilay D

    2018-05-01

    Background: Guidelines recommend annual mammography after curative-intent treatment for breast cancer. The goal of this study was to assess contemporary patterns of breast imaging after breast cancer treatment. Methods: Administrative claims data were used to identify privately insured and Medicare Advantage beneficiaries with nonmetastatic breast cancer who had residual breast tissue (not bilateral mastectomy) after breast surgery between January 2005 and May 2015. We calculated the proportion of patients who had a mammogram, MRI, both, or neither during each of 5 subsequent 13-month periods. Multinomial logistic regression was used to assess associations between patient characteristics, healthcare use, and breast imaging in the first and fifth years after surgery. Results: A total of 27,212 patients were followed for a median of 2.9 years (interquartile range, 1.8-4.6) after definitive breast cancer surgery. In year 1, 78% were screened using mammography alone, 1% using MRI alone, and 8% using both tests; 13% did not undergo either. By year 5, the proportion of the remaining cohort (n=4,790) who had no breast imaging was 19%. Older age was associated with an increased likelihood of mammography and a decreased likelihood of MRI during the first and fifth years. Black race, mastectomy, chemotherapy, and no MRI at baseline were all associated with a decreased likelihood of both types of imaging. Conclusions: Even in an insured cohort, a substantial proportion of breast cancer survivors do not undergo annual surveillance breast imaging, particularly as time passes. Understanding factors associated with imaging in cancer survivors may help improve adherence to survivorship care guidelines. Copyright © 2018 by the National Comprehensive Cancer Network.

  18. Proteomic classification of breast cancer.

    LENUS (Irish Health Repository)

    Kamel, Dalia

    2012-11-01

    Being a significant health problem that affects patients in various age groups, breast cancer has been extensively studied to date. Recently, molecular breast cancer classification has advanced significantly with the availability of genomic profiling technologies. Proteomic technologies have also advanced from traditional protein assays including enzyme-linked immunosorbent assay, immunoblotting and immunohistochemistry to more comprehensive approaches including mass spectrometry and reverse phase protein lysate arrays (RPPA). The purpose of this manuscript is to review the current protein markers that influence breast cancer prediction and prognosis and to focus on novel advances in proteomic classification of breast cancer.

  19. RAD51B in Familial Breast Cancer

    DEFF Research Database (Denmark)

    Pelttari, Liisa M; Khan, Sofia; Vuorela, Mikko

    2016-01-01

    Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition......, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD......51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients...

  20. Mechanisms driving local breast cancer recurrence in a model of breast-conserving surgery.

    LENUS (Irish Health Repository)

    Smith, Myles J

    2012-02-03

    OBJECTIVE: We aimed to identify mechanisms driving local recurrence in a model of breast-conserving surgery (BCS) for breast cancer. BACKGROUND: Breast cancer recurrence after BCS remains a clinically significant, but poorly understood problem. We have previously reported that recurrent colorectal tumours demonstrate altered growth dynamics, increased metastatic burden and resistance to apoptosis, mediated by upregulation of phosphoinositide-3-kinase\\/Akt (PI3K\\/Akt). We investigated whether similar characteristics were evident in a model of locally recurrent breast cancer. METHODS: Tumours were generated by orthotopic inoculation of 4T1 cells in two groups of female Balb\\/c mice and cytoreductive surgery performed when mean tumour size was above 150 mm(3). Local recurrence was observed and gene expression was examined using Affymetrix GeneChips in primary and recurrent tumours. Differential expression was confirmed with quantitative real-time polymerase chain reaction (qRT-PCR). Phosphorylation of Akt was assessed using Western immunoblotting. An ex vivo heat shock protein (HSP)-loaded dendritic cell vaccine was administered in the perioperative period. RESULTS: We observed a significant difference in the recurrent 4T1 tumour volume and growth rate (p < 0.05). Gene expression studies suggested roles for the PI3K\\/Akt system and local immunosuppression driving the altered growth kinetics. We demonstrated that perioperative vaccination with an ex vivo HSP-loaded dendritic cell vaccine abrogated recurrent tumour growth in vivo (p = 0.003 at day 15). CONCLUSION: Investigating therapies which target tumour survival pathways such as PI3K\\/Akt and boost immune surveillance in the perioperative period may be useful adjuncts to contemporary breast cancer treatment.

  1. Environmental cadmium and breast cancer risk

    OpenAIRE

    Gallagher, Carolyn M.; Chen, John J.; Kovach, John S.

    2010-01-01

    Breast cancer is the most prevalent women's cancer, with an age-adjusted incidence of 122.9 per 100,000 US women. Cadmium, a ubiquitous carcinogenic pollutant with multiple biological effects, has been reported to be associated with breast cancer in one US regional case-control study. We examined the association of breast cancer with urinary cadmium (UCd), in a case-control sample of women living on Long Island (LI), NY (100 with breast cancer and 98 without), a region with an especially high...

  2. Selection of metastatic breast cancer cells based on adaptability of their metabolic state.

    Directory of Open Access Journals (Sweden)

    Balraj Singh

    Full Text Available A small subpopulation of highly adaptable breast cancer cells within a vastly heterogeneous population drives cancer metastasis. Here we describe a function-based strategy for selecting rare cancer cells that are highly adaptable and drive malignancy. Although cancer cells are dependent on certain nutrients, e.g., glucose and glutamine, we hypothesized that the adaptable cancer cells that drive malignancy must possess an adaptable metabolic state and that such cells could be identified using a robust selection strategy. As expected, more than 99.99% of cells died upon glutamine withdrawal from the aggressive breast cancer cell line SUM149. The rare cells that survived and proliferated without glutamine were highly adaptable, as judged by additional robust adaptability assays involving prolonged cell culture without glucose or serum. We were successful in isolating rare metabolically plastic glutamine-independent (Gln-ind variants from several aggressive breast cancer cell lines that we tested. The Gln-ind cells overexpressed cyclooxygenase-2, an indicator of tumor aggressiveness, and they were able to adjust their glutaminase level to suit glutamine availability. The Gln-ind cells were anchorage-independent, resistant to chemotherapeutic drugs doxorubicin and paclitaxel, and resistant to a high concentration of a COX-2 inhibitor celecoxib. The number of cells being able to adapt to non-availability of glutamine increased upon prior selection of cells for resistance to chemotherapy drugs or resistance to celecoxib, further supporting a linkage between cellular adaptability and therapeutic resistance. Gln-ind cells showed indications of oxidative stress, and they produced cadherin11 and vimentin, indicators of mesenchymal phenotype. Gln-ind cells were more tumorigenic and more metastatic in nude mice than the parental cell line as judged by incidence and time of occurrence. As we decreased the number of cancer cells in xenografts, lung metastasis

  3. Selection of Metastatic Breast Cancer Cells Based on Adaptability of Their Metabolic State

    Science.gov (United States)

    Singh, Balraj; Tai, Karen; Madan, Simran; Raythatha, Milan R.; Cady, Amanda M.; Braunlin, Megan; Irving, LaTashia R.; Bajaj, Ankur; Lucci, Anthony

    2012-01-01

    A small subpopulation of highly adaptable breast cancer cells within a vastly heterogeneous population drives cancer metastasis. Here we describe a function-based strategy for selecting rare cancer cells that are highly adaptable and drive malignancy. Although cancer cells are dependent on certain nutrients, e.g., glucose and glutamine, we hypothesized that the adaptable cancer cells that drive malignancy must possess an adaptable metabolic state and that such cells could be identified using a robust selection strategy. As expected, more than 99.99% of cells died upon glutamine withdrawal from the aggressive breast cancer cell line SUM149. The rare cells that survived and proliferated without glutamine were highly adaptable, as judged by additional robust adaptability assays involving prolonged cell culture without glucose or serum. We were successful in isolating rare metabolically plastic glutamine-independent (Gln-ind) variants from several aggressive breast cancer cell lines that we tested. The Gln-ind cells overexpressed cyclooxygenase-2, an indicator of tumor aggressiveness, and they were able to adjust their glutaminase level to suit glutamine availability. The Gln-ind cells were anchorage-independent, resistant to chemotherapeutic drugs doxorubicin and paclitaxel, and resistant to a high concentration of a COX-2 inhibitor celecoxib. The number of cells being able to adapt to non-availability of glutamine increased upon prior selection of cells for resistance to chemotherapy drugs or resistance to celecoxib, further supporting a linkage between cellular adaptability and therapeutic resistance. Gln-ind cells showed indications of oxidative stress, and they produced cadherin11 and vimentin, indicators of mesenchymal phenotype. Gln-ind cells were more tumorigenic and more metastatic in nude mice than the parental cell line as judged by incidence and time of occurrence. As we decreased the number of cancer cells in xenografts, lung metastasis and then primary

  4. Breast cancer cells obtain an osteomimetic feature via epithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction.

    Science.gov (United States)

    Tan, Cong-Cong; Li, Gui-Xi; Tan, Li-Duan; Du, Xin; Li, Xiao-Qing; He, Rui; Wang, Qing-Shan; Feng, Yu-Mei

    2016-11-29

    Bone is one of the most common organs of breast cancer metastasis. Cancer cells that mimic osteoblasts by expressing bone matrix proteins and factors have a higher likelihood of metastasizing to bone. However, the molecular mechanisms of osteomimicry formation of cancer cells remain undefined. Herein, we identified a set of bone-related genes (BRGs) that are ectopically co-expressed in primary breast cancer tissues and determined that osteomimetic feature is obtained due to the osteoblast-like transformation of epithelial breast cancer cells that have undergone epithelial-mesenchymal transition (EMT) followed by bone morphogenetic protein-2 (BMP2) stimulation. Furthermore, we demonstrated that breast cancer cells that transformed into osteoblast-like cells with high expression of BRGs showed enhanced chemotaxis, adhesion, proliferation and multidrug resistance in an osteoblast-mimic bone microenvironment in vitro. During these processes, runt-related transcription factor 2 (RUNX2) functioned as a master mediator by suppressing or activating the transcription of BRGs that underlie the dynamic antagonism between the TGF-β/SMAD and BMP/SMAD signaling pathways in breast cancer cells. Our findings suggest a novel mechanism of osteomimicry formation that arises in primary breast tumors, which may explain the propensity of breast cancer to metastasize to the skeleton and contribute to potential strategies for predicting and targeting breast cancer bone metastasis and multidrug resistance.

  5. Liposomal curcumin alters chemosensitivity of breast cancer cells to Adriamycin via regulating microRNA expression.

    Science.gov (United States)

    Zhou, Siying; Li, Jian; Xu, Hanzi; Zhang, Sijie; Chen, Xiu; Chen, Wei; Yang, Sujin; Zhong, Shanliang; Zhao, Jianhua; Tang, Jinhai

    2017-07-30

    Emerging evidence suggests that curcumin can overcome drug resistance to classical chemotherapies, but poor bioavailability and low absorption have limited its clinical use and the mechanisms remain unclear. Also, Adriamycin (Adr) is one of the most active cytotoxic agents in breast cancer; however, the high resistant rate of Adr leads to a poor prognosis. We utilized encapsulation in liposomes as a strategy to improve the bioavailability of curcumin and demonstrated that liposomal curcumin altered chemosensitivity of Adr-resistant MCF-7 human breast cancer (MCF-7/Adr) by MTT assay. The miRNA and mRNA expression profiles of MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr cells were analyzed by microarray and further confirmed by real-time PCR. We focused on differentially expressed miR-29b-1-5p to explore the involvement of miR-29b-1-5p in the resistance of Adr. Candidate genes of dysregulated miRNAs were identified by prediction algorithms based on gene expression profiles. Networks of KEGG pathways were organized by the selected dysregulated miRNAs. Moreover, protein-protein interaction (PPI) was utilized to map protein interaction networks of curcumin regulated proteins. We first demonstrated liposomal curcumin could rescue part of Adriamycin resistance in breast cancer and further identified 67 differentially expressed microRNAs among MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr. The results showed that lower expressed miR-29b-1-5p decreased the IC50 of MCF-7/Adr cells and higher expressed miR-29b-1-5p, weaken the effects of liposomal curcumin to Adr-resistance. Besides, we found that 20 target genes (mRNAs) of each dysregulated miRNA were not only predicted by prediction algorithms, but also differentially expressed in the microarray. The results showed that MAPK, mTOR, PI3K-Akt, AMPK, TNF, Ras signaling pathways and several target genes such as PPARG, RRM2, SRSF1and EPAS1, may associate with drug resistance of breast cancer cells to Adr. We determined

  6. Breast cancer in Kumasi, Ghana

    International Nuclear Information System (INIS)

    Ohene-Yeboah, M.; Adjei, E.

