Abstract LB-257: Estrogen signaling in mature luminal and luminal progenitor cells of BRCA2 carriers and non-carriers

Abstract Background: Carriers of mutations in the breast cancer susceptibility gene BRCA2 have a 50-80% lifetime risk of developing breast cancers, about 70% of which are positive for estrogen receptor (ER), a key oncogenic hormone receptor. Metastatic ER+ tumors also respond to PARP inhibitors associated with their DNA repair defect. There remains much to understand regarding estrogen signaling in BRCA2 carriers and preventing cancers in this high-risk population. Methods: We studied the transcriptomes and in-vitro growth of luminal progenitors and mature luminal cells derived from primary human normal breast tissue obtained from BRCA2 carriers and wild-type patients undergoing prophylactic mastectomy and reduction mammoplasty procedures, respectively. Subsequently, formalin-fixed paraffin-embedded breast cancer tissue samples from twelve case-control matched pairs of BRCA2 carriers and wild-type patients were investigated for ER genomic binding, H3K27Ac enhancer marks, and gene expression changes. Results: Luminal progenitors and mature luminal cells have different gene expression patterns. Unsupervised clustering of transcriptomes from normal tissue of three pairs of BRCA2-mutant and wildtype patients suggested that BRCA2 mutation status can segregate transcriptomes from luminal progenitors but not mature luminal cells. These differential transcriptomes in luminal progenitor cells from BRCA2 carriers were enriched for cell proliferation genes. In agreement, greater proliferative phenotype was observed in BRCA2-mutant luminal progenitor cells in comparison to the wild-type cohort. Interestingly, clustering analyses of twelve pairs of breast tumors indicated no clear differences between ER cistromes, enhancer marks and gene expression between BRCA2 carriers and wildtype patients. Because luminal progenitor cells are more likely to contribute to tumorigenesis, we hypothesize that the identified BRCA2-mutant signature in normal progenitor cells could be retained in tumors obtained from BRCA2 carriers. Conclusions: There are differential gene expression patterns between luminal progenitors and mature luminal cells obtained from normal human breast tissue. The transcriptomes in the luminal progenitor but not mature luminal cells segregate differently based on the BRCA2 mutation status. This identified BRCA2-mutant gene signature in luminal progenitor cells is enriched for pro-proliferation pathways, and BRCA2-mutant luminal progenitor cells exhibit higher cell proliferation, suggesting a potential cell-of-origin in BRCA2-associated breast cancers. Importantly, no significant differences in transcriptomes and ER cistromes are observed in breast tumors from BRCA2 carriers and non-carriers, indicating a need to identify BRCA2-mutant gene signature that may assist in segregating ER+ breast cancers in this high-risk populations. The knowledge from this study may assist in pioneering strategies for cancer prevention in high-risk BRCA2 mutation carriers. Citation Format: Hari Singhal, David Chi, Elgene Lim, Housheng He, Raga Vadhi, Prakash K. Rao, Henry W. Long, Andrea L. Richardson, Judy Garber, Myles Brown. Estrogen signaling in mature luminal and luminal progenitor cells of BRCA2 carriers and non-carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-257. doi:10.1158/1538-7445.AM2017-LB-257

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