Hormonal interactions of BRCA2
Of specific interest is the tissue specificity of BRCA tumors. Both BRCA1/2 genes have a general role in DNA repair and genome integrity. This should equally predispose all cells to transformation, as evident for p53 mutations. Intriguingly, this has not been observed. Loss of BRCA function seems to be tissue specific.
One explanation relates to the dual role of oestrogens as hormones and carcinogens, and the tissue-specific carcinogenesis caused by electrophilic oestrogen metabolites that accumulate in endocrine responsive organs (breast and ovary tissues).
An alternative explanation concerns the protective role of BRCA protein during the stimulation of breast cell proliferation during puberty and pregnancies. BRCA1 is known to bind the AF-2 region of ER and may repress its transactivation and mitogenic function. Lack of BRCA1 function would then increase the likelihood of mutations in gatekeeper genes such as p53. DNA repair deficiency would play a secondary role in carcinogenesis but highly influence the progression and phenotype of these genetically unstable tumors. Somatic BRCA1 mutations occurring after these hormonal time windows would not have the same impact and would not be selected during sporadic breast tumor development.
By the same token, the specific role of BRCA2 deficiency in male breast and, to a certain extent, prostate cancer development could reflect a functional interaction of BRCA2 with other endocrine factors of importance in males. We propose to explore these possible interactions.