Received: JAccepted: OctoPublished: November 15, 2011Ĭopyright: © 2011 Maxwell et al. PLoS Biol 9(11):Īcademic Editor: Alan Ashworth, Breakthrough Breast Cancer Research Center, United Kingdom (2011) Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer. Our findings provide new insights into the mechanism through which BRCA1 may promote commitment of initially bipotent mammary cells towards the luminal lineage, and how loss of this function may predispose cells to become breast tumors of a basal-like type.Ĭitation: Maxwell CA, Benítez J, Gómez-Baldó L, Osorio A, Bonifaci N, Fernández-Ramires R, et al. This polarization process depends upon a balance between the activities of BRCA1 and the Aurora kinase A, with the kinase opposing BRCA1 function and promoting growth. The protein product of HMMR, which is called RHAMM, works in concert with BRCA1 to regulate the structure of normal breast cells as they grow and become polarized. This variation falls within a centrosomal gene, named HMMR. We have used genetic analyses of affected families to uncover additional genetic variation that is linked to the risk of developing cancer for carriers of BRCA1 mutations. Thus, the two genes may trigger different carcinogenic processes. Mutations in two genes that were initially identified as predisposing carriers to early-onset breast cancer, BRCA1 and BRCA2, cause similar perturbations in cellular responses to DNA damage but predispose carriers to distinct tumor types. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ( wHR) = 1.09 (95% CI 1.02–1.16), p trend = 0.017 and n = 3,965, wHR = 1.04 (95% CI 0.94–1.16), p trend = 0.43 respectively. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis.
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