BRCA1 directly modulates gene expression required for estrogen biosynthesis: a possible mechanism of tissue-specific tumor suppression
© BioMed Central 2005
Published: 17 June 2005
Mutations in the tumor suppressor gene BRCA1 are associated with an elevated risk of breast and ovarian cancer. The tissue-specific nature of BRCA1 mutation-associated tumors stands in stark contrast to the diverse array of nuclear functions mediated by the wild-type BRCA1. These functions include regulation of transcription and the DNA damage response. While the DNA repair function of BRCA1 clearly contributes to overall genetic stability, loss of BRCA1 function in DNA repair, a process that is universally important to all cell types in both genders, cannot easily explain why BRCA1 mutations predominantly affect breast and ovary, two major estrogen-responsive tissues in women. We hypothesize that BRCA1 confers tissue-specific tumor suppression by directly modulating expression of a set of breast-cancer-related genes.
Methods and results
Aromatase, which catalyzes conversion from androgen to estrogen, is a rate-limiting enzyme in estrogen biosynthesis and is a key player in breast cancer development. Aromatase is specifically expressed in ovarian granulosa cells and several peripheral tissues via the actions of multiple tissue-specific promoters. In premenopausal women, expression of aromatase in ovarian granulosa cells dictates levels of circulating estrogen. In many postmenopausal breast cancer and endometrial malignancy tissues, the in situ aromatase production is significantly elevated. Here, we show that the cyclic AMP-dependent expression of aromatase is inversely correlated with the protein level of BRCA1 in human ovarian granulosa cells. Importantly, transient knockdown of BRCA1 enhances the expression of aromatase in both ovarian granulosa cells and cells from breast tissue. Chromatin immunoprecipitation indicates that endogenous BRCA1 is preferentially associated with a tissue-specific transcriptional promoter of the aromatase gene. Thus, BRCA1 negatively controls estrogen biosynthesis by repressing aromatase expression, providing a novel and logical molecular explanation for the tissue-specificity conundrum in BRCA1 biology.
Conclusion and significance
The notion that BRCA1 confers tissue-specific tumor suppression in an endocrine fashion is also consistent with results from recent clinical and animal studies. In particular, prophylactic oophorectomy reduces the risk of both breast cancer and ovarian cancer in carriers of BRCA1 mutations [1, 2], suggesting that circulating estrogen in premenopausal women may contribute to the development of BRCA1-associated tumors. Moreover, tissue-specific knockout of Brca1 in mouse ovarian granulosa cells induces tumors in the ovaries and uterine horns. Importantly, these tumors still carry wild-type alleles of Brca1 . Given that aromatase inhibitors are one of the most efficacious endocrine agents in breast cancer treatment, the link between BRCA1 and aromatase expression may lead to novel therapies for both prevention and treatment of breast cancer.
This work was funded by grants from the National Institutes of Health and Department of Defense Breast Cancer Research Program.
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