Risk-Reducing Salpingo-oophorectomy in Women with a BRCA1 or BRCA2 Mutation

Loss of full-length Brca1 in mammary epithelial cells of the mouse mammary tumor virus (MMTV)-Cre Brca1 conditional exon 11 deletion mouse model results in the development of mammary adenocarcinomas with similar genetic changes to those found in human BRCA1-mutation-related breast cancers. We used this experimental model to evaluate the chemopreventive effect of tamoxifen on the development of mammary preneoplasia and adenocarcinoma. No protective effects of tamoxifen administration on mammary cancer development were found. Instead, tamoxifen treatment significantly increased rates of mammary epithelial cell proliferation and the prevalence of mammary hyperplasia at 6 months of age. Tamoxifen-exposed mice developed adenocarcinomas at younger ages than control mice and a higher percentage of mice developed adenocarcinomas by 12 months of age. Both whole mouse and tissue culture cell models were used to test if loss of full-length Brca1 was associated with a relative increase in the agonist activity of tamoxifen. Tamoxifen induced increased ductal growth in MMTV-Cre Brca1 conditional mice compared to wild type. Estrogen receptor alpha (ERa) expression was downregulated in the tamoxifen-induced hyperplasias. Reducing BRCA1 levels in MCF-7 cells using siRNA resulted in a relative increase in the agonist activity of tamoxifen. Results suggest a model of mammary cancer progression in which loss of full-length Brca1 altered the agonist/antagonist activity of tamoxifen, resulting in tamoxifen-induced mammary epithelial cell proliferation with subsequent loss of ERa expression and development of ERa-negative hyperplasias and adenocarcinomas.

Section: Discussionsupporting

confidence: 91%

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

Jones

Halama

et al. 2005

“…Furthermore, prophylactic oophorectomy reduces the risk of breast cancer in carriers of BRCA1 mutations (Kauff et al, 2002;Rebbeck et al, 2002). These observations suggest that, as it has long been associated with sporadic breast cancer, circulating estrogen in premenopausal women may also contribute to the development of BRCA1-associated tumors.…”

Section: A Gene-and Promoter-specific Effect Of Brca1mentioning

confidence: 91%

Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression

Ghosh

Amleh

et al. 2005

Mutations in BRCA1 increase risks of familial breast and ovarian cancers, particularly among premenopausal women. While BRCA1 plays an active role in DNA repair, this function alone may not be sufficient to explain why BRCA1-associated tumors predominantly occur in estrogen-responsive tissues. Aromatase is the rate-limiting enzyme in estrogen biosynthesis and a key target in breast cancer treatment. Aromatase expression in ovarian granulosa cells dictates levels of circulating estrogen in premenopausal women, and its aberrant overexpression in breast adipose tissues promotes breast cancer growth. Here, we show that BRCA1 modulates aromatase expression in ovarian granulosa cells and primary preadipocytes. The cyclic AMP-dependent expression of aromatase in ovarian granulosa cells is inversely correlated with the protein level of BRCA1. Importantly, transient knockdown of BRCA1 enhances aromatase expression in both ovarian granulosa cells and primary preadipocytes. We propose that BRCA1 deficiency in epithelial and certain nonepithelial cells may result in combined effects of aberrant estrogen biosynthesis and compromised DNA repair capability, which in turn may lead to specific cancers in the breast and ovary.

“…We and others have shown conclusively that prophylactic oophorectomy (PO) in women with BRCA1/2 mutations reduces the risk of ovarian cancer by approximately 90% (Kauff et al, 2002;Rebbeck et al, 2002;Rutter et al, 2003;Domchek et al, 2006). Data with short-term follow-up also suggests that oophorectomy is associated with an improvement in breast cancer-specific survival, ovarian cancer-specific survival and overall survival (Domchek et al, 2006) (Figure 1).…”

Section: Prophylactic Oophorectomymentioning

confidence: 89%

“…Primary peritoneal cancers have been reported in women with BRCA1/2 mutations following PO with an estimated frequency of 2-4%, and occur more frequently in BRCA1 compared to BRCA2 carriers (Piver et al, 1993;Kauff et al, 2002;Rebbeck et al, 2002;Casey et al, 2005). Primary peritoneal cancer may occur either owing to an occult ovarian cancer focus or from carcinoma arising de novo in peritoneal mesothelium.…”

