The Faculty

Focus

Mechanism of action of steroid hormones and their receptors, especially estrogen receptors, in hormone sensitive tissues and cancers

Education

Ph.D., Northwestern University, 1974

Research Summary

Mechanism of Action of Female Steroid Hormones and Nuclear Receptors in Breast Cancer. Development and Characterization of Novel SERMs.

The overall goal of my research is to determine the molecular mechanisms by which female steroid hormones regulate development, differentiation and/or cellular proliferation and survival in hormone responsive tissues and cancers.  Estrogens regulate the expression of diverse regulatory proteins and growth factors via one or both of two estrogen receptor subtypes (ERα & ERβ).  My lab is actively studying several aspects of ER action, including the role of post translational modifications in the transcriptional activation of ER, the roles of ER-associated proteins in receptor-mediated responses, the molecular nature of transcriptional activation and/or repression in the regulation of target gene expression, nongenomic actions of estrogens, and the detailed structural requirements for ligand binding to ERα/β, especially in regard to discrimination between estrogen agonists and selective estrogen receptor modulators (SERMs). I am also interested in using high throughput sequencing to identify and characterize ERα/β genomic targets and their regulated transcripts in breast cancer cells, as well as the transcription factors that co-associate at these targets and the mechanisms by which distal DNA response elements are able to organize and coordinate transcription initiation and repression. I am also interested in the role of tumor initiating cells in breast tumor invasion and metastasis.

Current areas of focus include: 1) defining the molecular/structural mechanisms by which SERMs elicit tissue-selective agonist or antagonist responses via one or both ER subtypes; 2) identifying novel ER subtype-selective SERMs via a combination of structure-based drug design and de novo drug discovery; 3) characterizing a mouse model in which ERα has been replaced with a mutant ERα that does not recognize endogenous estrogens, but will respond normally to several synthetic estrogen agonists and SERMs. This model is useful for studying estrogen dependent and independent development of ERα-expressing tissues, as well as for studying the genesis and progression of hormone dependent mammary cancers; 4) creating mouse models in which ERα, ERβ or PR (progesterone receptor) are selectively knocked out in one or more tissues, especially the mammary gland; 5) Determining how ERα suppresses inflammation by inhibiting NF-kB induced cytokine responses, 6) identifying the relative contributions and mechanisms of transcriptional versus rapid, non-genomic ERα/β actions in estrogen target tissues. 7) Using animal models of spontaneous human breast cancer to study prevention and/or treatment with novel drugs and natural products; 8) using a human breast tumor-in-mouse model to identify essential factors that control tumor cell invasion and metastasis; 9) identifying and characterizing ERα/β binding sites, their target genes, and signaling networks throughout the genomes of breast cancer cells and primary breast cancers. All of these projects have direct relevance and application to breast and uterine cancer genesis, progression, treatment and prevention, as well as to the development of compounds that can be used for hormone replacement therapy in postmenopausal women.

Selected Papers

Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL 1998 The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95:927-937

Shiau AK, Barstad D, Radek JT, Meyers MJ, Nettles KW, Katzenellenbogen BS, Katzenellenbogen JA, Agard DA, Greene GL 2002 Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat Struct Biol 9:359-364

Nettles KW, Sun J, Radek JT, Sheng S, Rodriguez AL, Katzenellenbogen JA, Katzenellenbogen BS, Greene GL 2004 Allosteric control of ligand selectivity between estrogen receptors alpha and beta: implications for other nuclear receptors. Mol Cell 13:317-327

Leong H, Sloan JR, Nash PD, Greene GL 2005 Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha. Mol Endocrinol 19:2930-2942

Wu YL, Yang X, Ren Z, McDonnell DP, Norris JD, Willson TM, Greene GL 2005 Structural basis for an unexpected mode of SERM-mediated ER antagonism. Mol Cell 18:413-424

Hsieh RW, Rajan SS, Sharma SK, Guo Y, DeSombre ER, Mrksich M, Greene GL 2006 Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity. J Biol Chem 281:17909-17919

Nettles KW, Bruning JB, Gil G, O'Neill EE, Nowak J, Hughs A, Kim Y, DeSombre ER, Dilis R, Hanson RN, Joachimiak A, Greene GL 2007 Structural plasticity in the oestrogen receptor ligand-binding domain. EMBO Rep 8:563-568 PMCID: PMC2002528

Hsieh RW, Rajan SS, Sharma SK, Greene GL 2008 Molecular characterization of a B-ring unsaturated estrogen: Implications for conjugated equine estrogen components of Premarin. Steroids 73:59-68 PMCID: PMC2225582

Leong H, Mathur PS, Greene GL 2008 Inhibition of mammary tumorigenesis in the C3(1)/SV40 mouse model by green tea. Breast cancer research and treatment 107:359-369 PMID: 17484049

Nettles KW, Bruning JB, Gil G, Nowak J, Sharma SK, Hahm JB, Kulp K, Hochberg RB, Zhou H, Katzenellenbogen JA, Katzenellenbogen BS, Kim Y, Joachmiak A, Greene GL 2008 NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nature chemical biology 4:241-247 PMCID: PMC2659626

Nettles KW, Gil G, Nowak J, Metivier R, Sharma VB, Greene GL 2008 CBP Is a dosage-dependent regulator of nuclear factor-kappaB suppression by the estrogen receptor. Molecular endocrinology 22:263-272 PMCID: PMC2234588

Leong, H., Mathur, P.S., and Greene, G.L. (2009). Green tea catechins inhibit angiogenesis through suppression of STAT3 activation. Breast cancer research and treatment 117, 505-515. PMID: 18821062

Walker, M.P., Zhang, M., Le, T.P., Wu, P., Laine, M., and Greene, G.L. (2011). RAC3 is a pro-migratory co-activator of ERalpha. Oncogene, 30 1984-1994.

Romero, I.L., Lee, W., Mitra, A.K., Gordon, I.O., Zhao, Y., Leonhardt, P., Penicka, C.V., Mui, K.L., Krausz, T.N., Greene, G.L., et al. (2011). The effects of 17beta-estradiol and a selective estrogen receptor modulator, bazedoxifene, on ovarian carcinogenesis. Gynecol Oncol. PMCID 3249832

Bockhorn J, Dalton R, Nwachukwu C, Huang S, Prat A, Yee K, Chang YF, Huo D, Wen Y, Swanson KE, Qiu T, Lu J, Young Park S, Eileen Dolan M, Perou CM, Olopade OI, Clarke MF, Greene GL, Liu H. MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nature communications. 2013;4:1393.

Bockhorn J, Yee K, Chang YF, Prat A, Huo D, Nwachukwu C, Dalton R, Huang S, Swanson KE, Perou CM, Olopade OI, Clarke MF, Greene GL, Liu H. MicroRNA-30c targets cytoskeleton genes involved in breast cancer cell invasion. Breast cancer research and treatment. 2012. PMCID 3583223