    2012-01-01

    Breast cancer is the leading cause of cancer deaths in Ghanaian women.To describes the characteristics of breast cancer patients attending the Komfo Anokye Teaching Hospital in Kumasi, Ghana.The study was conducted at the Komfo Anokye Teaching Hospital. Between July 1st 2004 and June 30th 2009 patients presenting with breast lumps were assessed by clinical examination, imaging studies and pathological examination. Relevant clinical and pathological were recorded prospectively data on all patients with microscopically proven breast cancer. The cancers were graded according to the modified Bloom-Richardson system. Tissue immunoperoxidase stains for oestrogen, progesterone receptors and c-erb2 oncogene were performed with commercially prepared antigens and reagents.Nineteen thousand four hundred and twenty – three (19,423) patients were seen during the study period. There were 330 (1.7%) patients with histologically proven breast cancer. The mean age was 49.1 years. A palpable breast lump was detected in 248 patients (75.2%). Two hundred and eighty –one patients (85.2%) presented with Stages III and IV , 271 (82.1%) invasive and 230 ( 85.2%) high grade carcinomas. Oestrogen and progesterone receptors were positive in 32 and 9 cases respectively. Her2 protein was positive in 11 cases. In Kumasi, as in other parts of Ghana, breast cancer affects mostly young pre-menopausal who present with advanced disease. The cancers have unfavourable prognostic features and are unlikely to respond to hormonal therapy. (au)

  7. Breast cancer screening in older women.

    Science.gov (United States)

    Caplan, L S; Haynes, S G

    1996-01-01

    There is currently an epidemic of breast cancer in women 65 years of age and older. The purposes of this paper are to explore the breast cancer screening behaviors of older women and to identify some of the determinants of screening in these women. Data were analyzed from the 1987 National Health Interview Survey, a continuous nationwide household interview survey of the U.S. civilian, noninstitutionalized population. As in other studies, the utilization of breast cancer screening by older women was less in older women than in younger women. This was true for both mammography and clinical breast examination. A number of determinants of screening in older women were identified here. Women with a usual source of care and/or no activity limitation, as well as high school graduates, were the ones most likely to have received a screening mammogram and/or a screening clinical breast exam during the past year. The failure of older women to receive adequate breast cancer screening is an important concern which should be reevaluated, given the breast cancer epidemic in this population. This study identified a number of determinants of breast cancer screening in older women. For the most part, these determinants point to the primary care physician as the key to breast cancer screening in these women. Therefore, the primary care physician must be informed of, and encouraged to follow, the recommendations for periodic breast cancer screening in older women.

  8. Breast self-examination: resistance to change.

    Science.gov (United States)

    Del Giudice, M Elisabeth; Tannenbaum, David; Goodwin, Pamela J

    2005-05-01

    To investigate whether Canadian family practitioners routinely teach breast self-examination (BSE) after publication of the 2001 Canadian Preventive Health Task Force guideline advising them to exclude teaching BSE from periodic health examinations. Self-administered cross-sectional mailed survey. Canada. A random sample of English-speaking general practitioners and physicians certified by the College of Family Physicians of Canada. Current and past BSE practices and opinions on the value of BSE. Response rate was 47.4%. Most respondents (88%) were aware of the new recommendations, yet only 16% had changed their usual practice of routinely teaching BSE. Most physicians agreed that before the recommendation they almost always taught BSE (74.3%). Only 9.5% agreed that physicians should follow the recommendation and not routinely teach BSE. A few also agreed that they now spend less time discussing BSE (25.7%) and that the recommendation has influenced them to stop teaching (12.4%) and encouraging (12.9%) women to practise BSE. Physicians who had changed their BSE practices were less likely to agree that BSE increases early detection of breast cancer and more likely to agree that BSE increases benign breast biopsies. They were also more likely to agree that screening mammography in women older than 50 decreases mortality from breast cancer. This survey, which assessed routine teaching of BSE, revealed poor adherence by Canadian family physicians to a well publicized evidence-based guideline update. Resistance to change could in part be attributed to a lack of knowledge of the supporting evidence, a lack of confidence in the evidence to date, and personal experiences with patients within their practices.

  9. Awareness of breast cancer and breast self-examination among ...

    African Journals Online (AJOL)

    Awareness of breast cancer and breast self-examination among female undergraduate students in a higher teachers training college in Cameroon. ... Conclusion: Though most students are aware of the existence of breast cancer, their overall knowledge on its risk factors and clinical presentation is insufficient with a ...

  10. Urinary estrogen metabolites and breast cancer

    DEFF Research Database (Denmark)

    Dallal, Cher M; Stone, Roslyn A; Cauley, Jane A

    2013-01-01

    Background: Circulating estrogens are associated with increased breast cancer risk, yet the role of estrogen metabolites in breast carcinogenesis remains unclear. This combined analysis of 5 published studies evaluates urinary 2-hydroxyestrone (2-OHE1), 16a-hydroxyestrone (16a-OHE1......), and their ratio (2:16a-OHE1) in relation to breast cancer risk. ¿Methods: Primary data on 726 premenopausal women (183 invasive breast cancer cases and 543 controls) and 1,108 postmenopausal women (385 invasive breast cancer cases and 723 controls) were analyzed. Urinary estrogen metabolites were measured using...... premenopausal 2:16a-OHE1 was suggestive of reduced breast cancer risk overall (study-adjusted ORIIIvsI=0.80; 95% CI: 0.49-1.32) and for estrogen receptor negative (ER-) subtype (ORIIIvsI=0.33; 95% CI: 0.13-0.84). Among postmenopausal women, 2:16a-OHE1 was unrelated to breast cancer risk (study-adjusted ORIIIvs...

  11. TOX3 mutations in breast cancer.

    Directory of Open Access Journals (Sweden)

    James Owain Jones

    Full Text Available TOX3 maps to 16q12, a region commonly lost in breast cancers and recently implicated in the risk of developing breast cancer. However, not much is known of the role of TOX3 itself in breast cancer biology. This is the first study to determine the importance of TOX3 mutations in breast cancers. We screened TOX3 for mutations in 133 breast tumours and identified four mutations (three missense, one in-frame deletion of 30 base pairs in six primary tumours, corresponding to an overall mutation frequency of 4.5%. One potentially deleterious missense mutation in exon 3 (Leu129Phe was identified in one tumour (genomic DNA and cDNA. Whilst copy number changes of 16q12 are common in breast cancer, our data show that mutations of TOX3 are present at low frequency in tumours. Our results support that TOX3 should be further investigated to elucidate its role in breast cancer biology.

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

    Science.gov (United States)

    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

  13. Breast cancer with axillary lymph node involvement

    International Nuclear Information System (INIS)

    Belaid, A.; Kanoun, S.; Kallel, A.; Ghorbel, I.; Azoury, F.; Heymann, S.; Marsiglia, H.; Bourgier, C.; Belaid, A.; Ghorbel, I.; Kanoun, S.; Kallel, A.; Pichenot, C.; Verstraet, R.; Marsiglia, H.

    2010-01-01

    Breast cancer is the most frequent cancer of women in western countries. There are one million new cases per year in the world which represents 22% of all female cancers, and more than 370.000 deaths due to breast cancer per year (14% of cancer mortality). More than half of breast cancers are associated with axillary nodal involvement. Post-operative radiation therapy (XRT) is a crucial part of locoregional treatment in axillary nodal involvement breast cancer owing to a 15-years risk reduction of locoregional recurrence of 70% and to a 5.4% risk reduction of specific mortality. In 3D-conformal irradiation in such breast cancers, target volumes are chest wall when mastectomy was performed or breast and boost of tumor bed in case of breast conservative surgery, and supra-clavicular and/or axillary and/or internal mammary node areas. The main organs at risk are ipsilateral lung, heart and brachial plexus. The aim of this article is to describe epidemiologic, radio anatomic and prognostic features of axillary nodal involvement breast cancer and to propose guidelines for 3D-conformal treatment planning in locally advanced breast cancers. This review is illustrated by a case report. (authors)

  14. Clinical utility of exemestane in the treatment of breast cancer 

    Directory of Open Access Journals (Sweden)

    Zucchini G

    2015-05-01

    Full Text Available Giorgia Zucchini,1 Elena Geuna,1 Andrea Milani,1 Caterina Aversa,2 Rossella Martinello,2 Filippo Montemurro1 1Investigative Clinical Oncology, Fondazione del Piemonte per l’Oncologia-Candiolo Cancer Institute (IRCCs, Candiolo, 2University of Turin Medical School, Turin, Italy Abstract: Breast cancer is the most prevalent cancer in women, causing a significant mortality worldwide. Different endocrine strategies are available for the treatment of hormone-sensitive breast cancer, including antiestrogen tamoxifen and fulvestrant, as well as third-generation aromatase inhibitors (AIs, such as letrozole, anastrozole, and exemestane. In this review, we will focus on exemestane, its clinical use, and its side effects. Exemestane is a steroidal third-generation AI now used in all treatment settings for breast cancer. In the metastatic disease, it has been extensively investigated as the first-, second-, and further-line treatment and it is now registered for the treatment of postmenopausal women with advanced estrogen-receptor-positive breast cancer whose disease has progressed following antiestrogen therapy. A potential lack of cross-resistance with nonsteroidal AIs has been described, giving additional therapeutic opportunities in sequences of endocrine agents. Exemestane is also approved for the adjuvant treatment of postmenopausal early breast cancer, either as upfront monotherapy for 5 years, as a switch following 2–3 years of tamoxifen, or as extended therapy beyond 5 years of adjuvant treatment. New promising data also showed a beneficial effect in young premenopausal early breast cancer patients, when administered together with ovarian suppression. Interesting results have also emerged when exemestane has been investigated as neodjuvant treatment as well as preventive agent in healthy women at high risk for breast cancer. Exemestane is generally well tolerated, with a side effect profile similar to that of other AIs, including menopausal

  15. What You Need to Know about Breast Cancer

    Science.gov (United States)

    ... Publications Reports What You Need To Know About™ Breast Cancer This booklet is about breast cancer. Learning about your cancer can help you take ... This booklet covers: Basics about breast anatomy and breast cancer Treatments for breast cancer, including taking part in ...

  16. Treatment of locally advanced/locally recurrent breast cancer and inflammatory breast cancer

    International Nuclear Information System (INIS)

    Murakami, Masao

    2000-01-01

    This paper summarizes the treatment of locally advanced breast cancer, inflammatory breast cancer, and locally recurrent breast cancer. A multidisciplinary approach considering subclinical distant metastases is needed to treat these types of breast cancer. Subclinical distant metastasis is observed in about 80% of case of locally advanced cancer, and treatment of subclinical distant metastases, e.g., by endocrinotherapy and chemotherapy, is therefore essential to improving the prognosis. The standard therapy for unresectable locally advanced breast cancer consists of induction chemotherapy with anthracyclines and local treatment with mastectomy or irradiation. Previous reports have stated that induction chemotherapy was effective in 60-80% of the primary lesions or lymph node metastasis, and the CR rates were in the 10-20% range. Combination therapy with induction chemotherapy clearly improved the outcome over local treatment alone. The usual irradiation dose is 50 to 60 Gy/5 to 7 weeks to the whole breast or the thoracic wall. Boost irradiation at a dose of 10 to 25 Gy is performed in unresectable cases. The boost irradiation dose to the lymph node area is usually 45 to 50 Gy/5 to 6 weeks in cases without gross lesions and 10 to 15 Gy in cases with gross lesions. Combination therapy consisting of conservative pectoral mastectomy and postoperative adjuvant chemo- endocrino-therapy (i.e., adjuvant therapy) has become the standard regimen for treating resectable locally advanced breast cancer, because it significantly improves the recurrence rate and survival rate compared to local treatment alone. Some clinical have studies indicated that neoadjuvant therapy (i.e., induction chemotherapy + surgery/radiation therapy) is comparable or superior to adjuvant therapy in terms of improving the prognosis. However, the efficacy and most appropriate method of breast-conserving therapy after induction chemotherapy are still unclear. More clinical trials are needed. It has been

  17. Environment and breast cancer - the role of xenooestrogens in breast cancer carcinogenesis

    International Nuclear Information System (INIS)

    Plesnicar, A.; Kralj, B.; Druzina, B.; Kovac, V.

