cancers Review BRCA1-Dependent Transcriptional Regulation: Implication in Tissue-Specific Tumor Suppression Xiaowen Zhang * and Rong Li * Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA * Correspondence: [email protected] (X.Z.); [email protected] (R.L.) Received: 14 October 2018; Accepted: 11 December 2018; Published: 14 December 2018 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. Keywords: BRCA1; transcriptional regulation; epigenetic regulation; chromatin organization 1. Introduction Approximately 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 mutation-carrying women have significantly higher risk of developing breast and ovarian cancers compared to the general population, with an estimated cumulative risk of 65% and 39% by the age of 70, respectively [3–5]. By comparison, BRCA1 mutation-carrying men have an estimated cumulative risk of 1.2% of developing breast carcinoma at the same age [6]. BRCA1-mutated breast cancers are typically more aggressive and higher grade with an increased rate of TP53 mutations [7–10]. In addition, 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 [11–14]. PARP inhibitor olaparib has recently been approved by the US Food and Drug Administration (FDA) to treat BRCA-mutated metastatic breast cancer; and several other PARP inhibitors are currently under clinical development [15,16]. Despite these exciting developments, chemotherapy is still the first-line therapy for BRCA1-related breast cancers [17,18]. Breast epithelia consist of two layers of epithelial cells (Figure1a): the inner layer with luminal progenitors and ductal/alveolar cells, and the outer layer with mammary stem cells and myoepithelial cells [19]. The luminal and basal cell lineages express distinct sets of fate-determining genes that fulfill lineage-specific functions. For example, 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]. BRCA1 mutation leads to aberrant luminal Cancers 2018, 10, 513; doi:10.3390/cancers10120513 www.mdpi.com/journal/cancers CancersCancers 20182018,, 1010,, x 513 2 2of of 16 16 side branching and alveologenesis in the breast epithelia [20,21]. BRCA1 mutation leads to aberrant luminallineage development.lineage development. Of note, Of luminal note, luminal progenitor progenitor cells from cells disease-free from disease-freeBRCA1 mutationBRCA1 mutation carriers carriers(BRCA1 mut/+(BRCA1) exhibitmut/+) exhibit deficiency deficiency to differentiate to differentiate into mature into mature luminal luminal cells [22 ,cells23]. Besides,[22,23]. Besides, luminal luminaldifferentiation-associated differentiation-associated gene expression gene expression is significantly is significantly reduced in reducedBRCA1mut/+ in BRCA1breast epitheliummut/+ breast epitheliumversus their versus non-carrier their non-carrier controls [22 controls,23]. Furthermore, [22,23]. Furthermore,in vitro proliferation in vitro proliferation of BRCA1 ofmut/+ BRCA1luminalmut/+ luminalprogenitors progenitors is less growth is less growth factor-dependent factor-dependent than their thanBRCA1 their BRCA1+/+ counterparts+/+ counterparts [22], consistent[22], consistent with withthe notion the notion that these that mutant these progenitorsmutant progenitors are aberrantly are proliferativeaberrantly proliferative yet defective yet in differentiation.defective in differentiation.The deficiencies The observed deficiencies in BRCA1 observedmutated in BRCA1 clinical mutated samples clinical were samples corroborated were corroborated by work using by workgenetically using engineeredgenetically mouseengineered models mouse with models lineage-specific with lineage-specific deletion of mouse deletionBrca1 of [mouse22,24]. Brca1 More [22,24].recent studiesMore recent indicate studies that the indicate RANK-RANKL that the RANK-RANKL axis, a key player axis, that a mediateskey player paracrine that mediates actions paracrinein luminal actions homeostasis, in luminal is abnormally homeostasis, activated is abnormally in breast epitheliaactivated of inBRCA1 breastmutation epithelia carriers of BRCA1 [25]. mutationOstensibly carriers normal [25].BRCA1 Ostensiblymut/+ breast normal tissue BRCA1 has amut/+ higher breast percentage tissue has ofa higher RANK +percentageluminal progenitors, of RANK+ luminalcells highly progenitors, proliferative cells highly and prone proliferative to DNA and damage prone to [25 DNA]. Inhibition damage [25]. of RANKL, Inhibition the of ligandRANKL, of theRANK, ligand attenuates of RANK, mammary attenuates tumorigenesis mammary tumorigenesis in Brca1-deficient in Brca1 mice-deficient [25]. Thus, mice despite [25]. Thus, the factdespite that theBRCA1 fact -associatedthat BRCA1 breast-associated tumors breast tend totumors be basal-like tend to andbe basal-like triple-negative, and triple-negative, both clinical and both preclinical clinical andstudies preclinical strongly studies suggest strongly that luminal suggest progenitor that luminal cells progenitor are the cell-of-origin cells are the of cell-of-originBRCA1-mutated of BRCA1 breast- mutatedcancers [breast22,23,26 cancers] (Figure [22,23,26]1b). While (Figure it is abundantly 1b). While clearit is abundantly that germ-line clearBRCA1 that germ-linemutations BRCA1 confer mutationstissue- and confer cell lineage-specific tissue- and cell cancer, lineage-specifi the mechanismc cancer, underlying the mechanism the context-dependent underlying the dysfunction context- dependentof cancer-predisposing dysfunction BRCA1of cancer-predisposingmutations remains BRCA1 largely mutations unknown. remains largely unknown. FigureFigure 1. 1. TheThe developmental developmental hierarchy hierarchy of ofhuman human breast. breast. (a) (Cross-sectiona) Cross-section of a of normal a normal breast breast duct. duct. (b) Breast(b) Breast epithelial epithelial hierarchy hierarchy and andBRCA1BRCA1-associated-associated breast breast cancer. cancer. BRCA1BRCA1 is is best best known known for for maintenance maintenance of of genomic genomic integrity integrity through through its its functions functions in in homologous homologous recombinationrecombination (HR)-dependent (HR)-dependent repair repair of of double-strand double-strand DNA DNA breaks breaks [27–29], [27–29], regulation regulation of of cell cell cycle cycle checkpointscheckpoints [30,31], [30,31], and and suppression suppression of of DNA DNA replic replicationation stress stress [32]. [32]. While While these these BRCA1-dependent BRCA1-dependent processesprocesses mostmost likelylikely contribute contribute to to its its tumor tumor suppressor suppressor function, function, they they may notmay be not sufficient be sufficient to explain to explainthe aforementioned the aforementioned longstanding longstanding conundrum conundrum in BRCA1 in-related BRCA1 cancer-related biology, cancer namely, biology, the namely, sex/tissue the sex/tissueselectivity selectivity and luminal-to-basal and luminal-to-basal lineage conversion lineage conversion during tumorigenesis. during tumorigenesis. Besides its well-documented Besides its well- documentedfunctions in maintenancefunctions in of genomemaintenance stability, of BRCA1genome is alsostability, implicated BRCA1 in transcriptionalis also implicated regulation in Cancers 2018, 10, 513 3 of 16 Cancers 2018, 10, x 3 of 16 andtranscriptional chromatin reorganization regulation and [30 chromatin,33–38], processes reorganization that primarily [30,33–38], dictate processes normal tissuethat primarily development dictate andnormal lineage-specific tissue development cell differentiation. and lineage-specific Here, we summarize cell differentiation. recent findings Here, concerningwe summarize the rolesrecent offindings BRCA1 inconcerning transcriptional the roles regulation of BRCA1 and in discuss transcriptional their potential regulation contributions and discuss to the their tissue- potential and lineage-specificcontributions tumorto the tissue- suppressor