- Virginia and D. K. Ludwig Professor and Director, The Ben May Dept. for Cancer Research, University of Chicago
Ben May Institute for Cancer Research
The University of Chicago
929 E. 57th St., GCIS W330
Chicago, IL 60637
Phone: 773 702 6964
Fax: 773 702 6964
The overall goal of my research is to determine the molecular mechanisms by which female steroid hormones regulate development, differentiation and/or cellular proliferation and survival in hormone responsive tissues and cancers. Estrogens regulate the expression of diverse regulatory proteins and growth factors via one or both of two estrogen receptor subtypes (ERα & ERβ ). My lab is actively studying several aspects of ER action, including the role of phosphorylation in transcriptional activation of ER, the roles of ER-associated proteins in receptor-mediated responses, the molecular nature of transcriptional activation and/or repression in the regulation of target gene expression, nongenomic actions of estrogens, and the detailed structural requirements for ligand binding in ERα/β , especially in regard to discrimination between estrogen agonists and antagonists (SERMs).
Current areas of focus include: 1) defining the molecular/structural mechanisms by which SERMs elicit tissue-selective agonist or antagonist responses via one or both ER subtypes; 2) identifying novel ER subtype-selective SERMs via a combination of structure-based drug design and de novo drug discovery; 3) generating a mouse model in which ERα is replaced with a mutant ERα that does not recognize endogenous estradiol but will respond normally to a synthetic estrogen such as DES. This model will be useful for studying estrogen-regulated development of the reproductive tract, bone, cardiovasculature and CNS, and will also be used for studying the genesis and progression of hormone dependent mammary cancers; 4) creating mouse models in which ERα , ERβ or PR (progesterone receptor) are selectively knocked out in one or more tissues, especially the mammary gland. 4) Determining how ERα suppresses inflammation by inhibiting NF- k B induced cytokine responses, 5) identifying the relative contributions and mechanisms of transcriptional versus rapid, nongenomic ERα/β actions in estrogen target tissues. 6) Using animal models of spontaneous human breast cancer to study prevention and/or treatment with novel drugs and natural products, such as green tea. All of these projects have direct relevance and application to breast and uterine cancer genesis, progression, treatment and prevention, as well as to the development of compounds that can be used for hormone replacement therapy in postmenopausal women.