    2002-01-01

    Background. The survival rate of breast cancer patients has not changed much in the last few decades in developed countries. In order to improve the efficacy of breast cancer prevention and treatment, the role of xenooestrogens in the mechanisms of its development has been evaluated. These industrial chemicals bear little structural resemblance to each other and bind to the oestrogen receptors of exposed cells and/or trigger oestrogenic responses in laboratory test systems. Exposure to xenooestrogens has been regarded as a risk factor for carcinogenesis and a preventable cause of breast carcinoma. Several epidemiological and experimental studies in in vivo and in in vitro conditions of the influence of xenooestrogens on the occurrence of breast cancer have been conducted in the last decades and have shown ambiguous results. Conclusions. No increase in breast carcinoma incidence could be found in women who were exposed to relatively high concentrations of xenooestrogens for extended periods and small quantities of these compounds that are present in the environment probably cannot act as etiological agents for the occurrence of this disease. A multi step approach is suggested regarding the sequence of studies and measures that should be taken to further assess the importance of xenooestrogens on breast cancer carcinogenesis. (author)

  18. Genetic factors and breast cancer laterality

    International Nuclear Information System (INIS)

    Amer, Magid H

    2014-01-01

    Women are more likely to develop cancer in the left breast than the right. Such laterality may influence subsequent management, especially in elderly patients with heart disease who may require radiation therapy. The purpose of this study was to explore possible factors for such cancer laterality. In this work, clinical data for consecutive patients with histologically confirmed breast cancer were reviewed, with emphasis on clinical presentation and family history. Between 2005 and 2012, 687 patients with breast cancer were seen. Two women with incomplete data and eleven men were excluded. In total, 343 (50.9%) patients presented with left breast cancer, 311 (46.1%) with right breast cancer, and 20 (3.0%) with simultaneous bilateral malignancy. There were no significant differences between the three groups, especially in regards to clinical presentation and tumor characteristics. A total of 622 (92.3%) patients had unilateral primary, 20 (3.0%) had simultaneous bilateral, and 32 (4.7%) had metachronous primary breast cancer with subsequent contralateral breast cancer after 7.5–236 months. The worst 10-year survival was for bilateral simultaneous (18%) compared with unilateral (28%) and metachronous primaries (90%). There were no differences in survival in relation to breast cancer laterality, handedness, and presence or absence of a family history of cancer. There were significant similarities between patients and first-degree relatives in regards to breast cancer laterality, namely same breast (30/66, 45.5%), opposite breast (9/66, 13.6%), and bilateral cancer (27/66, 40.9, P=0.01163). This was more evident among patients and their sisters (17/32, 53.1%) or mothers (11/27, 40.7%, P=0.0689). There were also close similarities in relation to age at initial diagnosis of cancer for patients and their first-degree relatives for age differences of ≤5 years (48/166, 28.9%), 6–10 years (34/166, 20.5%), and >11 years (84/166, 50.6%, P=0.12065). High similarities

  19. Assessment of SLX4 Mutations in Hereditary Breast Cancers.

    Directory of Open Access Journals (Sweden)

    Sohela Shah

    Full Text Available SLX4 encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose polymerase (PARP inhibitors. Recent studies have reported mutations in SLX4 in a new subtype of Fanconi anemia (FA, FA-P. Monoallelic defects in several FA genes are known to confer susceptibility to breast and ovarian cancers.To determine if SLX4 is involved in breast cancer susceptibility, we sequenced the entire SLX4 coding region in 738 (270 Jewish and 468 non-Jewish breast cancer patients with 2 or more family members affected by breast cancer and no known BRCA1 or BRCA2 mutations. We found a novel nonsense (c.2469G>A, p.W823* mutation in one patient. In addition, we also found 51 missense variants [13 novel, 23 rare (MAF1%], of which 22 (5 novel and 17 rare were predicted to be damaging by Polyphen2 (score = 0.65-1. We performed functional complementation studies using p.W823* and 5 SLX4 variants (4 novel and 1 rare cDNAs in a human SLX4-null fibroblast cell line, RA3331. While wild type SLX4 and all the other variants fully rescued the sensitivity to mitomycin C (MMC, campthothecin (CPT, and PARP inhibitor (Olaparib the p.W823* SLX4 mutant failed to do so.Loss-of-function mutations in SLX4 may contribute to the development of breast cancer in very rare cases.

  20. 14. Breast cancer prevention.

    Science.gov (United States)

    Salih, A K; Fentiman, I S

    2002-05-01

    Increased risk of breast cancer may result from potentially modifiable causes such as endogenous hormone levels, obesity, HRT, and non-lactation, or non-modifiable factors including genetic susceptibility and increasing age. The Gail model, based on known factors, may be useful for estimating lifetime risk in some individuals, but those risk factors that are easier to modify may have a limited impact on the totality of breast cancer. Tamoxifen prevention still remains contentious, with a significant reduction in risk of breast cancer in women given tamoxifen in the NSABP P1 study but no effect in the Italian and Royal Marsden trials. Raloxifene, tested in the MORE trial, reduced the incidence of breast cancer by 65% but this was restricted to oestrogen receptor positive tumours. Lifestyle factors such as diet, obesity, exercise and age at first full term pregnancy and number of pregnancies have a mild to moderate impact on risk, so may have little effect on the incidence of breast cancer. Reduction of alcohol intake could lead to a modest reduction in the risk of breast cancer but possibly adversely affect other diseases. Fat reduction and GnRH analogue reduce mammographic density but have not yet been shown to affect risk. For women with BRCA1/2 mutation, options include unproven surveillance and prophylactic mastectomy with an unquantified risk reduction. Interesting new candidates for chemoprevention include aromatase inhibitors, new generation SERMs, demethylating agents, non-selective COX inhibitors, tyrosine kinase inhibitors and polyamine synthetic inhibitors.

  1. Novel Targeted Therapies for Inflammatory Breast Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0461 TITLE: Novel Targeted Therapies for Inflammatory Breast Cancer PRINCIPAL INVESTIGATOR: Jose Silva CONTRACTING...CONTRACT NUMBER Novel Targeted Therapies for Inflammatory Breast Cancer 5b. GRANT NUMBER W81XWH-16-1-0461 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) l 5d...NOTES 14. ABSTRACT Inflammatory breast cancer (IBC, ~5% of all breast cancers ) is the most lethal form of breast cancer , presenting a 5- year

  2. Neoadjuvant therapy for early-stage breast cancer: the clinical utility of pertuzumab

    International Nuclear Information System (INIS)

    Gollamudi, Jahnavi; Parvani, Jenny G; Schiemann, William P; Vinayak, Shaveta

    2016-01-01

    Approximately 20% of breast cancer patients harbor tumors that overexpress human epidermal growth factor receptor 2 (HER2; also known as ErbB2), a receptor tyrosine kinase that belongs to the epidermal growth factor receptor family of receptor tyrosine kinases. HER2 amplification and hyperactivation drive the growth and survival of breast cancers through the aberrant activation of proto-oncogenic signaling systems, particularly the Ras/MAP kinase and PI3K/AKT pathways. Although HER2-positive (HER2 + ) breast cancer was originally considered to be a highly aggressive form of the disease, the clinical landscape of HER2 + breast cancers has literally been transformed by the approval of anti-HER2 agents for adjuvant and neoadjuvant settings. Indeed, pertuzumab is a novel monoclonal antibody that functions as an anti-HER2 agent by targeting the extracellular dimerization domain of the HER2 receptor; it is also the first drug to receive an accelerated approval by the US Food and Drug Administration for use in neoadjuvant settings in early-stage HER2 + breast cancer. Here, we review the molecular and cellular factors that contribute to the pathophysiology of HER2 in breast cancer, as well as summarize the landmark preclinical and clinical findings underlying the approval and use of pertuzumab in the neoadjuvant setting. Finally, the molecular mechanisms operant in mediating resistance to anti-HER2 agents, and perhaps to pertuzumab as well, will be discussed, as will the anticipated clinical impact and future directions of pertuzumab in breast cancer patients

  3. Fibroblast growth factor receptors in breast cancer.

    Science.gov (United States)

    Wang, Shuwei; Ding, Zhongyang

    2017-05-01

    Fibroblast growth factor receptors are growth factor receptor tyrosine kinases, exerting their roles in embryogenesis, tissue homeostasis, and development of breast cancer. Recent genetic studies have identified some subtypes of fibroblast growth factor receptors as strong genetic loci associated with breast cancer. In this article, we review the recent epidemiological findings and experiment results of fibroblast growth factor receptors in breast cancer. First, we summarized the structure and physiological function of fibroblast growth factor receptors in humans. Then, we discussed the common genetic variations in fibroblast growth factor receptors that affect breast cancer risk. In addition, we also introduced the potential roles of each fibroblast growth factor receptors isoform in breast cancer. Finally, we explored the potential therapeutics targeting fibroblast growth factor receptors for breast cancer. Based on the biological mechanisms of fibroblast growth factor receptors leading to the pathogenesis in breast cancer, targeting fibroblast growth factor receptors may provide new opportunities for breast cancer therapeutic strategies.

  4. The Effect of Personal Characteristics, Perceived Threat, Efficacy and Breast Cancer Anxiety on Breast Cancer Screening Activation

    Directory of Open Access Journals (Sweden)

    Patrick De Pelsmacker

    2017-09-01

    Full Text Available In order to activate women to participate in breast cancer screening programs, a good understanding is needed of the personal characteristics that influence how women can be activated to search for more information, consult friends and doctors, and participate in breast cancer screening programs. In the current study, we investigate the effect of six personal characteristics that have in previous research been identified as important triggers of health behavior on breast cancer screening activation: Health awareness, Need for Cognition, Affect Intensity, Breast cancer knowledge, Topic involvement, and the Perceived breast cancer risk. We test the effect of these factors on four activation variables: intention of future information seeking, forwarding the message to a friend, talking to a doctor, and actual breast cancer screening attendance. Additionally, we try to unravel the process by means of which the antecedents (the six personal characteristics lead to activation. To that end, we test the mediating role of perceived breast cancer threat, perceived efficacy of screening, and the evoked breast cancer anxiety as mediators in this process. The data were collected by means of a cross-sectional survey in a sample of 700 Flemish (Belgium women who were invited to the free-of-charge breast cancer population screening. Screening attendance of this sample was provided by the government agency in charge of the organisation of the screening. Health awareness, affects intensity, topic involvement, and perceived risk have the strongest influence on activation. Breast cancer anxiety and perceived breast cancer threat have a substantial mediation effect on these effects. Efficacy perceptions are less important in the activation process. Increased health awareness and a higher level of perceived risk lead to less participation in the free of charge population based breast screening program. Implications for theory and practice are offered. The limitation

  5. The Effect of Personal Characteristics, Perceived Threat, Efficacy and Breast Cancer Anxiety on Breast Cancer Screening Activation

    Science.gov (United States)

    De Pelsmacker, Patrick; Lewi, Martine; Cauberghe, Veroline

    2017-01-01

    In order to activate women to participate in breast cancer screening programs, a good understanding is needed of the personal characteristics that influence how women can be activated to search for more information, consult friends and doctors, and participate in breast cancer screening programs. In the current study, we investigate the effect of six personal characteristics that have in previous research been identified as important triggers of health behavior on breast cancer screening activation: Health awareness, Need for Cognition, Affect Intensity, Breast cancer knowledge, Topic involvement, and the Perceived breast cancer risk. We test the effect of these factors on four activation variables: intention of future information seeking, forwarding the message to a friend, talking to a doctor, and actual breast cancer screening attendance. Additionally, we try to unravel the process by means of which the antecedents (the six personal characteristics) lead to activation. To that end, we test the mediating role of perceived breast cancer threat, perceived efficacy of screening, and the evoked breast cancer anxiety as mediators in this process. The data were collected by means of a cross-sectional survey in a sample of 700 Flemish (Belgium) women who were invited to the free-of-charge breast cancer population screening. Screening attendance of this sample was provided by the government agency in charge of the organisation of the screening. Health awareness, affects intensity, topic involvement, and perceived risk have the strongest influence on activation. Breast cancer anxiety and perceived breast cancer threat have a substantial mediation effect on these effects. Efficacy perceptions are less important in the activation process. Increased health awareness and a higher level of perceived risk lead to less participation in the free of charge population based breast screening program. Implications for theory and practice are offered. The limitation of the study is

  6. Drugs Approved for Breast Cancer

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Breast Cancer This page lists cancer drugs approved by the ... are not listed here. Drugs Approved to Prevent Breast Cancer Evista (Raloxifene Hydrochloride) Raloxifene Hydrochloride Tamoxifen Citrate Drugs ...

