Abstract
Germ-line mutations in breast cancer susceptibility gene 1 (BRCA1) predominantly predispose women to breast and ovarian cancers. BRCA1 is best known for its functions in maintenance of genomic integrity including repairing DNA double-strand breaks through homologous recombination and suppressing DNA replication stress. However, whether these universally important BRCA1 functions in maintenance of genomic stability are sufficient to account for its tissue-specific tumor-suppressing function remains unclear. Accumulating evidence indicates that there are previously underappreciated roles of BRCA1 in transcriptional regulation and chromatin remodeling. In this review, we discuss the functional significance of interactions between BRCA1 and various transcription factors, its role in epigenetic regulation and chromatin dynamics, and BRCA1-dependent crosstalk between the machineries of transcription and genome integrity. Furthermore, we propose a model of how transcriptional regulation could contribute to tissue-dependent tumor-suppressing function of BRCA1.
Highlights
0.2% to 0.3% of the general population in the United States carries germ-line mutations in the tumor suppressor gene breast cancer susceptibility gene 1 (BRCA1) (BRCA1mut/+ ) [1,2]
0.2% to 0.3% of the general population in the United States carries germ-line mutations in the tumor suppressor gene BRCA1 (BRCA1mut/+ ) [1,2]. Unlike tumor suppressors such as p53 that are implicated in a broad spectrum of cancers, BRCA1 functions in a gender- and tissue-specific manner
BRCA1-mutated breast cancers are typically more aggressive and higher grade with an increased rate of TP53 mutations [7,8,9,10]. These BRCA1-associated breast tumors tend to be triple-negative for estrogen receptor α (ER-), progesterone receptor (PR-), and HER2 (HER2-), making it more challenging to develop targeted therapies [11,12,13,14]
Summary
0.2% to 0.3% of the general population in the United States carries germ-line mutations in the tumor suppressor gene BRCA1 (BRCA1mut/+ ) [1,2]. Mature luminal cells express ERα and PR, which, together with a number of additional luminal lineage-specific transcription factors, regulate side branching and alveologenesis in the breast epithelia [20,21]. Cancers 2018, 10, x and chromatin reorganization [30,33,34,35,36,37,38], processes that primarily dictate normal tissue development transcriptional regulation and chromatin reorganization [30,33,34,35,36,37,38], processes that primarily dictate and lineage-specific cell differentiation. We summarize recent findings concerning the roles normal tissue development and lineage-specific cell differentiation.
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