Non-Surgical Cancer Risk Reduction in BRCA1 Mutation Carriers: Disabling the Remote Control

Abstract

Women-specific cancers are a major health issue, particularly those associated with the BRCA1 germline mutation carrier state, which include triple-negative basal breast carcinomas and high-grade serous ovarian carcinomas (referred to as extra-uterine Müllerian carcinomas). Whereas many chronic diseases can currently be prevented (e.g., cardiovascular diseases), no recent tangible progress was made in cancer prevention of BRCA1 mutation carriers apart from surgical resections of at-risk organs. This lack of progress is largely due to (1) poor understanding of the initiating events triggered by known risk factors in the development of these cancers, (2) the fact that current preventive measures rely on evidence obtained from adjuvant breast cancer treatment that fail to protect against poor prognostic cancers, and (3) problems with using cancer incidence in high-risk women as an ethically justifiable endpoint in cancer prevention trials. Here, we propose that cancer predisposition in BRCA1 mutation carriers is driven, at least in part, by cell-nonautonomous mechanisms (i.e., driven by consequences of this carrier state on hormonal and other systemic factors controlled in organs other than those that are cancer-prone) and that biomarkers of epigenomic reprogramming, hypothesized to be a direct consequence of such cell-nonautonomous mechanisms, are attractive as intermediate surrogate endpoints to assess the efficacy of cancer risk-reducing strategies targeting these mechanisms.

Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women

“…The idea that germline mutations in the ubiquitously expressed BRCA1 gene drive cancer development primarily via a classical tumour-suppressor mechanism triggered by a reduced “chromosome custodian” function [ 14 ] does not account for the organ-specificity of the cancers associated with this carrier state [ 15 ]. We previously reported evidence for cell-nonautonomous mechanisms of cancer predisposition in humans and experimental animals carrying germline BRCA1 or Brca1 mutations [ 16 – 21 ]. By definition, such mechanisms are driven by consequences of this carrier state on organs that are different than (and are upstream of) those that are cancer-prone.…”

Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis

“…Unlike estrogen, which rises in the mid-follicular phase followed by a mid-luteal secondary peak, progesterone secretion is phase-specific, with levels up to 250-fold higher in the luteal phase than in the follicular phase [ 10 ]. In BRCA1/2 mutation carriers luteal phase progesterone levels are significantly higher than non-carriers, with evidence supporting physiological dysregulation in germline carriers as a potential tumorigenic mechanism [ 11 , 12 , 13 ]. The use of anti-progestins significantly reduces the metastatic potential of HGSOC further favoring progesterone as an immunosuppressant with a functionally relevant role in BRCA1 mutation carriers [ 14 ].…”