It is clear from the results of the Women's Health Initiative that there is an unmet medical need for estrogens that manifest their activity in a tissue-selective manner. Indeed, drugs with these properties like the SERMs raloxifene, bazedoxifene and lazofoxifene have already been developed. Unfortunately, none of these SERMs can treat the climacteric symptoms associated with estrogen deprivation. Furthermore, there is concern that long-term exposure to the available SERMs, while reducing the incidence of breast cancer in some women may actually facilitate the growth of cancers in others. Obviously, the next advance in this field will be the development of truly specific SERMs. This will be accomplished by defining the specific coactivators involved in a given process and selectively regulating these interactions with small molecules. With over 40 known ER-interacting proteins already identified, it may seem hard to believe that further discovery in this area is needed. However, our data suggests that there are important gaps in our understanding of ER action and that at least two additional classes of coactivators remain to be identified. To address this issue we have developed a high-throughput protein-protein interaction screen that will allow us to efficiently probe a large number of ER responsive tissues/cells for cofactors involved in determining the molecular pharmacology of estrogens and antiestrogens. In addition, we propose to investigate the mechanism(s) by which the RNA-binding protein RTAa,a cofactor recently identified by our laboratory, exerts its regulatory activities on ERa and determine its role in regulating the cellular responses to estrogens, antiestrogens and SERMs. Reflecting these objectives, we propose the following specific aims:
Aim 1. Identification of factors that interact with ERa-tamoxifen and ERa-estradiol complexes in a manner that is distinct from those previously identified.
Aim 2. Evaluation of the biological consequences of differential ERa-coactivator recruitment.
Aim 3. Elucidation of the molecular mechanism(s) underlying the tissueselective agonist/antagonist activities of tamoxifen.
Aim 4. Definition of the molecular mechanism by which the RNA binding protein RTAct/FXH-1 manifests its regulatory activity on ERa pharmacology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK048807-19
Application #
8423017
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
1994-12-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
19
Fiscal Year
2013
Total Cost
$500,031
Indirect Cost
$179,498
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Wardell, Suzanne E; Nelson, Erik R; Chao, Christina A et al. (2015) Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader. Endocr Relat Cancer 22:713-24
Choudhary, Mayur; Kazmin, Dmitri; Hu, Peng et al. (2015) Aryl hydrocarbon receptor knock-out exacerbates choroidal neovascularization via multiple pathogenic pathways. J Pathol 235:101-12
McDonnell, Donald P; Wardell, Suzanne E; Norris, John D (2015) Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer. J Med Chem 58:4883-7
Wardell, Suzanne E; Ellis, Matthew J; Alley, Holly M et al. (2015) Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer. Clin Cancer Res 21:5121-30
Wardell, Suzanne E; Nelson, Erik R; McDonnell, Donald P (2014) From empirical to mechanism-based discovery of clinically useful Selective Estrogen Receptor Modulators (SERMs). Steroids 90:30-8
Nelson, Erik R; Chang, Ching-yi; McDonnell, Donald P (2014) Cholesterol and breast cancer pathophysiology. Trends Endocrinol Metab 25:649-55
Wright, Tricia M; Wardell, Suzanne E; Jasper, Jeff S et al. (2014) Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer. Mol Cancer Res 12:1829-39
McDonnell, D P; Chang, C-Y; Nelson, E R (2014) The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer. Climacteric 17 Suppl 2:60-5
Scholtz, Elizabeth L; Krishnan, Shweta; Ball, Barry A et al. (2014) Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone. Proc Natl Acad Sci U S A 111:3365-70
McDonnell, Donald P; Park, Sunghee; Goulet, Matthew T et al. (2014) Obesity, cholesterol metabolism, and breast cancer pathogenesis. Cancer Res 74:4976-82

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