My lab studies the molecular mechanisms by which female steroid hormones regulate development, differentiation and cellular proliferation and survival in hormone responsive tissues and cancers. I have an extensive background in the investigation and modulation of breast and prostate cancer genesis, progression, treatment and prevention using diverse cell and animal models.

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 as treatments or preventive interventions for breast and prostate cancers. I have considerable expertise in the identification and characterization of novel compounds (SERMs, SERDs, SPRMs) that selectively target the two estrogen receptors, ERα and ERβ, and the progesterone receptor (PR). More recently, my group has also begun to focus on androgen receptor and glucocorticoid receptor therapeutics in castration resistant prostate cancer. One of our goals is to test and develop known and novel SERMs, SARMS, SPRMs and 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.

We have solved multiple 3D structures of the ERα/β ligand-binding domains bound to diverse SERMs and SERDs. These studies have contributed significantly to our understanding of the structural basis for agonist and antagonist activities for both ERs, and how the two ER subtypes differentially discriminate among structurally diverse ligands. We are especially interested in characterizing ERα somatic mutations that have been observed in a large subset of endocrine therapy resistant ER+ metastatic breast cancers, with the goal of targeting these constitutively active and more difficult to treat mutant ERs with next generation orally available SERMs or SERDs.

We develop both cell-derived explant and patient derived PDX models as platforms for studying ER+ and ER- breast cancer progression and treatment with existing as well as novel therapy combinations that target steroid receptors and their coregulators. We are also investigating the relatively unexplored cross talk between ERα and PR and potential therapeutic co-targeting of these receptors in ER+/PR+ breast cancers. Our data suggest that co-targeting of ERα and PR in ER+/PR+ breast cancers should be further explored as a therapy. It is also very likely that co-targeting of additional steroid receptors will prove beneficial in treating advanced breast and prostate cancers. We are actively exploring these possibilities.