BRCA1 and Breast Cancer: a Review of the Underlying Mechanisms Resulting in the Tissue-Specific Tumorigenesis in Mutation Carriers.

Since the first cloning of BRCA1 in 1994, many of its cellular interactions have been elucidated. However, its highly specific role in tumorigenesis in the breast tissue-carriers of BRCA1 mutations are predisposed to life-time risks of up to 80%-relative to many other tissues that remain unaffected, has not yet been fully enlightened. In this article, we have applied a universal model of tissue-specificity of cancer genes to BRCA1 and present a systematic review of proposed concepts classified into 4 categories. Firstly, tissue-specific differences in levels of BRCA1 expression and secondly differences in expression of proteins with redundant functions are outlined. Thirdly, cell-type specific interactions of BRCA1 are presented: its regulation of aromatase, its interaction with Progesterone- and receptor activator of nuclear factor-κB ligand-signaling that controls proliferation of luminal progenitor cells, and its influence on cell differentiation via modulation of the key regulators jagged 1-NOTCH and snail family transcriptional repressor 2. Fourthly, factors specific to the cell-type as well as the environment of the breast tissue are elucidated: distinct frequency of losses of heterozygosity, interaction with X inactivation specific transcript RNA, estrogen-dependent induction of genotoxic metabolites and nuclear factor (erythroid-derived 2)-like 2, and regulation of sirtuin 1. In conclusion, the impact of these concepts on the formation of hormone-sensitive and -insensitive breast tumors is outlined.