Mechanism of Action of Female Steroid Hormones and Nuclear Receptors. Development and Characterization of Novel SERMs.
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 post translational modifications in the 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 to ERα/β, especially in regard to discrimination between estrogen agonists and selective estrogen receptor modulators (SERMs). I am also interested in using high throughput sequencing to identify and characterize ERα/β genomic targets and their regulated transcripts in breast cancer cells, as well as the transcription factors that co-associate at these targets and the mechanisms by which distal DNA response elements are able to organize and coordinate transcription initiation and repression. I am also interested in the role of tumor initiating cells in breast tumor invasion and metastasis.
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) characterizing a mouse model in which ERα has been replaced with a mutant ERα that does not recognize endogenous estrogens, but will respond normally to several synthetic estrogen agonists and SERMs. This model is useful for studying estrogen dependent and independent development of ERα-expressing tissues, as well as 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; 5) Determining how ERα suppresses inflammation by inhibiting NF-kB induced cytokine responses, 6) identifying the relative contributions and mechanisms of transcriptional versus rapid, non-genomic ERα/β actions in estrogen target tissues. 7) Using animal models of spontaneous human breast cancer to study prevention and/or treatment with novel drugs and natural products; 8) using a human breast tumor-in-mouse model to identify essential factors that control tumor cell invasion and metastasis; 9) identifying and characterizing ERα/β binding sites, their target genes, and signaling networks throughout the genomes of breast cancer cells and primary breast cancers. 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.