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-alpha, 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 switching (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.

Circulating estrogens and estrogens within the breast among postmenopausal BRCA1/2 mutation carriers

“…The role of estrogen metabolites in BRCA1/2 -related breast carcinogenesis is complex and has not been well described [25, 26]. Estrogen receptor (ER)-α has been reported to activate BRCA1 expression within the breast and to provide protection against DNA damage and genome instability in ER-α positive breast cells.…”

Endocrine Metabolic Disorders in Patients with Breast Cancer, Carriers of BRCA1 Gene Mutations

“…Hence, BRCA1 gene mutation carriership even in breast cancer patients without verifi ed active tumor tissue was associated with signs of hyperestrogenemia and progenotoxic shift in the estrogen (4OHE1) and glucose systems (predominance of glucose-induced production of ROS over C-peptidemia/ insulinemia), which could have an unfavorable impact for the disease course and required correction. Treatment of this kind in breast cancer patients with BRCA1 gene mutations may include, with consideration for available data, aromatase inhibitors, biguanides (metformin), and antigenotoxicants (N-acetylcystein) [4,7,10], though it is obvious that the search for means useful in this respect should be continued. Note.…”

“…This interest, along with predominant receptor-negative phenotype of breast tumors in BRCA1+ cases [8], is explained, among other things, by possible role of hormonal support of realization of the genetic liability to malignant tumors. One more aspect of the problem is possible role of the mutant BRCA1 gene and its products as potential modulators of the endocrine genotoxic switch-over towards more intensive DNA-damaging effects of hormones and hormone-associated metabolites [1,4].…”

Abnormal Mammary Adipose Tissue Environment of Brca1 Mutant Mice Show a Persistent Deposition of Highly Vascularized Multilocular Adipocytes

“…Additionally, other studies demonstrated that estrogen deficiency in ovariectomized rats is followed by reduced UCP1 expression [25] while other studies have demonstrated that IGF-1 can induce UCP-1 expression in vitr o and in vivo models [26,27]. Indeed, several lines of evidence have demonstrated that both experimental mouse models and humans that are deficient in BRCA1 have abnormally high levels of estrogen/IGF-1 signaling and production [28-33]. In particular, experimental and epidemiological studies have demonstrated that loss of BRCA1 function can lead to the loss of the normal restraint on estrogen receptor signaling [34-36] and also an increase in estrogen production through increased expression of aromatase, an enzyme responsible for a key step in the biosynthesis of estrogens [37].…”