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

J Breast Cancer. 2019 Mar;22(1):1-14. doi: 10.4048/jbc.2019.22.e6.

Abstract

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.

Keywords: BRCA1 protein; Breast neoplasms; Genes, BRCA1; Haploinsufficiency; Organ specificity.

Publication types

  • Review