Section: Primary Peritoneal Cancer and Fallopian Tube Carcinomamentioning

confidence: 99%

“…In addition to this striking reduction in the risk of ovarian cancer, an approximately 50% breast cancer risk reduction after PO was also observed (HR ¼ 0.47; 95% CI: 0.29-0.77). In an another study with similar results, Kauff et al (2002) identified 170 women with BRCA1/2 mutations who had not previously undergone PO, who then chose to either undergo ovarian cancer surveillance or undergo PO. During a mean follow-up of 24.2 months, ovarian cancer or primary peritoneal carcinoma was diagnosed in one of 98 women who chose to undergo PO compared to five ovarian or peritoneal cancers in the 72 women who chose surveillance.…”

mentioning

confidence: 93%

See 1 more Smart Citation

Clinical management of BRCA1 and BRCA2 mutation carriers

Domchek

Weber

2006

The cancer susceptibility genes BRCA1 and BRCA2 appear to be responsible for virtually all hereditary breast ovarian families, and a smaller subset of hereditary sitespecific breast cancer families. Fortunately, effective strategies have been developed to reduce the risk for the development of breast and ovarian cancer in women with BRCA1/2 mutations, making genetic testing for these mutations an important part of the management at women with a strong family history of these diseases. Here, we review the current evidence for risk reduction strategies and outline future research directions. Oncogene (2006) 25, 5825-5831. doi:10.1038/sj.onc.1209881Keywords: BRCA1; BRCA2; oophorectomy; breast cancer; ovarian cancer; management Management of ovarian cancer risk Prophylactic oophorectomyThe lifetime risk of ovarian cancer for women with BRCA1 mutations is estimated at 40-50% (Ford et al., 1994;Antoniou et al., 2003;King et al., 2003) and in those with BRCA2 mutations, at 10-20% (1999;Antoniou et al., 2003;King et al., 2003). We and others have shown conclusively that prophylactic oophorectomy (PO) in women with BRCA1/2 mutations reduces the risk of ovarian cancer by approximately 90% (Kauff et al., 2002;Rebbeck et al., 2002;Rutter et al., 2003;Domchek et al., 2006). Data with short-term follow-up also suggests that oophorectomy is associated with an improvement in breast cancer-specific survival, ovarian cancer-specific survival and overall survival (Domchek et al., 2006) (Figure 1). Table 1 reports the details of studies examining PO in BRCA1/2 mutation carriers. Rebbeck et al. (2002) examined 551 women from 11 centers in North America and Europe who either did (n ¼ 259) or did not (n ¼ 292) undergo PO, with a mean follow-up of over 8 years in each group. Eight PO subjects (3.1%) were diagnosed with ovarian cancer or primary peritoneal cancer at or following PO compared with 58 controls (19.9%). Six of the eight PO subjects diagnosed with ovarian cancer were diagnosed at the time of PO, all of which were stage I. After excluding these six cases, only two women (both with BRCA1 mutations) who underwent PO subsequently developed primary peritoneal cancer. Compared with women who did not undergo PO, the occurrence of post-PO ovarian cancer corresponded to a hazard ratio (HR) of 0.04 (95% confidence interval (CI): 0.01-0.16). In addition to this striking reduction in the risk of ovarian cancer, an approximately 50% breast cancer risk reduction after PO was also observed (HR ¼ 0.47; 95% CI: 0.29-0.77). In an another study with similar results, Kauff et al. (2002) identified 170 women with BRCA1/2 mutations who had not previously undergone PO, who then chose to either undergo ovarian cancer surveillance or undergo PO. During a mean follow-up of 24.2 months, ovarian cancer or primary peritoneal carcinoma was diagnosed in one of 98 women who chose to undergo PO compared to five ovarian or peritoneal cancers in the 72 women who chose surveillance. This risk reduction corresponded to a HR of 0.15 (95% CI: 0.02-1.31).Finally, ...