Geoffrey Greene, PhD

  • Chair of Ben May Department of Cancer Research
    Virginia and D. K. Ludwig Professor of Ben May Department of Cancer Research
  • Research and Scholarly Interests: Androgen Receptor, Breast Cancer, Estrogen Receptors, Glucocorticoid Receptor, Hormone Receptors, Nuclear, Metastasis, organoids, PDX models, Progesterone Receptor, Prostate Cancer, SERDS, SERMs
  • Websites: Ben May Department web site, Research Network Profile
  • Contact: ggreene@uchicago.edu

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

The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.
Cocce KJ, Jasper JS, Desautels TK, Everett L, Wardell S, Westerling T, Baldi R, Wright TM, Tavares K, Yllanes A, Bae Y, Blitzer JT, Logsdon C, Rakiec DP, Ruddy DA, Jiang T, Broadwater G, Hyslop T, Hall A, Laine M, Phung L, Greene GL, Martin LA, Pancholi S, Dowsett M, Detre S, Marks JR, Crawford GE, Brown M, Norris JD, Chang CY, McDonnell DP. The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer. Cell Rep. 2019 Oct 22; 29(4):889-903.e10.
PMID: 31644911

Versatile Peptide Macrocyclization with Diels-Alder Cycloadditions.
Montgomery JE, Donnelly JA, Fanning SW, Speltz TE, Shangguan X, Coukos JS, Greene GL, Moellering RE. Versatile Peptide Macrocyclization with Diels-Alder Cycloadditions. J Am Chem Soc. 2019 Oct 16; 141(41):16374-16381.
PMID: 31523967

Next-Generation ERa Inhibitors for Endocrine-Resistant ER+ Breast Cancer.
Fanning SW, Greene GL. Next-Generation ERa Inhibitors for Endocrine-Resistant ER+ Breast Cancer. Endocrinology. 2019 04 01; 160(4):759-769.
PMID: 30753408

The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells.
Fanning SW, Jeselsohn R, Dharmarajan V, Mayne CG, Karimi M, Buchwalter G, Houtman R, Toy W, Fowler CE, Han R, Lainé M, Carlson KE, Martin TA, Nowak J, Nwachukwu JC, Hosfield DJ, Chandarlapaty S, Tajkhorshid E, Nettles KW, Griffin PR, Shen Y, Katzenellenbogen JA, Brown M, Greene GL. The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells. Elife. 2018 11 29; 7.
PMID: 30489256

Antagonists for Constitutively Active Mutant Estrogen Receptors: Insights into the Roles of Antiestrogen-Core and Side-Chain.
Sharma A, Toy W, Guillen VS, Sharma N, Min J, Carlson KE, Mayne CG, Lin S, Sabio M, Greene G, Katzenellenbogen BS, Chandarlapaty S, Katzenellenbogen JA. Antagonists for Constitutively Active Mutant Estrogen Receptors: Insights into the Roles of Antiestrogen-Core and Side-Chain. ACS Chem Biol. 2018 12 21; 13(12):3374-3384.
PMID: 30404440

Publisher Correction: Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance.
Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. Publisher Correction: Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Nat Rev Cancer. 2018 Oct; 18(10):662.
PMID: 30185950

Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity.
Fanning SW, Hodges-Gallagher L, Myles DC, Sun R, Fowler CE, Plant IN, Green BD, Harmon CL, Greene GL, Kushner PJ. Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity. Nat Commun. 2018 06 18; 9(1):2368.
PMID: 29915250

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance.
Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Nat Rev Cancer. 2018 06; 18(6):377-388.
PMID: 29662238

A "cross-stitched" peptide with improved helicity and proteolytic stability.
Speltz TE, Mayne CG, Fanning SW, Siddiqui Z, Tajkhorshid E, Greene GL, Moore TW. A "cross-stitched" peptide with improved helicity and proteolytic stability. Org Biomol Chem. 2018 05 23; 16(20):3702-3706.
PMID: 29725689

Endoxifen, 4-Hydroxytamoxifen and an Estrogenic Derivative Modulate Estrogen Receptor Complex Mediated Apoptosis in Breast Cancer.
Maximov PY, Abderrahman B, Fanning SW, Sengupta S, Fan P, Curpan RF, Rincon DMQ, Greenland JA, Rajan SS, Greene GL, Jordan VC. Endoxifen, 4-Hydroxytamoxifen and an Estrogenic Derivative Modulate Estrogen Receptor Complex Mediated Apoptosis in Breast Cancer. Mol Pharmacol. 2018 08; 94(2):812-822.
PMID: 29739819

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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