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.
The University of Chicago
Chicago, IL
postdoc - Biochemical Endocrinology
1977
Northwestern University
Evanston, IL
Ph.D. - Chemistry
1974
The College of Wooster
Wooster, Ohio
B.A. - Chemistry
1969
ERa/PR crosstalk is altered in the context of the ERa Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation.
ERa/PR crosstalk is altered in the context of the ERa Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation. NPJ Breast Cancer. 2023 Nov 30; 9(1):96.
PMID: 38036546
Glucocorticoid Receptor Activation in Lobular Breast Cancer Is Associated with Reduced Cell Proliferation and Promotion of Metastases.
Glucocorticoid Receptor Activation in Lobular Breast Cancer Is Associated with Reduced Cell Proliferation and Promotion of Metastases. Cancers (Basel). 2023 Sep 22; 15(19).
PMID: 37835373
Reinvestigating the Synthesis and Characterization of Ethyl 3-[5-(2-Ethoxycarbonyl-1-methylvinyloxy)-1-methyl-1H-indol-3-yl]-but-2-enoate.
Reinvestigating the Synthesis and Characterization of Ethyl 3-[5-(2-Ethoxycarbonyl-1-methylvinyloxy)-1-methyl-1H-indol-3-yl]-but-2-enoate. ACS Omega. 2023 Sep 05; 8(35):31941-31945.
PMID: 37692243
Evaluating steroid hormone receptor interactions using the live-cell NanoBRET proximity assay.
Evaluating steroid hormone receptor interactions using the live-cell NanoBRET proximity assay. bioRxiv. 2023 Jul 26.
PMID: 37546915
Dynamic epi-transcriptomic landscape mapping with disease progression in estrogen receptor-positive breast cancer.
Dynamic epi-transcriptomic landscape mapping with disease progression in estrogen receptor-positive breast cancer. Cancer Commun (Lond). 2023 05; 43(5):615-619.
PMID: 36670046
Demethylation of dimethyl phosphonate esters with sodium ethanethiolate: Improved synthesis of 5'-methylene substituted 2',5'-deoxyribonucleotides.
Demethylation of dimethyl phosphonate esters with sodium ethanethiolate: Improved synthesis of 5'-methylene substituted 2',5'-deoxyribonucleotides. Nucleosides Nucleotides Nucleic Acids. 2023; 42(7):538-546.
PMID: 36629008
Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells.
Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells. NPJ Breast Cancer. 2022 Dec 14; 8(1):130.
PMID: 36517522
Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains.
Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains. Nat Biotechnol. 2023 04; 41(4):541-551.
PMID: 36302987
Labeling of a mutant estrogen receptor with an Affimer in a breast cancer cell line.
Labeling of a mutant estrogen receptor with an Affimer in a breast cancer cell line. Biophys J. 2022 10 04; 121(19):3651-3662.
PMID: 35778844
Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells.
Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells. Elife. 2022 05 16; 11.
PMID: 35575456
AAAS Fellow
American Association for the Advancement of Science
2017
Susan G. Komen for the Cure Brinker Award for Scientific Distinction
Susan G. Komen Foundation
2009
NAMS/Wyeth Pharmaceutical SERMs award
North American Menopausal Society
2006
Virginia and D. K. Ludwig Professor for Cancer Research
Ludwig Institute for Cancer Research
2003
Tartikoff-Semel Award
Revlon/UCLA Women’s Cancer Research Program
1997
Ernst Oppenheimer Award
The Endocrine Society
1988