There is good reason to accept that defective maintenance of genomic integrity, as described in BRCA-deficient cells, is an accelerator of cancer progression. If so, how does such a generic defect translate into specifically increased breast or ovarian cancer risk?
The breast epithelium proliferates rapidly during puberty and under the influence of oestrogenic hormones. Unlike the cells of many rapidly proliferating epithelia, such as those of the intestine or of the uterine endometrium, progeny of this proliferative burst are retained within the breast epithelium. This is demonstrated by the finding that breast lobules are clonal33
. If, before lobular development, a lobular precursor cell had sustained a cancer-predisposing mutation at a relevant locus (such as p53
), the entire lobule would then carry that mutation. This, in turn, could amplify the risk of subsequent neoplastic progression. Some germline p53
mutations (such as in Li–Fraumeni syndrome) confer a particularly elevated risk of adult-onset breast cancer. Similarly, high-dose ionizing chest radiation during puberty, or even in early childhood (for example, atom-bomb exposure; mantle zone therapeutic radiation), specifically predisposes women to adult-onset breast cancer34,35
These observations could be relevant to BRCA
-linked disease, especially if the BRCA+/-
genotype were haplo-insufficient in genome integrity maintenance function—an unanswered question at present. BRCA
gene haplo-insufficiency could, in principle, increase the risk of additional cancer-promoting mutations occurring during breast development, including mutation of the BRCA
gene, itself. Indeed, if puberty constitutes a limited ‘window’ during which a BRCA
mutation carrier is at special risk of developing carcinogenic mutations, this might account for the relative absence of BRCA
gene inactivation in sporadic breast or ovarian cancer. In sporadic disease, biallelic BRCA
gene inactivation might occur too late to have an impact on disease risk36
That the breast and ovary are oestrogen-responsive tissues could also be relevant to the tissue specificity of BRCA
disease risk. Some oestrogen metabolites can adduct DNA, and so could act as tissue-specific carcinogens (so-called “remote carcinogenesis”)37
. Conceivably, this effect might be exacerbated by BRCA
mutation, if the relevant DNA repair pathways were dysfunctional.
BRCA proteins associate with chromosomal pairing events on the synaptanemal complex. In some model organisms, homologous chromosomal pairing is also known to occur in certain somatic cells where it can influence development by affecting transcriptional regulation (“transvection”) as well as imprinting38
. Potentially analogous, homology-dependent transcriptional regulation may also operate in mammals39
and could represent a link between homologous pairing and tissue-specific gene expression. If homologous chromosomal pairing occurs in the breast or ovarian epithelium, are BRCA proteins involved and does such an involvement contribute to their organ-specific tumour suppression function?
Human cells express alternatively spliced BRCA1
transcripts, the biological significance of which is unclear40
. Whether products of such transcripts contribute to the tissue specificity of BRCA
tumour suppression bears future investigation.