  7. Environmental exposures, breast development and cancer risk: Through the looking glass of breast cancer prevention.

    Science.gov (United States)

    Forman, Michele R; Winn, Deborah M; Collman, Gwen W; Rizzo, Jeanne; Birnbaum, Linda S

    2015-07-01

    This review summarizes the report entitled: Breast Cancer and the Environment: Prioritizing Prevention, highlights research gaps and the importance of focusing on early life exposures for breast development and breast cancer risk. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Self assessment and detection of breast cancer

    International Nuclear Information System (INIS)

    Singh, Priyanka; Yadav, Umesh

    2016-01-01

    Cancer is one of the leading causes of deaths in India. Approx. three million patients suffering from the disease while Breast cancer is the second most common cancer among women in India. Post operative radiotherapy after the breast conservative surgery and mastectomy have been shown to reduce the rates of local recurrence and death due to breast carcinomas. Hence awareness of breast cancer signs, symptoms and self assessment plays critical role in the care of breast cancer patients

  9. Efficacy of reovirus against breast cancer

    International Nuclear Information System (INIS)

    Zhu Jingzhi; Chen Jue; Dong Shengxiang; Yan Weili; Wu Zhiyong

    2011-01-01

    To investigate the role of oncolytic reovirus in breast cancer, a tumor xenograft model of NOD/SCID mice was established using a biopsy sample of a primary infiltrating ductal carcinoma obtained from a breast cancer patient. The result of HE and TUNEL was analyzed after injecting the reovirus peritoneally for 3 days. The results showed that estrogen supplementation was required to establish appropriate human breast cancer xenograft model of NOD/SCID mice. 29.6% of these transplanted tumors grew with supplementation of Estrogen. Otherwise none grew (P<0.01). ER of the xenograft model was positive.After treatment with reovirus for 3 days, breast cancer cells were disrupted and disappeared which induced tissue looseness. The rate of apoptosis increased double than before. The biological characteristics of tumor xenograft model confirm with the primary breast cancer. The oncolytic reovirus can kill breast cancer in short time. (authors)

  10. Early diagnosis of breast cancer

    International Nuclear Information System (INIS)

    Semiglazov, V.F.

    1989-01-01

    Modern data are presentd on epidemology etiopathogensis and statistics of breast cancer. Home and international clinical and histological classifications is given. Much attention is paid to the methods for early diagnosis of pretumor diseases and breast cancer: clinical roentgenomammography, thrmography and computerized tomomammography. The role of self-examination in cancer early detection has been analyzed. Special attention is paid to system of detection of minimal and unpalpable form of breast cancer, screening of these tumors. 113 refs.; 60 figs.; 6 tabs

  11. MRI evaluation of the contralateral breast in patients with recently diagnosed breast cancer

    International Nuclear Information System (INIS)

    Taneja, Sangeeta; Jena, Amarnath; Zaidi, Syed Mohd. Shuaib; Khurana, Anuj

    2012-01-01

    Contralateral breast cancer can be synchronous and/or metachronous in patients with cancer of one breast. Detection of a synchronous breast cancer may affect patient management. Dynamic contrast-enhanced MRI of the breast (DCE-MRI) is a sensitive technique for detecting contralateral lesions occult on the other imaging modalities in women already diagnosed with cancer of one breast. The aim was to assess the incidence of mammographically occult synchronous contralateral breast cancer in patients undergoing MRI mammography for the evaluation of a malignant breast lesion. A total of 294 patients with recently diagnosed breast cancer who underwent MRI of the breast were evaluated for lesions in the opposite breast. The incidence of synchronous contralateral malignancy detected by preoperative MRI mammography done for evaluation of extent of disease was 4.1%. Preoperative breast MRI may detect clinically and mammographically occult synchronous contralateral cancer, and can help the patient avoid an additional second surgery or a second course of chemotherapy later; also, as theoretically these lesions are smaller, there may be a survival benefit as well

  12. Broccoli Sprout Extract in Treating Patients With Breast Cancer

    Science.gov (United States)

    2018-06-04

    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

  13. New use of an old drug: Inhibition of breast cancer stem cells by benztropine mesylate

    OpenAIRE

    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...

  14. Patient-initiated breast cancer screening

    International Nuclear Information System (INIS)

    Chilcote, W.

    1990-01-01

    This paper reviews the results of a breast cancer screening program sponsored by organizations at workplace or community locations. A comprehensive mobile breast cancer screening program, including education, breast physical examination, and mammography, was provided to 89 local organizations at $50.00 per examination over an 18-month period. The examination was patient initiated, following the ACS screening guidelines. Estimates of eligible women were provided by each organization. A total of 5,030 women at 89 organizations were screened for breast cancer. Approximately 25,727 women were eligible

  15. Screen-detected versus interval cancers: Effect of imaging modality and breast density in the Flemish Breast Cancer Screening Programme

    Energy Technology Data Exchange (ETDEWEB)

    Timmermans, Lore; Bacher, Klaus; Thierens, Hubert [Ghent University, Department of Basic Medical Sciences, QCC-Gent, Ghent (Belgium); Bleyen, Luc; Herck, Koen van [Ghent University, Centrum voor Preventie en Vroegtijdige Opsporing van Kanker, Ghent (Belgium); Lemmens, Kim; Ongeval, Chantal van; Steen, Andre van [University Hospitals Leuven, Department of Radiology, Leuven (Belgium); Martens, Patrick [Centrum voor Kankeropsporing, Bruges (Belgium); Brabander, Isabel de [Belgian Cancer Registry, Brussels (Belgium); Goossens, Mathieu [UZ Brussel, Dienst Kankerpreventie, Brussels (Belgium)

    2017-09-15

    To investigate if direct radiography (DR) performs better than screen-film mammography (SF) and computed radiography (CR) in dense breasts in a decentralized organised Breast Cancer Screening Programme. To this end, screen-detected versus interval cancers were studied in different BI-RADS density classes for these imaging modalities. The study cohort consisted of 351,532 women who participated in the Flemish Breast Cancer Screening Programme in 2009 and 2010. Information on screen-detected and interval cancers, breast density scores of radiologist second readers, and imaging modality was obtained by linkage of the databases of the Centre of Cancer Detection and the Belgian Cancer Registry. Overall, 67% of occurring breast cancers are screen detected and 33% are interval cancers, with DR performing better than SF and CR. The interval cancer rate increases gradually with breast density, regardless of modality. In the high-density class, the interval cancer rate exceeds the cancer detection rate for SF and CR, but not for DR. DR is superior to SF and CR with respect to cancer detection rates for high-density breasts. To reduce the high interval cancer rate in dense breasts, use of an additional imaging technique in screening can be taken into consideration. (orig.)

  16. Screen-detected versus interval cancers: Effect of imaging modality and breast density in the Flemish Breast Cancer Screening Programme

    International Nuclear Information System (INIS)

    Timmermans, Lore; Bacher, Klaus; Thierens, Hubert; Bleyen, Luc; Herck, Koen van; Lemmens, Kim; Ongeval, Chantal van; Steen, Andre van; Martens, Patrick; Brabander, Isabel de; Goossens, Mathieu

    2017-01-01

    To investigate if direct radiography (DR) performs better than screen-film mammography (SF) and computed radiography (CR) in dense breasts in a decentralized organised Breast Cancer Screening Programme. To this end, screen-detected versus interval cancers were studied in different BI-RADS density classes for these imaging modalities. The study cohort consisted of 351,532 women who participated in the Flemish Breast Cancer Screening Programme in 2009 and 2010. Information on screen-detected and interval cancers, breast density scores of radiologist second readers, and imaging modality was obtained by linkage of the databases of the Centre of Cancer Detection and the Belgian Cancer Registry. Overall, 67% of occurring breast cancers are screen detected and 33% are interval cancers, with DR performing better than SF and CR. The interval cancer rate increases gradually with breast density, regardless of modality. In the high-density class, the interval cancer rate exceeds the cancer detection rate for SF and CR, but not for DR. DR is superior to SF and CR with respect to cancer detection rates for high-density breasts. To reduce the high interval cancer rate in dense breasts, use of an additional imaging technique in screening can be taken into consideration. (orig.)

  17. Weight gain following breast cancer diagnosis: Implication and proposed mechanisms

    Science.gov (United States)

    Makari-Judson, Grace; Braun, Barry; Jerry, D Joseph; Mertens, Wilson C

    2014-01-01

    Weight gain occurs in the majority of women following breast cancer treatment. An overview of studies describing weight gain amongst women treated with early to modern chemotherapy regimens is included. Populations at higher risk include women who are younger, closer to ideal body weight and who have been treated with chemotherapy. Weight gain ranges between 1 to 5 kg, and may be associated with change in body composition with gain in fat mass and loss in lean body mass. Women are unlikely to return to pre-diagnosis weight. Possible mechanisms including inactivity and metabolic changes are explored. Potential interventions are reviewed including exercise, dietary changes and pharmacologic agents. Although breast cancer prognosis does not appear to be significantly impacted, weight gain has negative consequences on quality of life and overall health. Future studies should explore change in body composition, metabolism and insulin resistance. Avoiding weight gain in breast cancer survivors following initial diagnosis and treatment should be encouraged. PMID:25114844

  18. A randomized cross-over trial to detect differences in arm volume after low- and heavy-load resistance exercise among patients receiving adjuvant chemotherapy for breast cancer at risk for arm lymphedema

    DEFF Research Database (Denmark)

    Bloomquist, Kira; Hayes, Sandi; Adamsen, Lis

    2016-01-01

    changes after resistance exercise with heavy loads in this population. The purpose of this study is to determine acute changes in arm volume after a session of low- and heavy-load resistance exercise among women undergoing adjuvant chemotherapy for breast cancer at risk for arm lymphedema. METHODS....../DESIGN: This is a randomized cross-over trial. PARTICIPANTS: Women receiving adjuvant chemotherapy for breast cancer who have undergone axillary lymph node dissection will be recruited from rehabilitation centers in the Copenhagen area. INTERVENTION: Participants will be randomly assigned to engage in a low- (two sets of 15...... was calculated based on changes in L-Dex scores between baseline and 72-hours post exercise sessions. DISCUSSION: Findings from this study are relevant for exercise prescription guidelines, as well as recommendations regarding participating in activities of daily living for women following surgery for breast...

  19. Effects of irradiation for cervical cancer on subsequent breast cancer

    International Nuclear Information System (INIS)

    Harlan, L.C.M.

