RESUMO
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. 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. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. 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: nâ=â7,584, weighted hazard ratio ((w)HR)â=â1.09 (95% CI 1.02-1.16), p(trend)â=â0.017; and nâ=â3,965, (w)HRâ=â1.04 (95% CI 0.94-1.16), p(trend)â=â0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. 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.
Assuntos
Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Polaridade Celular , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Aurora Quinase A , Aurora Quinases , Proteína BRCA1/genética , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Mama/citologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Polaridade Celular/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Variação Genética , Genótipo , Células HeLa , Heterozigoto , Humanos , Microtúbulos/fisiologia , Microtúbulos/ultraestrutura , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Estrogênio/análiseRESUMO
A germline mutation in the Von-Hippel Lindau (VHL) gene predisposes carriers to development of abundantly vascularised tumours in the retina, cerebellum, spine, kidney, adrenal gland and pancreas. Most VHL patients die from the consequences of cerebellar haemangioblastoma or renal cell carcinoma. The VHL gene is a tumour suppressor gene and is involved in angiogenesis by regulation of the activity of hypoxia-inducible factor 1-alpha (HIF1-alpha). Clinical diagnosis of VHL can be confirmed by molecular genetic analysis of the VHL gene, which is informative in virtually all VHL families. A patient with (suspicion for) VHL is an indication for genetic counselling and periodical examination.