Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer.
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ABSTRACT:
SUBMITTER: Rottenberg S
PROVIDER: S-EPMC1914039 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Genomic profile of 47 tumors from hereditary breast cancer cases by Array CGH, 7 of which were BRCA mutation carriers (4 in BRCA2 and 3 in BRCA1), previously analyzed for BRCA1 expression by immunohistochemistry. Our goal was to identify specific alterations for BRCA1 not expressing tumors
2015-07-07 | GSE70541 | GEO
Project description:Genomic profile of 47 tumors from hereditary breast cancer cases by Array CGH, 7 of which were BRCA mutation carriers (4 in BRCA2 and 3 in BRCA1), previously analyzed for BRCA1 expression by immunohistochemistry. Our goal was to identify specific alterations for BRCA1 not expressing tumors DNA from 47 Tumors versus DNA pool from normal tissue. BRCA1 expression, Hierarchical clustering and overall survival analyses.
2015-07-07 | E-GEOD-70541 | biostudies-arrayexpress
Project description:UnlabelledInhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here, we show that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors.SignificanceIn this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors.
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Project description:The majority of BRCA1-associated breast cancers are basal cell-like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53-mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (n = 8) show complete pathologic response. At greater dosages, 100% show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8% to 8.0% (mean, 5.9%) of tumor cells express the normal mammary stem cell markers, CD29(hi)24(med), and these cells are tumorigenic, whereas CD29(med)24(-/lo) and CD29(med)24(hi) cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6% to 11.0% (mean, 8.8%) tumor cells are CD29(hi)24(med); these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; P < 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant-derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29(hi)24(med) populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance.
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Project description:The objective of the study was to characterize hereditary breast tumors based on their miRNA expression profiles. To this end, we performed global miRNA expression analysis of more than 800 human miRNA genes in a large series of 80 FFPE breast tissue samples. The series included 66 hereditary breast primary tumors from 13 BRCA1 mutation carriers, 10 BRCA2 mutation carriers and 43 non-BRCA12 tumors denominated hereafter as BRCAX tumors. In addition we have analyzed 10 sporadic breast carcinomas and 4 normal breast tissues obtained after breast reduction surgery from healthy donors with no family history of breast cancer. To avoid contamination with normal breast tissue, tumoral area on FFPE blocks was marked by a pathologist and macrodissected for subsequent total RNA extraction. Microarray expression profiling was performed using miRCURY LNATM microRNA Array v.11 (Exiqon A/S, Denmark), in a single color experiments in a pairwise comparison experimantal design.
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