RESUMEN
Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.
Asunto(s)
Proteína BRCA1/genética , Neoplasias de la Mama/genética , Ligando RANK/metabolismo , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Animales , Proteína BRCA2/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Daño del ADN/efectos de los fármacos , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Receptor alfa de Estrógeno/metabolismo , Femenino , Genotipo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Ligando RANK/antagonistas & inhibidores , Ligando RANK/genética , Receptor Activador del Factor Nuclear kappa-B/genética , Receptores de Progesterona/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Células Madre/citología , Células Madre/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Humans are chronically exposed to the plasticizer, Bisphenol A (BPA), that can adversely affect the normal hormonal regulation of cellular functions by mimicking the actions of estrogen. This biological response to BPA may vary according to an individual's genetic characteristics (e.g., BRCA1 mutations or deletion). In this study, both cell culture and mouse models were used to elucidate whether the loss of BRCA1 function could affect BPA-mediated cell proliferation. In studies using BPA levels comparable to human exposures, we found that loss of BRCA1 enhances BPA-induced cell proliferation in both systems. In vitro, we found that loss of BRCA1 enhances BPA-induced ERα signaling. In vivo, we found that BPA administration stimulates mammary gland epithelial tissue/cell proliferation leading to hyperplasia in Brca1 mutant mice compared to wild-type control mice. These results suggest that the biological responses in BRCA1-deficient cells may depend on environmental exposures, specifically BPA.