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

Abstract

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 (ERa 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 BRCAmutated 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) Approximately 5% of all cases of breast cancer are associated with inherited predisposition syndromes and about half of these are attributable to mutations in the BRCA1 and BRCA2 genes (Hopper, 2001). Carriers of mutations in the BRCA1 and BRCA2 genes have up to a 90% lifetime risk of developing breast cancer (Rebbeck, 2002) and effective preventative strategies are required for these women.A number of trials have now shown that endocrine agents such as tamoxifen (TAM) or raloxifene can prevent breast cancer in women at increased risk of the disease (Cuzick et al, 2003). The question arises as to whether agents such as these can be used for prevention specifically in women bearing BRCA1 or BRCA2 mutations. The prevalence of mutations in the total cohort in the NSABP P1 trial was unknown (Fisher et al, 1998) and therefore no conclusion regarding the effectiveness of TAM in mutation carriers can be made from this study. It has been suggested that endocrine agents such as TAM will not be effective in preventing breast cancer in BRCA1 mutation carriers because the majority of tumours (up to 80%) arising in these women are oestrogen receptor a (ERa) negative, have a high mitotic rate and are of high histological grade (Lakhani, 1999;Lakhani et al, 2002). All these features are associated with resistance to endocrine therapy and it is clear from the overview that TAM and raloxifene reduce the incidence of ERa-positive but not -negative tumours (Cuzick et al, 2003). ...

Endocrinology of the Wild and Mutant Brca1 Gene and Types of Hormonal Carcinogenesis

“…This finding conforms to the results demonstrating that, in the same cells, the stimulation of mitogen-activated protein kinase and cell proliferation with estradiol was prevented by wild-type but not mutant BRCA1 [31]. On the other hand, in a study using the implantation of normal mammary epithelium tissue samples from normal women or BRCA1 mutation carriers to nude mice, estradiol-stimulated cell proliferation in both cases, but only induced progesterone receptors in the former case [50]. This suggests impaired hormonal signal transduction and a possible divergence (splitting) of the estrogenic effects when BRCA1 is mutated.…”

Prospective multicenter cohort study of estrogen and insulin-like growth factor system in BRCA mutation carriers

“…Wild-type BRCA 1 gene was found to negatively regulate aromatase expression in a human granulosa cell line [9]. Normal BRCA 1 gene expression was induced by estrogen in experimental models [24,25], and BRCA 1/2 haplo-insufficiency alters the estrogen sensitivity of normal breast epithelium as assessed by proliferation and induction of estrogen-induced genes [26]. Clinically, tamoxifen, an estrogen receptor modulator, is known to decrease the risk of a secondary breast malignancy [27,28], and prophylactic oophorectomy decreases the risk of breast carcinoma in BRCA [29][30][31].…”

Normal Breast Tissue Implanted into Athymic Nude Mice Identifies Biomarkers of the Effects of Human Pregnancy Levels of Estrogen

“…This protective effect can be mimicked in rodent models by treatment with pregnancy levels of exogenous E 2 . Previous work from this laboratory successfully used a mouse xenograft model to investigate menstrual cycle levels of E 2 on cell proliferation and gene expression (14)(15)(16)(17). Here, we have used this xenograft model to simulate parity by implanting nulliparous human breast tissue in immunocompromised nude mice and treating them with high-dose E 2 .…”

“…Previously, we have successfully used a mouse xenograft model to investigate the effect of serum concentrations of estradiol equivalent to those observed in the luteal phase of the menstrual cycle on normal human breast cell proliferation (14)(15)(16) and gene expression (17). Here, we develop a xenograft mouse model of human breast tissue where the effects of estrogen intervention can be tested by implanting nulliparous human tissue and treating with high-dose E 2 pellets to achieve human pregnancy levels of serum E 2 for a 1-month period.…”