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keywords
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Hormone Receptors, Nuclear
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overview
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The overall objective of my research is to determine the molecular distinctions between estrogen, androgen, progestin, and glucocorticoid agonism and antagonism in hormone-dependent tissues and cancers and to use this information to identify, develop and characterize novel compounds that can be used as breast and prostate cancer chemopreventatives and chemotherapeutics. I have considerable experience and expertise with the identification and characterization of novel compounds (SERMs, SERDs, SPRMs) that selectively target the two estrogen receptors, ERalpha and ERbeta, and progesterone receptor (PR). More recently, my lab has also begun to focus on AR and GR therapeutics. One of our specific goals is to test and develop known and novel SERMs/SARMS/SPRMs/SGRMs for their ability to selectively alter ER/PR, ER/AR and ER/GR recruitment of coregulator subsets that reflect differential responses to these ligands. My lab has solved multiple crystal structures of the ERalpha and ERbeta ligand-binding domains bound to diverse SERMs, which has contributed significantly to our understanding of the structural basis for agonist and antagonist interactions with both ERs, and how the two ER subtypes differentially discriminate among ligands. We have also solved the crystal structure of AR LBD bound to DHT and ERalpha LBD bound to several stapled peptides that bind to and inhibit the transcriptional activating AF2 function of ERalpha. Structural studies are being expanded to include cryoEM analysis of receptor/DNA/coregulator complexes. In addition, we are actively characterizing ERalpha somatic mutations that have been observed in endocrine therapy resistant metastatic breast cancers, with the goal of targeting these mutant ERs with next generation SERMs/SERDs. More recently, we have been studying the role of NCoA3 and other nuclear receptor coregulators as mediators of survival, invasion and metastasis in TNBC. We use and are developing both cell-derived explant and PDX models as platforms for studying both ER+ and ER- breast cancer progression and treatment with existing as well as novel therapy combinations that target multiple steroid receptors and their coregulators. I have a strong background in understanding and modulating breast cancer genesis, progression, treatment and prevention.
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