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NF-Κb at the Crossroads of Normal Mammary Gland Biology and the Pathogenesis and Prevention of BRCA1-Mutated Breast Cancer

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NF-Κb at the Crossroads of Normal Mammary Gland Biology and the Pathogenesis and Prevention of BRCA1-Mutated Breast Cancer Published OnlineFirst November 3, 2017; DOI: 10.1158/1940-6207.CAPR-17-0225 Review Cancer Prevention Research NF-kB at the Crossroads of Normal Mammary Gland Biology and the Pathogenesis and Prevention of BRCA1-Mutated Breast Cancer Andrea Sau, Miguel A. Cabrita, and M.A. Christine Pratt Abstract Recent studies have shown that progesterone receptor BRCA1-deficientcellsresultsinaDNAdamageresponse (PR)–expressing cells respond to progesterone in part (DDR) that activates a persistent NF-kB signal, which through the induction of the receptor activator of NF- supplants progesterone/RANKL signaling for an extend- kB ligand (RANKL), which acts in a paracrine manner ed time period. Thus, the transcriptional targets normally to induce expansion of a RANK-expressing luminal pro- activated by RANKL that promote a proliferative þ genitor cell population. The RANK population in response in luminal progenitors can contribute to the human breast tissue from carriers of BRCA1 mutations susceptibility of mammary epithelial cells to BRCA1- þ (BRCA1mut/ )aswellastheluminalprogenitorpopu- mutated breast cancers as a consequence of DDR- lation in Brca1-deficient mouse mammary glands is induced NF-kB. Together, these latest findings mark þ À abnormally amplified. Remarkably, mouse Brca1 / substantial progress in uncovering the mechanisms driv- þ and human BRCA1mut/ progenitor cells are able to form ing high rates of breast tumorigenesis in BRCA1 muta- colonies in vitro in the absence of progesterone, demon- tion carriers and ultimately reveal possibilities for non- strating a hormone-independent proliferative capacity. surgical prevention strategies. Cancer Prev Res; 11(2); 1–12. Our research has demonstrated that proliferation in Ó2017 AACR. The Mammary Gland Contains Stem and a common luminal progenitor or from the basal progen- Progenitor Cells that Are Cells of Origin itor pool (reviewed in refs. 2, 3). On the basis of their gene expression profile, human for Breast Cancer Subtypes breast cancers have been categorized into five molecular In 1998, Kordon and Smith showed that a single cell was subtypes: luminal A, luminal B, receptor tyrosine protein able to regenerate a ductal lobular outgrowth with com- kinase erbB-2 (ERBB2) positive, basal-like, and normal- plete luminal and myoepithelial cells (1). FACS based on like (4). Although the mammary stem cell genomic cell surface receptor immunoreactivity is used to enrich signature is most aligned with the normal-like subtype, stem/progenitor populations within the mammary gland. the luminal progenitor signature more closely resembles Primitive mammary stem cells have been functionally the basal-like subtype (5). Subpopulations of luminal defined in transplantation assays as able to regenerate an progenitors are also proposed to be the target of trans- entire mammary gland in mice. Transit amplification of formation in luminal A, luminal B, and the ERBB2- progenitors results in subpopulations that include luminal positive breast cancers (6). Approximately 15% of all progenitor cells (LP) and basal (myoepithelial) progeni- breast cancers belong to the basal-like, and more than tors (2). Primitive luminal progenitor cells are thought to 90% of BRCA1-associated breast cancers belong to this give rise to hormone receptor–positive and negative ductal subtype (7). progenitors and ultimately mature ductal cells. Evidence from lineage-tracing studies suggests that the hormone Breast Cancer–Associated Gene 1 receptor–negative alveolar lineage may derive from either The BRCA1 gene was originally mapped in 1990 and cloned in 1994 (8). Mutations in one copy of BRCA1 University of Ottawa, Ottawa, Ontario, Canada. gene in the germline lead to the hereditary breast and ovarian cancer syndrome, which is characterized by Corresponding Author: M.A. Christine Pratt, Department of Cellular and Molec- ular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, early-onset cancers and lifetime risks of up to 80% by Canada. Phone: 613-562-5800, ext. 8366; Fax: 613-562-5636; E-mail: the age of 70. The BRCA1 protein plays an important role [email protected] in maintaining global genomic stability. Single or dou- doi: 10.1158/1940-6207.CAPR-17-0225 ble DNA strand breaks (SSB or DSB) can occur during Ó2017 American Association for Cancer Research. normal cellular replication or during exposure to www.aacrjournals.org OF1 Downloaded from cancerpreventionresearch.