Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations

There is considerable interest in whether anti-oestrogens can be used to prevent breast cancer in women bearing mutations in the BRCA1 and BRCA2 genes. The effects of oestradiol (E-2), tamoxifen (TAM) and fulvestrant ( FUL) on proliferation and steroid receptor expression were assessed in normal breast epithelium taken from women at varying risks of breast cancer and implanted into athymic nude mice, which were treated with E-2 in the presence and absence of TAM or FUL. Tissue samples were taken at various time points thereafter for assessment of proliferative activity and expression of oestrogen and progesterone receptors ( ER alpha and PgR) by immunohistochemistry. Oestradiol increased proliferation in the breast epithelium from women carrying mutations in the BRCA1/2 genes, those otherwise at increased risk and those at population risk of breast cancer. This increase was reduced by both TAM and FUL in all risk groups. In the absence of E-2, PgR expression was reduced in all risk groups but significantly more so in the BRCA-mutated groups. Subsequent E-2 treatment caused a rapid, complete induction of PgR expression in the population- risk group but not in the high- risk or BRCA-mutated groups in which PgR induction was significantly delayed. These data suggest that the mechanisms by which E-2 induces breast epithelial PgR expression are impaired in BRCA1/2 mutation carriers, whereas those regulating proliferation remain intact. We conclude that early anti-oestrogen treatment should prevent breast cancer in very high- risk women. British Journal of Cancer (2006).