Role of the BRCA1 gene in stem cells and treatment of mammary gland cancer

The mammary gland is a dynamic organ that undergoes significant developmental changes during pregnancy, lactation, and involution. Mammary gland cancer may develop through dysregulation of self-renewal pathways of normal mammary stem cells. The regulation of the self-renewal, differentiation, and migration of mammary stem cells and their progenitors that are localized in the mammary glands appears to be assumed through distinct developmental signalling pathways such as hormones, EGF, hedgehog, Wnt/β-catenin, Notch, and Bmi-1. Several tumour suppressors inhibit regenerative capacity by promoting cell death or senescence in stem cells. The breast cancer susceptibility gene (BRCA1) is a tumour suppressor gene expressed in many nuclear processes, including stem cell regulation, DNA damage repair, recombination, transcription, ubiquitination, cell cycle checkpoint enforcement, and centrosome regulation. BRCA1 is mutated in about one-half of all hereditary mammary gland cancer cases, and its expression is frequently decreased in sporadic cancers. Women with hereditary mammary gland and ovarian cancer due to BRCA1 mutations are born with a mutation in one BRCA1 allele, but only develop cancer after mutation or allelic loss of the other BRCA1 allele. BRCA1 plays a critical role in the differentiation of ER-negative stem/progenitor cells from ER-positive luminal cells. Defects of the BRCA1 gene may result in the accumulation of genetically unstable mammary gland stem cells, providing prime targets for further carcinogenic events, because BRCA1 also plays a role in DNA repair. Our study indicates that restoration of normal wild-type BRCA1 expression levels in many mammary gland cancers may inhibit tumours by a genetic correction strategy, wherein the loss of BRCA1 expression contributes to tumorigenesis.