Carolyn L. Smith, Ph.D.
Department of Molecular and Cellular Biology
Ph.D.: University of Western Ontario, London, Canada
Postdoctoral training: Baylor College of Medicine, Houston
Estrogen Receptors and Coregulators Define the Selectivity of Gene Expression by SERMs
The research interest of my laboratory is to define the molecular pharmacology of estrogen receptors and the approach we employ is to elucidate the molecular mechanisms by which the estrogen receptors, ERα and ERβ, activate target gene expression. The ERs are transcription factors whose activity is stimulated upon binding to their cognate ligand, estradiol. Together with coactivator proteins, ERα and ERβ form multi-protein complexes at the promoter region of target genes and stimulate mRNA synthesis. We are currently pursuing several different approaches to better understand the molecular basis of ER function, and how ER activity can be manipulated in a selective fashion to positively impact human health. In this regard, ERβ is being evaluated as a therapeutic target for bladder cancer.
Our first approach is to study how selective estrogen receptor modulators (SERMs) such as tamoxifen, regulate ER activity in a tissue-specific manner. For example, tamoxifen inhibits ERs in the breast, but stimulates them in uterus, suggesting that cells can interpret ER-ligand complexes in a cell-specific manner. It is our hypothesis that the net input for the cellular environment, including cell signaling pathways and the relative population of coactivators and corepressors in any given target tissue determines whether SERMs activate or inhibit ER transcriptional activity. Factors are being examined that influence ER interaction with coactivators and corepressors, including the role of cellular signaling. Experiments are also addressing the mechanisms employed by corepressors to down regulate gene expression, in both estrogen and antiestrogen-treated cells.
We also are examining the role of estrogen receptors in bladder cancer. One of our approaches is to examine the ability of ER ligands to impact the development of bladder cancer, and to determine whether estrogen receptors play a role in determining the gender-dependent difference in incidence of bladder cancer. Secondly, we are examining the ability of nuclear receptor coregulators to influence the growth of bladder cancer and responsive to estrogen receptor ligands. It is the goal of these studies to evaluate the potential of estrogen receptor ligands in treatment and prevention of bladder carcinogenesis.
Baylor College of Medicine
One Baylor Plaza, DeBakey M522
Houston, TX 77030
- Karmakar S, Foster EA, Blackmore JK and Smith CL. (2011) Distinctive functions of p160 steroid receptor coactivators in proliferation of an estrogen-independent, tamoxifen-resistant breast cancer cell line. Endocrine-Related Cancer, 18:113-127.
- Karmakar S, Gao T, Pace MC, Oesterreich S and Smith CL. (2010). Cooperative activation of cyclin D1 and progesterone receptor gene expression by the SRC-3 coactivator and SMRT corepressor. Molecular Endocrinology 24:1187-1202.
- Karmakar S, Foster EA and Smith CL (2009). Estradiol down-regulation of the tumor suppressor gene BTG2 requires estrogen receptor and the REA corepressor. International Journal of Cancer 124:1841-1851.
- Karmakar S, Foster EA and Smith CL (2009). Unique roles of p160 coactivators for regulation of breast cancer cell proliferation and estrogen receptor-a transcriptional activity. Endocrinology 150:1588-1596.
- Peterson TJ, Karmakar S, Pace MC, Gao T and Smith CL (2007). The Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor (SMRT) corepressor is required for full estrogen receptor-α transcriptional activity. Molecular and Cellular Biology 27:5933-5948.
- Sonpavde G, Okuno N, Weiss H, Yu J, Shen SS, Younes M, Jian W, Lerner SP and Smith CL. (2007). Efficacy of selective estrogen receptor modulators (SERMs) in nude mice bearing human transitional cell carcinoma. Urology 69:1121-1226.
- Jaber BM, Gao T, Huang L, Karmakar S and Smith CL. (2006). The pure estrogen receptor antagonist ICI 182,780 promotes a novel interaction of estrogen receptor-α with the 3’,5’-cyclin adenosine monophosphate response element-binding protein-binding protein/p300 coactivators. Molecular Endocrinology 20:2695-2710.
- Shen S*, Smith CL*, Hsieh JT, Yu J, Kim IY, Jian W, Sonpavde G, Ayala G, Younes M and Lerner SP. (2006). Expression of estrogen receptor α and β in bladder cancer cell lines and human bladder tumor tissue. Cancer 106:2610-2616.
- Labhart P, Karmakar S, Salicru EM, Egan BS, Alexiadis V, O’Malley BW and Smith CL. (2005). Identification of target genes in breast cancer cells directly regulated by the SRC-3/AIB1 coactivator. Proceedings of the National Academy of Sciences USA 102:1339-1344.
- Jaber B, Mukopadhyay R and Smith CL. (2004). Estrogen receptor-α interaction with the CREB bind protein coactivator is regulated by the cellular environment. Journal of Molecular Endocrinology 32:307-323.