Sam C. Brooks,Ph.D.

Two important gene regulatory proteins in breast cancer, the estrogen receptor (ERa) and the tumor suppressor p53, are transcription factors. ERa, required for hormone dependent growth of some ER + breast tumors, is the target for tamoxifen based breast cancer therapy. Estradiol regulates the transcriptional and growth activites of ERa. The biological activities of p53 are mainly attributed to its ability to control the expression of various regulatory genes involved in cell growth, DNA damage repair and apoptosis. p53 activity is feed-back regulated and its cellular level is controlled by the oncoprotein mdm2. In response to DNA damage, p53 is protected from mdm2 dependent down regulation. Interestingly, p53 represses the transcription of certain genes, such as TPA, c-fos, c-jun and bcl-2, which contain estrogen response elements and are thus potential targets for activation by ERa. How p53 suppresses the expression of Era responsive genes is unclear. We have hypothesized that the ERa-p53- mdm2 interaction may hold the key to the above questions. Preliminary studies reveal that ERa can physically interact with both p53 and mdm2. The ERa-p53 interaction leads to both suppression of estrogen induced expression of certain ER-dependent genes as well as protection of p53 activity against mdm2 induced deactivation. Thus, this interaction is biologically significant, representing an important process in breast cancer cells. Current efforts are focussed on examining the specifics of this interaction and determining its biological consequences in breast cancer cells, as well as the functional consequences of the ERa-mdm2 interaction. We are also investigating the possibility that selective ERa expression may be a method of cellular regulation of p53.

Liu, G., Schwartz, J.A., Brooks, S.C. Estrogen receptor protects p53 from deactivation by human double minute-2. Cancer Research 60:1810-1814, 2000.

Liu, G., Schwartz, J.A., Brooks, S.C. p53 down-regulates ER-responsive genes by interfering with the binding of ER to ERE. Biochem. Biophys. Res. Commun. 264:359-364, 1999.

Davis, M.D., VanderKuur, J.A., Brooks, S.C. Ligand structure influences autologous downregulation of estrogen receptor-alpha messenger RNA. J. Steroid Biochem. Mol. Biol. 70:27-37, 1999.

Schwartz, J.A., Brooks, S.C. Changes in the structure of the ligand or substitutions to AF2 residues in the estrogen receptor make independent contributions to coactivator sensitivity by SRC-1. J. Steroid Biochem. Mol. Biol. 67:223-232, 1998.

Schwartz, J.A., Brooks, S.C. Genistein-mediated attenuation of tamoxifen-induced antagonism from estrogen receptor-regulated genes. Biochem. Biophys. Res. Commun..253:38-43, 1998.