    1985-01-01

    Previous research suggests that cervical cancer patients have a lower risk of breast cancer than women in the general population. Possible explanations include opposing risk factors for cervical cancer and breast cancer, the effect of irradiation used to treat cervical cancer, or both. The purpose of this study was to explore the relationship between irradiation for cervical cancer and the subsequent development of breast cancer. There was no statistically significant relationship between radiation to the ovarian area and the risk of breast cancer in this study. However, the results were consistent with a 19% reduction in risk for women irradiated for cervical cancer when compared to nonirradiated women. In a dose-response analysis, there was a nonsignificant trend of decreased risk of breast cancer with increased radiation up to 1800 rad. There was no consistent pattern for higher doses. The trend, although nonsignificant, differed by age. Women <60 years of age at irradiation were generally at a lower risk of breast cancer than nonirradiated women. Women over 59 years were at an increased risk. There are some potentially important findings from this study which might influence medical care. These should be examined in the larger International Radiation Study

  20. Bilateral breast cancer : mammographic and clinical findings

    International Nuclear Information System (INIS)

    Kim, Eun Kyung; Oh, Ki Keun; Jun, Hwang Yoon; Lee, Byung Chan; Lee, Kyong Sik; Lee, Yong Hee

    1997-01-01

    To evaluate the mammographic and clinical features of bilateral breast cancer. We retrospectively reviewed clinical records(n=23) and mammograms (n=15) of 23 patients with bilateral breast cancer. Patients' age, location of the tumor and pathologic staging were determined from clinical records. Mammographic features were classified as spiculated mass, nonspiculated mass, mass with microcalcification, microcalcification only, asymmetric density, and normal. Of the 23 cases of bilateral breast cancer, 8(34.8%) were synchronous and 15(65.2%) were metachronous. Age at diagnosis of cancer in the first breast was between 27 and 59(mean 43) years ; there was no statistically significant difference in mean age between patients with synchronous and metachronous cancer. The mean interval between the diagnosis of each lesion of the metachronous pairs was 9.1 years. In 11 of 23 cases(48%), tumors were locaated in the same quadrant, and in the other 12 cases(52%), they were in different quadrant. At mammography, five of 15 metachronous cancers(33%) were similar in appearance and 10 pairs(67%) were different. In 4 of 23 cases(17%), cancer in the first breast was at stage 0 and stage 1, and in 13 of 23(57%), cancer in the second breast was at this same stage. In bilateral breast cancer, the two breasts frequently show different mammographic features. Cancer of the second breast was at an early stage; this suggest that regular examination and mammography are important and can allow early detection of contralateral breast cancer

  1. Advancements in the Treatment of Metastatic Breast Cancer (MBC: The Role of Ixabepilone

    Directory of Open Access Journals (Sweden)

    Massimo Cristofanilli

    2012-01-01

    Full Text Available Successful management of breast cancer in the metastatic setting is often confounded by resistance to chemotherapeutics, in particular anthracyclines and taxanes. The limited number of effective treatment options for patients with more aggressive biological subtypes, such as triple-negative metastatic breast cancer, is especially concerning. As such, a therapy clinically proven to be effective in this subtype would be of great value. Ixabepilone, a novel synthetic lactam analog of epothilone B, demonstrated better clinical outcomes in metastatic disease, particularly in triple-negative breast cancer. Most recently, studies have shown the activity of ixabepilone in the neoadjuvant setting, suggesting a role for this drug in primary disease. Notably, treating in the neoadjuvant setting might allow clinicians to explore the predictive value of biomarkers and response to treatment, as pharmacogenomic approaches to therapy continue to evolve. In this article, we review the efficacy and safety data of ixabepilone as a monotherapy and as a component of combination therapy for metastatic and primary breast cancer.

  2. Novel Growth Factor as Prognostic Marker for Estrogen-Independence in Breast Cancer

    National Research Council Canada - National Science Library

    Serrero, Ginette

    2002-01-01

    ...-independence and tamoxifen resistance. Here, wave conducted a study with 206 paraffin embedded human breast cancer biopsies and measured PCDGF expression by immunohistochemistry using an anti-PCDGF developed in our laboratory...

  3. Novel Growth Factor as Prognostic Marker for Estrogen-Independence in Breast Cancer

    National Research Council Canada - National Science Library

    Serrero, Ginette

    2003-01-01

    The Concept Award focused on investigating the expression on the biomarker PCDGF/GP88 in breast cancer and its effect on the acquisition of estrogen independence and tamoxifen resistance, a hallmark...

  4. Aromatase inhibitors and breast cancer prevention.

    Science.gov (United States)

    Litton, Jennifer Keating; Arun, Banu K; Brown, Powel H; Hortobagyi, Gabriel N

    2012-02-01

    Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer. This review evaluates the available prevention data, as evidenced by the decrease in contralateral breast cancers, when aromatase inhibitors are used in the adjuvant setting, as well as the emerging data of the aromatase inhibitors specifically tested in the prevention setting for women at high risk. Exemestane is a viable option for breast cancer prevention. We continue to await further follow-up on exemestane as well as other aromatase inhibitors in the prevention setting for women at high risk of developing breast cancer or with a history of ductal carcinoma in situ.

  5. Breast cancer screening in Korean woman with dense breast tissue

    International Nuclear Information System (INIS)

    Shin, Hee Jung; Ko, Eun Sook; Yi, Ann

    2015-01-01

    Asian women, including Korean, have a relatively higher incidence of dense breast tissue, compared with western women. Dense breast tissue has a lower sensitivity for the detection of breast cancer and a higher relative risk for breast cancer, compared with fatty breast tissue. Thus, there were limitations in the mammographic screening for women with dense breast tissue, and many studies for the supplemental screening methods. This review included appropriate screening methods for Korean women with dense breasts. We also reviewed the application and limitation of supplemental screening methods, including breast ultrasound, digital breast tomosynthesis, and breast magnetic resonance imaging; and furthermore investigated the guidelines, as well as the study results

  6. Breast cancer screening in Korean woman with dense breast tissue

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Hee Jung [Dept. of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul (Korea, Republic of); Ko, Eun Sook [Dept. of Radiology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul (Korea, Republic of); Yi, Ann [Dept. of Radiology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul (Korea, Republic of)

    2015-11-15

    Asian women, including Korean, have a relatively higher incidence of dense breast tissue, compared with western women. Dense breast tissue has a lower sensitivity for the detection of breast cancer and a higher relative risk for breast cancer, compared with fatty breast tissue. Thus, there were limitations in the mammographic screening for women with dense breast tissue, and many studies for the supplemental screening methods. This review included appropriate screening methods for Korean women with dense breasts. We also reviewed the application and limitation of supplemental screening methods, including breast ultrasound, digital breast tomosynthesis, and breast magnetic resonance imaging; and furthermore investigated the guidelines, as well as the study results.

  7. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes

    DEFF Research Database (Denmark)

    Broeks, Annegien; Schmidt, Marjanka K; Sherman, Mark E

    2011-01-01

    Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtype...... stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.......Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes...... were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations...

  8. ATM variants and cancer risk in breast cancer patients from Southern Finland

    Directory of Open Access Journals (Sweden)

    Aittomäki Kristiina

    2006-08-01

    Full Text Available Abstract Background Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for breast cancer but the role for ATM genetic variants for breast cancer risk has remained unclear. Recently, a common ATM variant, ATMivs38 -8T>C in cis with the ATMex39 5557G>A (D1853N variant, was suggested to associate with bilateral breast cancer among familial breast cancer patients from Northern Finland. We have here evaluated the 5557G>A and ivs38-8T>C variants in an extensive case-control association analysis. We also aimed to investigate whether there are other ATM mutations or variants contributing to breast cancer risk in our population. Methods Two common ATM variants, 5557G>A and ivs38-8T>C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls. Results Neither of the two common variants, 5557G>A and ivs38-8T>C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls. Conclusion Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G>A or ivs38-8T>C variant with

  9. A gene expression signature of Retinoblastoma loss-of-function predicts resistance to neoadjuvant chemotherapy in ER-positive/HER2-positive breast cancer patients.

    Science.gov (United States)

    Risi, Emanuela; Grilli, Andrea; Migliaccio, Ilenia; Biagioni, Chiara; McCartney, Amelia; Guarducci, Cristina; Bonechi, Martina; Benelli, Matteo; Vitale, Stefania; Biganzoli, Laura; Bicciato, Silvio; Di Leo, Angelo; Malorni, Luca

    2018-07-01

    HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients. We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR. Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively; Fisher's exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER-)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group. Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.

  10. Human Breast Cancer Histoid

    Science.gov (United States)

    Kaur, Pavinder; Ward, Brenda; Saha, Baisakhi; Young, Lillian; Groshen, Susan; Techy, Geza; Lu, Yani; Atkinson, Roscoe; Taylor, Clive R.; Ingram, Marylou

    2011-01-01

    Progress in our understanding of heterotypic cellular interaction in the tumor microenvironment, which is recognized to play major roles in cancer progression, has been hampered due to unavailability of an appropriate in vitro co-culture model. The aim of this study was to generate an in vitro 3-dimensional human breast cancer model, which consists of cancer cells and fibroblasts. Breast cancer cells (UACC-893) and fibroblasts at various densities were co-cultured in a rotating suspension culture system to establish co-culture parameters. Subsequently, UACC-893, BT.20, or MDA.MB.453 were co-cultured with fibroblasts for 9 days. Co-cultures resulted in the generation of breast cancer histoid (BCH) with cancer cells showing the invasion of fibroblast spheroids, which were visualized by immunohistochemical (IHC) staining of sections (4 µm thick) of BCH. A reproducible quantitative expression of C-erbB.2 was detected in UACC-893 cancer cells in BCH sections by IHC staining and the Automated Cellular Imaging System. BCH sections also consistently exhibited qualitative expression of pancytokeratins, p53, Ki-67, or E-cadherin in cancer cells and that of vimentin or GSTPi in fibroblasts, fibronectin in the basement membrane and collagen IV in the extracellular matrix. The expression of the protein analytes and cellular architecture of BCH were markedly similar to those of breast cancer tissue. PMID:22034518

  11. Classification of Breast Cancer Resistant Protein (BCRP) Inhibitors and Non-Inhibitors Using Machine Learning Approaches.

    Science.gov (United States)

    Belekar, Vilas; Lingineni, Karthik; Garg, Prabha

    2015-01-01

    The breast cancer resistant protein (BCRP) is an important transporter and its inhibitors play an important role in cancer treatment by improving the oral bioavailability as well as blood brain barrier (BBB) permeability of anticancer drugs. In this work, a computational model was developed to predict the compounds as BCRP inhibitors or non-inhibitors. Various machine learning approaches like, support vector machine (SVM), k-nearest neighbor (k-NN) and artificial neural network (ANN) were used to develop the models. The Matthews correlation coefficients (MCC) of developed models using ANN, k-NN and SVM are 0.67, 0.71 and 0.77, and prediction accuracies are 85.2%, 88.3% and 90.8% respectively. The developed models were tested with a test set of 99 compounds and further validated with external set of 98 compounds. Distribution plot analysis and various machine learning models were also developed based on druglikeness descriptors. Applicability domain is used to check the prediction reliability of the new molecules.

  12. Breast Cancer: Reactions, Choices, Decisions

    Science.gov (United States)

    Waring, Alexia N.

    2000-01-01

    Women with breast cancer often experience a predictable set of emotional and psychological reactions to their cancer diagnosis according to recognized influencing factors such as age at the time of diagnosis and stage of life. The time between a breast biopsy and the receipt of the pathology results has been identified by patients as the most stressful period throughout the entire cancer experience. Treatment decisions, until recently, were made solely by physicians while patients assumed passive roles. Increasingly, breast cancer patients want to assume an active role in their treatment decisions and care and are no longer satisfied to be passive observers. More and more women educate themselves about their disease through the Internet, investigating available treatment options, side effects, and in some cases, alternative therapies. This new type of breast cancer patient wants to be cared for by physicians who embrace the patient as part of the team. They appreciate the physician who is not threatened by the educated breast cancer patient and understands that she is ultimately motivated by an attempt to regain some of the control the cancer has taken away from her. PMID:21765661

  13. BRCA1/2 associated hereditary breast cancer

    Institute of Scientific and Technical Information of China (English)

    Li-song TENG; Yi ZHENG; Hao-hao WANG

    2008-01-01

    Breast cancer is one of the leading causes of death in women today. Some of the patients are hereditary, with a large proportion characterized by mutation in BRCA1 and/or BRCA2 genes. In this review, we provide an overview of these two genes,focusing on their relationship with hereditary breast cancers. BRCA1/2 associated hereditary breast cancers have unique features that differ from the general breast cancers, including alterations in cellular molecules, pathological bases, biological behavior, and a different prevention strategy. But the outcome of BRCA1/2 associated hereditary breast cancers still remains controversial;further studies are needed to elucidate the nature of BRCA1/2 associated hereditary breast cancers.

