BRCA1 in hormonal carcinogenesis: basic and clinical research

Abstract

The breast and ovarian cancer susceptibility gene-1 (BRCA1) located on chromosome 17q21 encodes a tumor suppressor gene that functions, in part, as a caretaker gene in preserving chromosomal stability. The observation that most BRCA1 mutant breast cancers are hormone receptor negative has led some to question whether hormonal factors contribute to the etiology of BRCA1-mutant breast cancers. Nevertheless, the caretaker function of BRCA1 is a generic one and does not explain why BRCA1 mutations confer a specific risk for tumor types that are hormoneresponsive or that hormonal factors contribute to the etiology, including those of the breast, uterus, cervix, and prostate. An accumulating body of research indicates that in addition to its wellestablished roles in regulation of the DNA damage response, the BRCA1 protein interacts with steroid hormone receptors (estrogen receptor (ER-a) and androgen receptor (AR)) and regulates their activity, inhibiting ER-a activity and stimulating AR activity. The ability of BRCA1 to regulate steroid hormone action is consistent with clinical-epidemiological research suggesting that: (i) hormonal factors contribute to breast cancer risk in BRCA1 mutation carriers; and (ii) the spectrum of risk-modifying effects of hormonal factors in BRCA1 carriers is not identical to that observed in the general population. These data suggest a model for BRCA1 carcinogenesis in which genomic instability leads to the initiation of cancerous cell clones, while loss of normal restraint on hormonal stimulation of mammary epithelial cell proliferation allows amplification of these pre-existing clones. Further research will be required to substantiate this hypothesis.

Androgen receptors as a prognostic and predictive factor in breast cancer.

“…When estrogens are lacking, they stimulate tumor growth by direct binding to ER alpha; this effect is blocked by antiestrogens. When estrogens are present, however, androgens act as their antagonists and inhibit the growth of the tumor; this is probably mediated by AR and can be blocked by antiandrogens [8]. The clinical consequence of such influence of androgens on cell receptors is poor prognosis of those female patients receiving hormone therapy, whose cancer cells do not show AR expression.…”

DNA Double-Strand Breaks Repair and Signaling of Human Gliomas and Normal Brain Cells in Response to Radiation: Potential Impact of the ATM-and BRCA1- Dependent Pathways

“…Our findings raised the question of the implication of this protein in the tumorigenicity of brain tumours as well. Such assumption is supported by the fact that BRCA1 tumor suppressor activity is not necessarily restricted to inherited breast and/or ovarian cancer (Rosen et al, 2005). Notably, adenovirus experiments pointed out the potential role of BRCA1 in lung and colon malignancies (Marot et al, 2006).…”

Correlation between BRCA1 expression and clinicopathological factors including brain metastases in patients with non-small-cell lung cancer

“…BRCA1 (breast cancer 1) is a 100kb, 220kD, multifunctional nuclear phosphoprotein, ubiquitously expressed in all tissues and serves as a tumor suppressor in part, as a "caretaker", as well as "gatekeeper" in preserving genomic stability 5 . It has been implicated in normal cellular functions including cell cycle regulation, replication, mitotic spindle assembly, transcription regulation and higher chromatin hierarchical control 5 .…”