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst November 3, 2017; DOI: 10.1158/1940-6207.CAPR-17-0225 Sau et al. genotoxic compounds. During replication in S-phase, NF-kB not only regulates the transcription of genes the genome is particularly susceptible to SSBs that are involved in proliferation, but also many genes controlling converted into DSBs. In S-phase, BRCA1 has a role in the apoptosis/survival and the secondary immune response high fidelity process of homology-directed DNA repair and plays a critical role in cancer biology (20). Extracellular where it acts as a scaffold protein to assemble a cohort of signal–mediated induction of NF-kB occurs through the other DNA repair proteins, including BRCA2, Rad50, and TNFa family of receptors and ligands that include RANK Rad51, to the DSB (9). In the presence of a deleterious and RANKL. Activation of the RANK receptor can activate mutation in carriers coupled to loss of the normal allele both types of NF-kB signaling called the canonical pathway of BRCA1, HR is dysfunctional, and DSBs can result in and the alternative pathway (21). The canonical NF-kB chromosome rearrangements and genomic instability pathway typically consists of a p65/RelA;p50 heterodimer leading to cellular transformation. whose nuclear translocation is stimulated by the inhibitor More recently, BRCA1 has also been found to have a of kB kinase (IKKa/IKKb/NEMO) complex, which results critical role in the protection of stalled replication forks in in the degradation of the cytoplasmic inhibitor, IkBa. This an HR-independent manner (10). Replication fork pro- releases p65/p50, which then moves into the nucleus. The gression is frequently impaired as a consequence of DNA proteins p52 and RelB constitute the alternative NF-kB breaks caused by exogenous (such as UV) or endogenous pathway, which is dependent on IKKa-mediated phos- (such as reactive oxygen species) factors or nucleotide phorylation for its activation and nuclear localization depletion. If left unprotected, the meiotic recombination (reviewed in ref. 22). Interestingly, NEMO and IKKa can 11 protein (MRE-11) can recognize and degrade stalled also form a functional IKK complex able to activate the replication forks, inducing DNA damage and chromosome alternative NF-kB pathway (23). Once in the nucleus, NF- instability.BRCA1,togetherwiththeFanconianemiagroup kB dimers bind kB enhancer sequences in target genes and D2 protein (FANCD2), BRCA2, and Rad51 can protect regulate transcription through the recruitment of coacti- stalled forks to prevent nucleotide degradation during rep- vators or corepressors. lication stress (10). Thus BRCA1 has a critical role in main- taining global genomic stability during normal cell repli- NF-kB Drives Normal Mammary Cell cation and under stressed conditions. Proliferation and Contributes to BRCA1 also plays a role in the differentiation of the Tumorigenesis mammary glands through gene regulation at both the k transcriptional and epigenetic levels (11) in response to NF- B is an integral player in the normal postnatal k ovarian hormones (12). Gene expression profiling morphogenesis of the mammary gland. NF- B activity is showed that depletion of BRCA1 upregulates the genes high during pregnancy, decreases during lactation, and involved in proliferation but downregulates those asso- increases again during involution. This pattern demon- k ciated with differentiation (13). Indeed, an important strates the contrasting regulatory roles of NF- B during target of BRCA1 is the estrogen receptor (ER) gene, which the pregnancy (proliferative) and involution (apoptotic) is positively regulated by BRCA1 through direct DNA phases of the mammary gland (24, 25). Mice deleted for Rank Rankl binding (14). or had normal mammary gland develop- ment after birth; however, mammary glands showed Progesterone Regulates Progenitor increased apoptosis and failed to form lobuloalveolar k structures during pregnancy (26). Transgenic expression Cell Proliferation through NF- B of mammary gland Rank in mice prevents development Mammary stem and progenitor cells are highly respon- of a functional mammary gland, showing increased sive to steroid hormones. Progesterone targets progesterone proliferation during pregnancy, impaired differentia- receptor (PR)–positive mammary epithelial cells to induce tion, and decreased expression of the milk protein, proliferation in a cyclin D1–dependent manner (15). In b-casein. Moreover, constitutive overexpression of RANK addition, progesterone induces the synthesis and release of resulted in the development of hyperplasias at advanced the receptor activator for NF-kBligand(RANKL).Paracrine age (27). Importantly, mice lacking the catalytic domain þ RANKL, released from PR luminal cells, induces the expan- of IKKa show a lactation defect similar to Rank-null sion of the RANK-expressing progenitor cell compartment mice (18), suggesting that the alternative NF-kBpath- in the mouse mammary gland. RANKL functions by bind- wayplaysakeyroleintheresponsetoRANKLinthe À ing to its receptor
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