Review Out-RANKing BRCA1 in Mutation Carriers Emma Nolan 1,2 , Geoffrey J. Lindeman 1,3,4 , and Jane E. Visvader 1,2 Abstract Beyond prophylactic mastectomy, there are currently very few options available to BRCA1 mutation carriers to help reduce their risk of developing breast cancer. An effective prevention therapy therefore remains a pressing area of need. Accumulat- ing evidence points to amplification of the progesterone sig- naling axis in precancerous tissue from BRCA1 mutation car- riers. Given that RANKL is an important paracrine mediator of hormonal signaling in breast tissue, there has been consider- able interest in exploring a potential role for this pathway in oncogenesis. Recent findings indicate that the RANK and NF-kB pathways are aberrantly activated in luminal progenitor cells resident in preneoplastic BRCA1 mut/þ breast tissue. The aug- mented proliferation of these cells and their predilection for DNA damage suggest that they are prime cellular targets for basal-like cancers arising in BRCA1 mutation carriers. The end result is a hyperactive pathway, initiated by progesterone and amplified by DNA damage–induced NF-kB signaling, that likely accounts for the susceptibility of BRCA1 mut/þ luminal progenitor cells to oncogenesis and tissue specificity. Specific targeting of this progenitor subset has revealed a compelling new prevention strategy for these and possibly other high-risk women. Cancer Res; 77(3); 595–600. Ó2017 AACR. Introduction Germline mutations in the breast cancer susceptibility gene BRCA1 confer a significantly increased risk of breast and ovarian cancer. Breast cancers that arise in BRCA1 mutation carriers are usually early-onset basal-like tumors associated with a poor prog- nosis (1). Over the past two decades, there has been an exponential increase in our understanding of the biological functions of BRCA1 that include DNA repair, cell-cycle checkpoint control, protein ubiquitylation, and chromatin remodeling (2). However, the cel- lular mechanisms that culminate in breast carcinogenesis in BRCA1 mutation carriers remain undefined. An understanding of the mechanisms governing the transition from normal breast epithe- lium to malignancy is pivotal for the identification of an effective, noninvasive prevention strategy for these high-risk women. BRCA1 is critical for maintenance of genomic integrity, largely facilitated by its role in homologous recombination (HR)-medi- ated repair of DNA double-strand breaks (2). In cells deficient in functional BRCA1, homologous recombination–mediated repair is impaired and more error-prone mechanisms such as nonho- mologous end joining are employed, resulting in increased chro- mosomal instability and a higher degree of genomic alterations compared with sporadic breast cancers. Given the requirement for high-fidelity double-strand break repair in all cells to ensure survival, the loss of genomic stability associated with a germline BRCA1 mutation would be anticipated to promote tumor for- mation in all tissues. Notably, however, BRCA1 mutation carriers almost exclusively develop breast and ovarian cancers. Several hypotheses have been put forward to explain this remarkable tumor specificity. High-fidelity DNA damage repair (DDR) in breast and ovarian tissues has been posited to rely on functional BRCA1 protein, while other tissues may utilize com- pensatory mechanisms (3). Breast and ovarian tissues have also been speculated to undergo an accelerated rate of loss of hetero- zygosity at the BRCA1 locus compared with other tissues, perhaps via enhanced mitotic recombination. Conversely, evidence sug- gests that loss of the wild-type BRCA1 allele does not occur in all tumor cells and may not be the rate-limiting tumor-initiating step (4). Many of these hypotheses have primarily focused on findings in cells where both BRCA1 alleles have been lost, or on events directly preceding this (in the case of an accelerated loss of heterozygosity). However, it seems likely that the tissue specificity associated with BRCA1-mutated cancers is facilitated by earlier events initiated in heterozygous BRCA1 breast tissue. In line with this, Sedic and colleagues (5) recently demonstrated that sub- stantial haploinsufficiency and genomic instability occur in BRCA1-mutant breast epithelial cells relative to breast fibroblasts, culminating in premature senescence of epithelial cells and a higher risk of neoplastic transformation. Of note, heterozygous cells also appear to be defective in stalled replication fork repair and/or suppression of fork collapse (6). Cell-intrinsic properties, such as haploinsufficiency for DNA repair, are likely to act in concert with extrinsic influences to promote neoplastic transfor- mation (see below). In this review, we discuss recent advances in our understand- ing of cellular and molecular mechanisms that contribute to the initiation of breast tumorigenesis in BRCA1 mutation carriers. Hormone-driven activation of progenitor cells in the preneoplastic state is likely to be a key initiation event, thus contributing to the tissue specificity of tumors arising in BRCA1 mutation carriers and providing a rationale for a new chemo- prevention strategy. 1 Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. 2 Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia. 3 Parkville Familial Cancer Centre, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Victoria, Australia. 4 Department of Medicine, University of Melbourne, Parkville, Victoria, Australia. Corresponding Author: Jane E. Visvader, Stem Cells and Cancer Division, The Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia. Phone: 613-9345-2494; Fax: 613-9347-0852; E-mail: visvader@wehi.edu.au doi: 10.1158/0008-5472.CAN-16-2025 Ó2017 American Association for Cancer Research. Cancer Research www.aacrjournals.org 595 on May 25, 2020. © 2017 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst January 19, 2017; DOI: 10.1158/0008-5472.CAN-16-2025