  14. Oxidative stress: development and progression of breast cancer:review article

    Directory of Open Access Journals (Sweden)

    Arash Salmaninejad

    2017-04-01

    Full Text Available Breast cancer is the most commonly diagnosed cancer in women worldwide. Enormous advancement has been made over the last decades in understanding the biology of breast cancer. Nevertheless, the molecular mechanisms regulating progression, gaining of invasive and metastatic phenotypes, and therapeutic resistance are still not completely understood. Oxidative stress initiate by disbalance in redox status of body. In this case, increase of free radicals in body cause tissue damage. One of the significant species of free radicals is reactive oxygen species (ROS that produced by various metabolic pathways, comprising aerobic metabolism in the mitochondrial respiratory chain. They play a serious role in cellular physiology and pathophysiology likewise beginning and evolution of numerous types of cancers. ROS overproduction is deleterious to cells, and considered key-factors for the development of numerous diseases, such as cardiovascular disorders, neurodegenerative diseases, and cancer. Cancer cells are commonly submitted to upper ROS levels that further incite malignant phenotype through motivation to preserved proliferation, angiogenesis, death evasion, invasiveness, and metastasis. ROS impress various signaling pathways, comprising mitogenic pathways and growth factors, and also controls numerous cellular processes, containing cell proliferation, thus stimulates the undisciplined growth of cells which inspires the development of tumors and initiates the progression of carcinogenesis. The importance of ROS on breast cancer development and etiology is being increasingly clarified. Nevertheless, fewer consideration has been given to the progress of redox system-targeted strategies for breast cancer treatment. Augmented oxidative stress caused by reactive species can diminish the body’s antioxidant defense against angiogenesis and metastasis in cancer cells. These processes are core factors in the development of cancer. Bimolecular reactions cause

  15. Breast cancer detection using sonography in women with mammographically dense breasts

    International Nuclear Information System (INIS)

    Okello, Jimmy; Kisembo, Harriet; Bugeza, Sam; Galukande, Moses

    2014-01-01

    Mammography, the gold standard for breast cancer screening misses some cancers, especially in women with dense breasts. Breast ultrasonography as a supplementary imaging tool for further evaluation of symptomatic women with mammographically dense breasts may improve the detection of mass lesions otherwise missed at mammography. The purpose of this study was to determine the incremental breast cancer detection rate using US scanning in symptomatic women with mammographically dense breasts in a resource poor environment. A cross sectional descriptive study. Women referred for mammography underwent bilateral breast ultrasound, and mammography for symptom evaluation. The lesions seen by both modalities were described using sonographic BI-RADS lexicon and categorized. Ultrasound guided core biopsies were performed. IRB approval was obtained and all participants provided informed written consent. In total 148 women with mammographically dense breasts were recruited over six months. The prevalence of breast cancer in symptomatic women with mammographically dense breasts was 22/148 (15%). Mammography detected 16/22 (73%) of these cases and missed 6/22 (27%). The six breast cancer cases missed were correctly diagnosed on breast ultrasonography. Sonographic features typical of breast malignancy were irregular shape, non-parallel orientation, non circumscribed margin, echogenic halo, and increased lesion vascularity (p values < 0.005). Typical sonofeatures of benign mass lesions were: oval shape, parallel orientation and circumscribed margin (p values <0.005). Breast ultrasound scan as a supplementary imaging tool detected 27% more malignant mass lesions otherwise missed by mammography among these symptomatic women with mammographically dense breasts. We recommend that ultra sound scanning in routine evaluation of symptomatic women with mammographically dense breasts

  16. Levels of estrogen, carcinoembryonic antigen and cancer antigen of breast in Sudanese female with breast cancer

    International Nuclear Information System (INIS)

    Abdelhadi, H. A.; Sirelkhatim, D. A.; Eltayeb, E. A.; Ahmed, W. A.; Elhussein, B.

    2006-12-01

    This study was conducted during the period from february 2004 to july 2004; with the objective of measuring the levels of estrogen (E2), carcinoembryonic antigen (CEA) and cancer antigen of breast (CA-15.3) so as to facilitate the early diagnosis of breast cancer and to determine the involvement of these parameters as risk factors for breast cancer. Ninety blood samples were collected from Sudanese females, divided into two groups; control group and patients groups. The patients group was sixty Sudanese females visiting the Radio Isotope Center, Khartoum (RICK) and they were confirmed as breast cancer patients by histopathology. The levels of the above mentioned parameters were determined by using radioimmunoassay technique. The results showed that , no significant (P=0.05) difference between the levels of the estrogen in patients compared to the control, on the other hand, there was non-significant (p<0.05) elevation in CEA levels in the patients with breast cancer compared to the control. The levels of CA 15.3 was significantly (p<0.0001) higher in the breast cancer patients compared to the control.(Author)

  17. The Japanese Guidelines for Breast Cancer Screening.

    Science.gov (United States)

    Hamashima, Chisato; Hamashima C, Chisato; Hattori, Masakazu; Honjo, Satoshi; Kasahara, Yoshio; Katayama, Takafumi; Nakai, Masahiro; Nakayama, Tomio; Morita, Takako; Ohta, Koji; Ohnuki, Koji; Sagawa, Motoyasu; Saito, Hiroshi; Sasaki, Seiju; Shimada, Tomoyuki; Sobue, Tomotaka; Suto, Akihiko

    2016-05-01

    The incidence of breast cancer has progressively increased, making it the leading cause of cancer deaths in Japan. Breast cancer accounts for 20.4% of all new cancers with a reported age-standardized rate of 63.6 per 100 000 women. The Japanese guidelines for breast cancer screening were developed based on a previously established method. The efficacies of mammography with and without clinical breast examination, clinical breast examination and ultrasonography with and without mammography were evaluated. Based on the balance of the benefits and harms, recommendations for population-based and opportunistic screenings were formulated. Five randomized controlled trials of mammographic screening without clinical breast examination were identified for mortality reduction from breast cancer. The overall relative risk for women aged 40-74 years was 0.75 (95% CI: 0.67-0.83). Three randomized controlled trials of mammographic screening with clinical breast examination served as eligible evidence for mortality reduction from breast cancer. The overall relative risk for women aged 40-64 years was 0.87 (95% confidence interval: 0.77-0.98). The major harms of mammographic screening were radiation exposure, false-positive cases and overdiagnosis. Although two case-control studies evaluating mortality reduction from breast cancer were found for clinical breast examination, there was no study assessing the effectiveness of ultrasonography for breast cancer screening. Mammographic screening without clinical breast examination for women aged 40-74 years and with clinical breast examination for women aged 40-64 years is recommended for population-based and opportunistic screenings. Clinical breast examination and ultrasonography are not recommended for population-based screening because of insufficient evidence regarding their effectiveness. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. RGS16 inhibits breast cancer cell growth by mitigating phosphatidylinositol 3-kinase signaling.

    Science.gov (United States)

    Liang, Genqing; Bansal, Geetanjali; Xie, Zhihui; Druey, Kirk M

    2009-08-07

    Aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway supports growth of many tumors including those of breast, lung, and prostate. Resistance of breast cancer cells to targeted chemotherapies including tyrosine kinase inhibitors (TKI) has been linked to persistent PI3K activity, which may in part be due to increased membrane expression of epidermal growth factor (EGF) receptors (HER2 and HER3). Recently we found that proteins of the RGS (regulator of G protein signaling) family suppress PI3K activity downstream of the receptor by sequestering its p85alpha subunit from signaling complexes. Because a substantial percentage of breast tumors have RGS16 mutations and reduced RGS16 protein expression, we investigated the link between regulation of PI3K activity by RGS16 and breast cancer cell growth. RGS16 overexpression in MCF7 breast cancer cells inhibited EGF-induced proliferation and Akt phosphorylation, whereas shRNA-mediated extinction of RGS16 augmented cell growth and resistance to TKI treatment. Exposure to TKI also reduced RGS16 expression in MCF7 and BT474 cell lines. RGS16 bound the amino-terminal SH2 and inter-SH2 domains of p85alpha and inhibited its interaction with the EGF receptor-associated adapter protein Gab1. These results suggest that the loss of RGS16 in some breast tumors enhances PI3K signaling elicited by growth factors and thereby promotes proliferation and TKI evasion downstream of HER activation.

  19. Radioisotope techniques used in breast cancer

    International Nuclear Information System (INIS)

    Au-Yong Ting Kun

    2001-01-01

    Breast cancer is one of the commonest cancer in women. Treatment and prognosis of breast cancer depend very much on accurate diagnosis, staging and follow-up of patients. Recently, there are several radioisotope techniques developed and have great impact on management of breast cancer. These include scintimammography, sentinel lymph node detection and positron emission tomography. This article is to review these important techniques

  20. Prognostic outcomes in advanced breast cancer: the metastasis-free interval is important.

    Science.gov (United States)

    Shen, Tiansheng; Gao, Cheng; Zhang, Kui; Siegal, Gene P; Wei, Shi

    2017-12-01

    Metastatic breast cancer is a heterogeneous disease with a diverse clinical course. There have been limited studies regarding prognostic outcomes in patients with de novo metastatic breast cancer versus those with metastatic recurrence, with controversial observations. In this study, we sought to examine the difference in survival outcomes among patients with advanced breast cancer stratified based on metastasis-free interval (MFI) and to further explore the role of systemic therapy in these patient groups. Of 569 consecutive patients with stage IV breast cancer between 1998 and 2013, 201 had de novo metastatic disease (metastasis at diagnosis) and 368 developed metastatic recurrence, including 168 with an MFI≤24 months and 200 with an MFI>24 months. In the 492 patients who received systemic therapy, de novo metastasis was an independent favorable prognostic factor for overall survival after metastasis when compared with metastatic recurrence irrespective of MFI. Compared with the patients with metastatic recurrence with an MFI≤24 months, those with an MFI>24 months had a superior survival outcome, although it did not reach statistical significance by multivariate analysis. In contrast, de novo metastatic breast cancer was associated with a worse prognosis when compared with recurring metastasis in the patients who did not receive systemic treatment. These findings provide more insight into the natural history of advanced breast cancer, thus necessitating further investigation into the molecular mechanism of drug resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. MMP9 polymorphisms and breast cancer risk: a report from the Shanghai Breast Cancer Genetics Study.

    Science.gov (United States)

    Beeghly-Fadiel, Alicia; Lu, Wei; Shu, Xiao-Ou; Long, Jirong; Cai, Qiuyin; Xiang, Yongbin; Gao, Yu-Tang; Zheng, Wei

    2011-04-01

    In addition to tumor invasion and angiogenesis, matrix metalloproteinase (MMP)9 also contributes to carcinogenesis and tumor growth. Genetic variation that may influence MMP9 expression was evaluated among participants of the Shanghai Breast Cancer Genetics Study (SBCGS) for associations with breast cancer susceptibility. In stage 1, 11 MMP9 single nucleotide polymorphisms (SNPs) were genotyped by the Affymetrix Targeted Genotyping System and/or the Affymetrix Genome-Wide Human SNP Array 6.0 among 4,227 SBCGS participants. One SNP was further genotyped using the Sequenom iPLEX MassARRAY platform among an additional 6,270 SBCGS participants. Associations with breast cancer risk were evaluated by odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models that included adjustment for age, education, and genotyping stage when appropriate. In Stage 1, rare allele homozygotes for a promoter SNP (rs3918241) or a non-synonymous SNP (rs2274756, R668Q) tended to occur more frequently among breast cancer cases (P value = 0.116 and 0.056, respectively). Given their high linkage disequilibrium (D' = 1.0, r (2) = 0.97), one (rs3918241) was selected for additional analysis. An association with breast cancer risk was not supported by additional Stage 2 genotyping. In combined analysis, no elevated risk of breast cancer among homozygotes was found (OR: 1.2, 95% CI: 0.8-1.8). Common genetic variation in MMP9 was not found to be significantly associated with breast cancer susceptibility among participants of the Shanghai Breast Cancer Genetics Study.

