Endocrinology of the wild and mutant BRCA1 gene and types of hormonal carcinogenesis

Abstract

Information related to the BRCA1 gene has increasingly become a subject for analysis by endocrinologists. For example, it is hard to dismiss the fact that, in BRCA1 mutation carriers, tumors develop predominantly in such estrogen-dependent organs as the mammary glands and ovaries but not in the endometrium. Another characteristic feature is that although BRCA1 mutants and knock-downs are unable to inhibit the transcriptional activity of estrogen receptor-α, in BRCA1 mutation carriers breast cancers are often estrogen receptor-negative and originate from the basal rather than the luminal epithelium. The latter, together with other data, suggests that BRCA1-positive breast neoplasms could be considered to be a consequence of the genotoxic variant of hormonal carcinogenesis (that is, associated with DNA damaging rather then with pure hormonal/physiological properties of hormones or their derivatives). Of indisputable significance are the data demonstrating that knocking down of the BRCA1 gene is accompanied by aromatase overexpression and the abolishment of IGF-1 receptor expression suppression, thus increasing both steroid and insulin signaling. Importantly, the endocrine–genotoxic ‘liberation’ found upon transfer from the wild-type to the mutant BRCA1 provides grounds to regard BRCA1 as a modulator of endocrine–genotoxic switchings (predominantly into a direction of DNA-damaging hormone effects) and also to ask whether this is a property of only this or some other tumor suppressor’s.