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
postdoc - Biochemical Endocrinology
Ph.D. - Chemistry
The College of Wooster
B.A. - Chemistry
A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice.
Boudreau MW, Duraki D, Wang L, Mao C, Kim JE, Henn MA, Tang B, Fanning SW, Kiefer J, Tarasow TM, Bruckheimer EM, Moreno R, Mousses S, Greene GL, Roy EJ, Park BH, Fan TM, Nelson ER, Hergenrother PJ, Shapiro DJ. A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice. Sci Transl Med. 2021 07 21; 13(603).
Defining the Energetic Basis for a Conformational Switch Mediating Ligand-Independent Activation of Mutant Estrogen Receptors in Breast Cancer.
Mayne CG, Toy W, Carlson KE, Bhatt T, Fanning SW, Greene GL, Katzenellenbogen BS, Chandarlapaty S, Katzenellenbogen JA, Tajkhorshid E. Defining the Energetic Basis for a Conformational Switch Mediating Ligand-Independent Activation of Mutant Estrogen Receptors in Breast Cancer. Mol Cancer Res. 2021 Sep; 19(9):1559-1570.
Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer.
Lainé M, Fanning SW, Chang YF, Green B, Greene ME, Komm B, Kurleto JD, Phung L, Greene GL. Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer. Breast Cancer Res. 2021 05 12; 23(1):54.
Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis.
Cui C, Chakraborty K, Tang XA, Zhou G, Schoenfelt KQ, Becker KM, Hoffman A, Chang YF, Blank A, Reardon CA, Kenny HA, Vaisar T, Lengyel E, Greene G, Becker L. Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis. Cell. 2021 Jun 10; 184(12):3163-3177.e21.
Facilitating Drug Discovery in Breast Cancer by Virtually Screening Patients Using In Vitro Drug Response Modeling.
Gruener RF, Ling A, Chang YF, Morrison G, Geeleher P, Greene GL, Huang RS. Facilitating Drug Discovery in Breast Cancer by Virtually Screening Patients Using In Vitro Drug Response Modeling. Cancers (Basel). 2021 Feb 20; 13(4).
Rapid Induction of the Unfolded Protein Response and Apoptosis by Estrogen Mimic TTC-352 for the Treatment of Endocrine-Resistant Breast Cancer.
Abderrahman B, Maximov PY, Curpan RF, Fanning SW, Hanspal JS, Fan P, Foulds CE, Chen Y, Malovannaya A, Jain A, Xiong R, Greene GL, Tonetti DA, Thatcher GRJ, Jordan VC. Rapid Induction of the Unfolded Protein Response and Apoptosis by Estrogen Mimic TTC-352 for the Treatment of Endocrine-Resistant Breast Cancer. Mol Cancer Ther. 2021 01; 20(1):11-25.
The Structure-Function Relationship of Angular Estrogens and Estrogen Receptor Alpha to Initiate Estrogen-Induced Apoptosis in Breast Cancer Cells.
Maximov PY, Abderrahman B, Hawsawi YM, Chen Y, Foulds CE, Jain A, Malovannaya A, Fan P, Curpan RF, Han R, Fanning SW, Broom BM, Quintana Rincon DM, Greenland JA, Greene GL, Jordan VC. The Structure-Function Relationship of Angular Estrogens and Estrogen Receptor Alpha to Initiate Estrogen-Induced Apoptosis in Breast Cancer Cells. Mol Pharmacol. 2020 07; 98(1):24-37.
The NF-?B Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor-Positive Breast Cancers.
Kastrati I, Joosten SEP, Semina SE, Alejo LH, Brovkovych SD, Stender JD, Horlings HM, Kok M, Alarid ET, Greene GL, Linn SC, Zwart W, Frasor J. The NF-?B Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor-Positive Breast Cancers. Mol Cancer Res. 2020 07; 18(7):1018-1027.
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 10 22; 29(4):889-903.e10.
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 10 16; 141(41):16374-16381.
American Association for the Advancement of Science
Susan G. Komen for the Cure Brinker Award for Scientific Distinction
Susan G. Komen Foundation
NAMS/Wyeth Pharmaceutical SERMs award
North American Menopausal Society
Virginia and D. K. Ludwig Professor for Cancer Research
Ludwig Institute for Cancer Research
Revlon/UCLA Women’s Cancer Research Program
Ernst Oppenheimer Award
The Endocrine Society