  2. Adipocyte activation of cancer stem cell signaling in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Benjamin; Wolfson; Gabriel; Eades; Qun; Zhou

    2015-01-01

    Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment,have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6(IL-6) have a paracrine effect on breast cancer cells. In adipocyte-adjacent breast cancer cells, the leptin and IL-6 signaling pathways activate janus kinase 2/signal transducer and activatorof transcription 5, promoting the epithelial-mesenchymal transition, and upregulating stemness regulators such as Notch, Wnt and the Sex determining region Y-box 2/octamer binding transcription factor 4/Nanog signaling axis. In this review we will summarize the major signaling pathways that regulate cancer stem cells in breast cancer and describe the effects that adipocyte secreted IL-6 and leptin have on breast cancer stem cell signaling. Finally we will introduce a new potential treatment paradigm of inhibiting the adipocyte-breast cancer cell signaling via targeting the IL-6 or leptin pathways.

  3. Knowledge of breast density and awareness of related breast cancer risk.

    Science.gov (United States)

    Manning, Mark A; Duric, Neb; Littrup, Peter; Bey-Knight, Lisa; Penner, Louis; Albrecht, Terrance L

    2013-06-01

    Little is known about women's knowledge of breast density or between-race differences in this knowledge. In the current study, we examined knowledge of breast density and awareness of its role as a breast cancer risk factor among women who had previously taken part in a breast imaging study. Seventy-seven women (54.5 % Black) returned a survey assessing perceptions and accuracy of breast density knowledge, knowledge of one's own breast density, and breast cancer risk awareness. White women had greater perceived knowledge of breast density compared to Black women; however, differences in the accuracy of definitions of breast density were due to education. Black women were less likely to know how dense their own breasts were. Black and White women both lacked awareness that having dense breast increased breast cancer risk. The results highlight the need to disseminate information regarding breast density to women, while ensuring that the information is equally accessible to both Black and White women.

  4. Progesterone in Breast Cancer Angiogenesis

    OpenAIRE

    Botelho, Monica C.; Soares, Raquel; Alves, Helena

    2015-01-01

    The involvement of steroid hormones in breast carcinogenesis is well established. Recent evidence suggests that angiogenesis can be regulated by hormones. Both oestrogen and progesterone have been implicated in the angiogenic process of hormone-dependent cancers, such as breast cancer. Vascular Endothelial Growth Factor (VEGF) is a growth factor involved in angiogenesis in breast cancer that is up-regulated by estrogens. In our study we evaluated the role of progesterone in the expression of ...

  5. Developing Breast Cancer Program at Xavier; Genomic and Proteomic Analysis of Signaling Pathways Involved in Xenohormone and MEK5 Regulation of Breast Cancer

    Science.gov (United States)

    2010-05-01

    Tagatose are rare. In this study we have determined the effect of these rare ketohexoses on breast cancer cell proliferation and estrogen signalling...Cancer Center (TCC) will build a core of human talent that will address scientific problems such as drug resistance and the effect of environmental agents...pathways for ER(+) (MCF-7) and ER(-) (MCF-7-MEK5) as potentially more effective therapeutic targets. 11 Abstract of RCMI proposal submitted to

  6. Radiation response of drug-resistant variants of a human breast cancer cell line

    International Nuclear Information System (INIS)

    Lehnert, S.; Greene, D.; Batist, G.

    1989-01-01

    The radiation response of drug-resistant variants of the human tumor breast cancer cell line MCF-7 has been investigated. Two sublines, one resistant to adriamycin (ADRR) and the other to melphalan (MLNR), have been selected by exposure to stepwise increasing concentrations of the respective drugs. ADRR cells are 200-fold resistant to adriamycin and cross-resistant to a number of other drugs and are characterized by the presence of elevated levels of selenium-dependent glutathione peroxidase and glutathione-S-transferase. MLNR cells are fourfold resistant to melphalan and cross-resistant to some other drugs. The only mechanism of drug resistance established for MLNR cells to date is an enhancement of DNA excision repair processes. While the spectrum of drug resistance and the underlying mechanisms differ for the two sublines, their response to radiation is qualitatively similar. Radiation survival curves for ADRR and MLNR cells differ from that for wild-type cells in a complex manner with, for the linear-quadratic model, a decrease in the size of alpha and an increase in the size of beta. There is a concomitant decrease in the size of the alpha/beta ratio which is greater for ADRR cells than for MLNR cells. Analysis of results using the multitarget model gave values of D0 of 1.48, 1.43, and 1.67 Gy for MCF-7 cells are not a consequence of cell kinetic differences between these sublines. Results of split-dose experiments indicated that for both drug-resistant sublines the extent of sublethal damage repair reflected the width of the shoulder on the single-dose survival curve. For MCF-7 cells in the stationary phase of growth, the drug-resistant sublines did not show cross-resistance to radiation; however, delayed subculture following irradiation of stationary-phase cultures increased survival to a greater extent for ADRR and MLNR cells than for wild-type cells

  7. Promoting Breast Cancer Screening through Storytelling by Chamorro Cancer Survivors

    Science.gov (United States)

    Manglona, Rosa Duenas; Robert, Suzanne; Isaacson, Lucy San Nicolas; Garrido, Marie; Henrich, Faye Babauta; Santos, Lola Sablan; Le, Daisy; Peters, Ruth

    2017-01-01

    The largest Chamorro population outside of Guam and the Mariana Islands reside in California. Cancer health disparities disproportionally affect Pacific Islander communities, including the Chamorro, and breast cancer is the most common cancer affecting women. To address health concerns such as cancer, Pacific Islander women frequently utilize storytelling to initiate conversations about health and to address sensitive topics such as breast health and cancer. One form of storytelling used in San Diego is a play that conveys the message of breast cancer screening to the community in a culturally and linguistically appropriate way. This play, Nan Nena’s Mammogram, tells the story of an older woman in the community who learns about breast cancer screening from her young niece. The story builds upon the underpinnings of Chamorro culture - family, community, support, and humor - to portray discussing breast health, getting support for breast screening, and visiting the doctor. The story of Nan Nena’s Mammogram reflects the willingness of a few pioneering Chamorro women to use their personal experiences of cancer survivorship to promote screening for others. Through the support of a Chamorro community-based organization, these Chamorro breast cancer survivors have used the success of Nan Nena’s Mammogram to expand their education activities and to form a new cancer survivor organization for Chamorro women in San Diego.

  8. Breast cancer in women using digoxin

    DEFF Research Database (Denmark)

    Biggar, Robert J; Andersen, Louise Elisabeth; Kroman, Niels

    2013-01-01

    INTRODUCTION: Digoxin use is associated with increased incidence of breast and uterus cancers. We postulated that digoxin use might affect tumor characteristics and increase relapse risk in women with breast cancer. METHODS: Incident breast cancer cases in Danish women (n = 49,312; 1995 to 2008...... in Cox regression models. RESULTS: At diagnosis, tumors in digoxin users were more likely ER+ (85.4% vs. 78.6%: P = 0.002) and have grade 1 ductal histology (37.2% vs. 25.7%; P = 0.004), compared to non-users. 45 relapses occurred in women already using digoxin at breast cancer diagnosis (1,487 person...... cancers arising in digoxin-using women had better prognostic features. After adjustment for markers, overall breast cancer relapse risk in digoxin users was not increased significantly, although recurrence hazards for ER+ tumors were higher in the first year following diagnosis....

  9. Breast cancer cell lines: friend or foe?

    International Nuclear Information System (INIS)

    Burdall, Sarah E; Hanby, Andrew M; Lansdown, Mark RJ; Speirs, Valerie

    2003-01-01

    The majority of breast cancer research is conducted using established breast cancer cell lines as in vitro models. An alternative is to use cultures established from primary breast tumours. Here, we discuss the pros and cons of using both of these models in translational breast cancer research

  10. RAD51B in Familial Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Liisa M Pelttari

    Full Text Available Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC that were genotyped on a custom chip (iCOGS. We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259 and population controls (n = 3586 from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR: 1.15, 95% confidence interval (CI: 1.11-1.19, P = 8.88 x 10-16 and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11, compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

  11. RAD51B in Familial Breast Cancer

    Science.gov (United States)

    Pelttari, Liisa M.; Khan, Sofia; Vuorela, Mikko; Kiiski, Johanna I.; Vilske, Sara; Nevanlinna, Viivi; Ranta, Salla; Schleutker, Johanna; Winqvist, Robert; Kallioniemi, Anne; Dörk, Thilo; Bogdanova, Natalia V.; Figueroa, Jonine; Pharoah, Paul D. P.; Schmidt, Marjanka K.; Dunning, Alison M.; García-Closas, Montserrat; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Hopper, John L.; Southey, Melissa C.; Rosenberg, Efraim H.; Fasching, Peter A.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Nordestgaard, Børge G.; Benitez, Javier; González-Neira, Anna; Neuhausen, Susan L.; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Brüning, Thomas; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Van Dyck, Laurien; Janssen, Hilde; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; Hallberg, Emily; Olson, Janet E.; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Schumacher, Fredrick; Simard, Jacques; Dumont, Martine; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Grip, Mervi; Andrulis, Irene L.; Glendon, Gord; Devilee, Peter; Seynaeve, Caroline; Hooning, Maartje J.; Collée, Margriet; Cox, Angela; Cross, Simon S.; Shah, Mitul; Luben, Robert N.; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Couch, Fergus J.; Yannoukakos, Drakoulis; Orr, Nick; Swerdlow, Anthony; Darabi, Hatef; Li, Jingmei; Czene, Kamila; Hall, Per; Easton, Douglas F.; Mattson, Johanna; Blomqvist, Carl; Aittomäki, Kristiina; Nevanlinna, Heli

    2016-01-01

    Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk. PMID:27149063

  12. Breast Cancer awareness among Saudi females in Jeddah.

    Science.gov (United States)

    Radi, Sahar Mahmoud

    2013-01-01

    Breast cancer is the most frequent malignancy of women worldwide. It is the leading cause of female cancer related disability and mortality. In Saudi Arabia breast cancer ranks first among cancerous diseases in females. In the Gulf region, and especially in Saudi Arabia, few studies have been conducted to address breast cancer awareness. The purpose of the current study was therefore to investigate the level of breast cancer awareness among Saudi females in Jeddah, focusing on knowledge of breast cancer warning signs, risk factors, screening programs and breast self-examination (BSE). The design of this study was an exploratory correlational analysis. The sample comprised 200 Saudi females aged 20 and older living in Jeddah. Data were collected using face-to- face interviews. Breast cancer awareness was measured using a modified Arabic version of the Breast Cancer Awareness Measure (Breast CAM) version 2. Descriptive statistical analysis, Pearson's Product Moment correlation coefficients and ANOVA test were used to answer study questions. Out of 200 participants, 50.5% were aware of breast lump as a warning sign of breast cancer, 57.5% claimed that family history was risk factor, 20.5% had undergone breast screening, 79% heard about BSE, and 47.5% knew how to perform BSE. Findings indicated that Saudi females level of awareness of breast cancer is very inadequate. Public awareness interventions are needed in order to overcome an ever-increasing burden of this disease among Saudi females.

