Our long-term goal is to understand how inactivation of the breast cancer susceptibility gene, BRCA1, leads to breast tumorigenesis. At the cellular level, BRCA1 ensures global genome stability by coupling DNA damage-induced signals to downstream responses, including DNA damage repair and cell-cycle checkpoint activation. Because the DNA damage-induced signaling pathways that converge on BRCA1 are conserved in most cell types, BRCA1 is likely to function ubiquitously in the maintenance of genome integrity. Nonetheless, germline inactivation of BRCA1 leads principally to cancer of the breast and ovary, and the underlying basis for its tissue-restricted tumor suppressor function remains poorly defined. Recently, we discovered a novel function for BRCA1 in suppressing the ligand-independent transcriptional activity of the estrogen receptor alpha (ERalpha), a principal determinant of the growth and differentiation of breasts and ovaries. Importantly, we showed that clinically validated BRCA1 missense mutations abrogate this repression activity, suggesting that its ERalpha-specific repression function is important for the biological activity of BRCA1 in breast and ovarian tumor suppression. In human breast cancer cells, we observed an association between BRCA1 and ERalpha at endogenous estrogen-responsive gene promoters before, but not after, estrogen stimulation. Furthermore, we demonstrated that forced reduction of BRCA1 in estrogen-dependent human ovarian cancer cells could be correlated with increases in both the estrogen-independent transcription of ERalpha-target genes and estrogen-independent proliferation. We therefore hypothesize that BRCA1 represents a ligand-reversible barrier to transcriptional activation by unliganded ERalpha, and further, that mutational inactivation of BRCA1 promotes breast and ovarian epithelial cell proliferation through aberrant expression of estrogen-responsive genes. To confirm and extend this hypothesis, we propose the following aims.
Aim 1 is to elucidate the mechanism by which BRCA1 represses the ligand-independent transcriptional activity of ERalpha.
Aim 2 is to characterize the regulation of BRCA1-mediated ERalpha repression by both estrogen-dependent and estrogen-independent cell signals.
Aim 3 is to establish the biological role of BRCA1 in the control of cellular proliferation through modulation of ligand-independent ERalpha activity. These studies should reveal novel insight into the tissue-specific tumor suppressor function of BRCA1 and provide defined molecular targets for future intervention in breast cancer.
| Ding, Ning; Zhou, Haiying; Esteve, Pierre-Olivier et al. (2008) Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation. Mol Cell 31:347-59 |
| Trauernicht, Amy M; Kim, Se Jin; Kim, Nam Hee et al. (2007) Modulation of estrogen receptor alpha protein level and survival function by DBC-1. Mol Endocrinol 21:1526-36 |
| Kim, Seokjoong; Xu, Xuan; Hecht, Andreas et al. (2006) Mediator is a transducer of Wnt/beta-catenin signaling. J Biol Chem 281:14066-75 |
| Tan, Wei; Zheng, Lei; Lee, Wen-Hwa et al. (2004) Functional dissection of transcription factor ZBRK1 reveals zinc fingers with dual roles in DNA-binding and BRCA1-dependent transcriptional repression. J Biol Chem 279:6576-87 |
| Tan, Wei; Kim, Seokjoong; Boyer, Thomas G (2004) Tetrameric oligomerization mediates transcriptional repression by the BRCA1-dependent Kruppel-associated box-zinc finger protein ZBRK1. J Biol Chem 279:55153-60 |