  13. Breast Density and Benign Breast Disease: Risk Assessment to Identify Women at High Risk of Breast Cancer.

    Science.gov (United States)

    Tice, Jeffrey A; Miglioretti, Diana L; Li, Chin-Shang; Vachon, Celine M; Gard, Charlotte C; Kerlikowske, Karla

    2015-10-01

    Women with proliferative breast lesions are candidates for primary prevention, but few risk models incorporate benign findings to assess breast cancer risk. We incorporated benign breast disease (BBD) diagnoses into the Breast Cancer Surveillance Consortium (BCSC) risk model, the only breast cancer risk assessment tool that uses breast density. We developed and validated a competing-risk model using 2000 to 2010 SEER data for breast cancer incidence and 2010 vital statistics to adjust for the competing risk of death. We used Cox proportional hazards regression to estimate the relative hazards for age, race/ethnicity, family history of breast cancer, history of breast biopsy, BBD diagnoses, and breast density in the BCSC. We included 1,135,977 women age 35 to 74 years undergoing mammography with no history of breast cancer; 17% of the women had a prior breast biopsy. During a mean follow-up of 6.9 years, 17,908 women were diagnosed with invasive breast cancer. The BCSC BBD model slightly overpredicted risk (expected-to-observed ratio, 1.04; 95% CI, 1.03 to 1.06) and had modest discriminatory accuracy (area under the receiver operator characteristic curve, 0.665). Among women with proliferative findings, adding BBD to the model increased the proportion of women with an estimated 5-year risk of 3% or higher from 9.3% to 27.8% (P<.001). The BCSC BBD model accurately estimates women's risk for breast cancer using breast density and BBD diagnoses. Greater numbers of high-risk women eligible for primary prevention after BBD diagnosis are identified using the BCSC BBD model. © 2015 by American Society of Clinical Oncology.

  14. GENOMIC PREDICTOR OF RESPONSE AND SURVIVAL FOLLOWING TAXANE-ANTHRACYCLINE CHEMOTHERAPY FOR INVASIVE BREAST CANCER

    Science.gov (United States)

    Hatzis, Christos; Pusztai, Lajos; Valero, Vicente; Booser, Daniel J.; Esserman, Laura; Lluch, Ana; Vidaurre, Tatiana; Holmes, Frankie; Souchon, Eduardo; Martin, Miguel; Cotrina, José; Gomez, Henry; Hubbard, Rebekah; Chacón, J. Ignacio; Ferrer-Lozano, Jaime; Dyer, Richard; Buxton, Meredith; Gong, Yun; Wu, Yun; Ibrahim, Nuhad; Andreopoulou, Eleni; Ueno, Naoto T.; Hunt, Kelly; Yang, Wei; Nazario, Arlene; DeMichele, Angela; O’Shaughnessy, Joyce; Hortobagyi, Gabriel N.; Symmans, W. Fraser

    2017-01-01

    CONTEXT Accurate prediction of who will (or won’t) have high probability of survival benefit from standard treatments is fundamental for individualized cancer treatment strategies. OBJECTIVE To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer. DESIGN Development of different predictive signatures for resistance and response to neoadjuvant chemotherapy (stratified according to estrogen receptor (ER) status) from gene expression microarrays of newly diagnosed breast cancer (310 patients). Then prediction of breast cancer treatment-sensitivity using the combination of signatures for: 1) sensitivity to endocrine therapy, 2) chemo-resistance, and 3) chemo-sensitivity. Independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response. SETTING Prospective multicenter study to develop and test genomic predictors for neoadjuvant chemotherapy. PATIENTS Newly diagnosed HER2-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens then endocrine therapy (if hormone receptor-positive). MAIN OUTCOME MEASURES Distant relapse-free survival (DRFS) if predicted treatment-sensitive and absolute risk reduction (ARR, difference in DRFS of the two predicted groups) at median follow-up (3 years), and their 95% confidence intervals (CI). RESULTS Patients in the independent validation cohort (99% clinical Stage II–III) who were predicted to be treatment-sensitive (28% of total) had DRFS of 92% (CI 85–100) and survival benefit compared to others (absolute risk reduction (ARR) 18%; CI 6–28). Predictions were accurate if breast cancer was ER-positive (30% predicted sensitive, DRFS 97%, CI 91–100; ARR 11%, CI 0.1–21) or ER-negative (26% predicted sensitive, DRFS 83%, CI 68–100; ARR 26%, CI 4–28), and were significant in multivariate analysis after adjusting for relevant clinical-pathologic characteristics. Other

  15. Plasma isoflavones and fibrocystic breast conditions and breast cancer among women in Shanghai, China.

    Science.gov (United States)

    Lampe, Johanna W; Nishino, Yoshikazu; Ray, Roberta M; Wu, Chunyuan; Li, Wenjin; Lin, Ming-Gang; Gao, Dao Li; Hu, Yongwei; Shannon, Jackilen; Stalsberg, Helge; Porter, Peggy L; Frankenfeld, Cara L; Wähälä, Kristiina; Thomas, David B

    2007-12-01

    Proliferative benign breast conditions are associated with elevated risk of breast cancer, whereas nonproliferative conditions are not strongly associated with risk. Factors acting before onset of hyperplasia might be associated with both benign conditions and breast cancer, whereas those on the proliferative disease-to-cancer pathway would be associated only with cancer. Soy isoflavone exposure may influence breast cancer risk, but little is known of its association with benign conditions. We examined possible relationships between plasma genistein and daidzein concentrations and risk of breast disease in women, in a breast self-examination trial in Shanghai, China, diagnosed with breast cancer (n = 196) or a benign breast condition (n = 304), and 1,002 age-matched controls with no known breast disease. Benign conditions were classified as nonproliferative (n = 131) or proliferative with or without atypia (n = 173). Isoflavone concentrations were inversely associated with risk of nonproliferative and proliferative benign fibrocystic conditions, as well as with breast cancer, both with and without concomitant proliferative changes in ipsilateral noncancerous mammary epithelium (P(trend) 76.95 ng/mL) were less likely to have breast cancer (odds ratio, 0.26; 95% confidence interval, 0.13-0.50) or benign conditions (odds ratio, 0.40; 95% confidence interval, 0.23-0.70) compared with women in the lowest quartile (breast cancer with and without surrounding proliferative changes were not different, respectively, from observed risks for benign proliferative and nonproliferative conditions alone. Isoflavone exposure was inversely associated with fibrocystic breast conditions and breast cancer, and the results suggest that effects on cancer risk occur early in carcinogenesis.

  16. Gradient phenomenon of multidrug resistance gene expression in breast cancer during neoadjuvant chemotherapy is related to disease progression

    Directory of Open Access Journals (Sweden)

    N. V. Litviakov

    2013-01-01

    Full Text Available The paper examined 106 patients with breast cancer (BC treated with neoadjuvant chemotherapy (NАС. In the biopsy material, derived from primary tumor before NAC and surgical samples after chemotherapy the expression of 8 multidrug resistance genes (MDR ABCB1, АВСВ2, ABCC1, ABCC2, АВСС5, ABCG1, ABCG2 и MVP was evaluated using quantitative RT-PCR. During the NAC course 75 % of patients manifested gradient phenomenon for gene expression that means a unidirectional change in the expression of all five MDR genes ABCB1, ABCC1, ABCC2, ABCG1 и ABCG2 closely associated with the NAC efficacy: the reduction in MDR gene expression was related to good response to NAC while the expression increase associated with poor response to NAC. In 25% of patients there was no such change in studied gene expression that means the lack of a gradient phenomenon. The objective was to study whether gradient phenomenon for MDR gene expression during NAC is related to disease free survival in breast cancer patients. Five-year metastasis-free survival in patients having a gradient phenomenon was 73 % versus 39 % in patients who lack a gradient phenomenon (log-rank test p=0,0018. So, the presence of a gradient phenomenon in patients is appeared to be associated with a good disease prognosis. It is assumed that the gradiThe paper examined 106 patients with breast cancer (BC treated with neoadjuvant chemotherapy (NАС. In the biopsy material, derived from primary tumor before NAC and surgical samples after chemotherapy the expression of 8 multidrug resistance genes (MDR ABCB1, АВСВ2, ABCC1, ABCC2, АВСС5, ABCG1, ABCG2 и MVP was evaluated using quantitative RT-PCR. During the NAC course 75 % of patients manifested gradient phenomenon for gene expression that means a unidirectional change in the expression of all five MDR genes ABCB1, ABCC1, ABCC2, ABCG1 и ABCG2 closely associated with the NAC efficacy: the reduction in MDR gene expression was related to good

  17. [Diagnostic imaging of breast cancer : An update].

    Science.gov (United States)

    Funke, M

    2016-10-01

    Advances in imaging of the female breast have substantially influenced the diagnosis and probably also the therapy and prognosis of breast cancer in the past few years. This article gives an overview of the most important imaging modalities in the diagnosis of breast cancer. Digital mammography is considered to be the gold standard for the early detection of breast cancer. Digital breast tomosynthesis can increase the diagnostic accuracy of mammography and is used for the assessment of equivocal or suspicious mammography findings. Other modalities, such as ultrasound and contrast-enhanced magnetic resonance imaging (MRI) play an important role in the diagnostics, staging and follow-up of breast cancer. Percutaneous needle biopsy is a rapid and minimally invasive method for the histological verification of breast cancer. New breast imaging modalities, such as contrast-enhanced spectral mammography, diffusion-weighted MRI and MR spectroscopy can possibly further improve breast cancer diagnostics; however, further studies are necessary to prove the advantages of these methods so that they cannot yet be recommended for routine clinical use.

  18. Breast cancer

    CERN Multimedia

    2002-01-01

    "Cancer specialists will soon be able to compare mammograms with computerized images of breast cancer from across Europe, in a bid to improve diagnosis and treatment....The new project, known as MammoGrid, brings together computer and medical imaging experts, cancer specialists, radiologists and epidemiologists from Bristol, Oxford, Cambridge, France and Italy" (1 page).

  19. Metastasis of breast cancer rectum

    International Nuclear Information System (INIS)

    Suárez, L.; Santander, G.

    2004-01-01

    Introduction: Metastases to the breast are rare, corresponding approximately to 3% of breast cancers. Primary tumors that spread more commonly are own breast, often following them in melanomas, neuroendocrine, ovarian and lymphoma. Medical history: A 59-year consultation rectoragias repeated and thinning. It is studied and finally intervenes (low anterior resection) diagnosed with rectal cancer whose Histopathology revealed a poorly differentiated adenocarcinoma stage III. Concomitantly the patient has a left breast lump that was studied with mammography, which revealed a dense mass of larger diameter 4 cm in topografiada 3 hour left breast with well defined contours and ultrasonographic structure solid. MI lumpectomy is performed whose pathology reports a poorly differentiated adenocarcinoma with cytoarchitectural features matching the lesion of rectum. Hormone receptors were negative. The patient is treated as a rectal cancer with RT spread over QT (5FU i /c). Died 7 months after diagnosis. Discusion: In literature are reported only 3 cases of breast metastases secondary to rectal cancer; how unusual this presentation justify this report.In this event they occurred in patients with a previous diagnosis of rectal cancer and in the context of systemic lesion progression. In our case clinician early diagnosis of rectal and breast metastases was synchronous. The mammographic image consistent with those described for these cases in the literature.The development of metastases in breast tissue is associated with a poor prognosis as which correlates with the survival of the patient

  20. Molecular basis of the triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Ayse Feyda Nursal

    2015-06-01

    Full Text Available Breast cancer is the most common type of cancer in women and more than 1 million breast cancer cases are diagnosed each year all over the world. Breast cancer is a complex and heterogeneous disease in terms of its molecular structure, mutation type, metastase properties, clinical course and therapeutic response. Breast cancer is divided into subtypes based on expression properties of molecular markers as estrogen receptor, progestron receptor, human epidermal growth factor receptor 2. Triple-negative breast cancer is characterized by the lack of tumors that estrogen receptor, progestron receptor, human epidermal growth factor receptor 2 gene expression. These type of tumors lead to agressive clinical course due to unresponsiveness to systemic endocrine therapy and poor prognosis. Triple negative breast cancer constitutes 10-20% of all breast cancers. It affects generally young and African-American women. Triple negative breast cancer have several subtypes based on the gene expression properties. The majority of them are basal-like breast cancers. In this review, current literature is revised and summarized with respect to the molecular basis of triple negative cancers. [Archives Medical Review Journal 2015; 24(2.000: 251-259