Aromatase is the enzyme that converts androgen to estrogen. The applicant has hypothesized and demonstrated that aromatase is an important target of endocrine disrupting chemicals. These compounds have been found to inhibit aromatase activity, which results in both a decrease in the level of estrogen and an increase in the level of androgen in treated cells. Animal experiments have been performed that demonstrated the in vivo action of anti-aromatase chemicals. Additionally, environmental chemicals (both phytochemicals and xenochemicals) were found to modify the expression of aromatase in various tissues, which results in a change in the conversion ratio of androgen to estrogen. The compounds that inhibit aromatase or suppress aromatase expression behave as antiestrogens or androgen-like compounds in vivo. Conversely, compounds that either increase aromatase expression or enhance aromatase activity (or stability) may actually function as anti-androgens or estrogen-like compounds. Research conducted in the applicant's laboratory during the last four years demonstrated that estrogen-related receptor alpha (ERR-alpha) and estrogen receptor alpha (ER-alpha) can regulate the expression of aromatase. It has also been shown that endocrine disrupting chemicals, by acting as the ligands of these two receptors, can modify the expression of aromatase in treated cells. Aromatase, ER-alpha, and ERR-alpha are all important players in maintaining our endocrine function. To continue with and expand on the current efforts in the applicant's laboratory to identify endocrine disrupting chemicals, it is proposed in this competitive renewal application that they utilize their newly established high throughput computer-assisted virtual screening approach to search endocrine disrupting chemicals which serve as ligands/inhibitors of these proteins. It is also further proposed that they determine the structural characteristics of these chemicals by evaluating their structure activity relationship. Such structural information will be valuable for the identification of unanticipated endocrine disrupting chemicals. The proposed studies will focus on 1014 phytochemicals (including chalcones, chromones, coumarins, flavanones, flavones and isoflavones) that would be purchased from Indofine Co (Somerville, New Jersey). In addition, it is proposed that the endocrine disrupting actions of compounds (which have been identified by the high throughput screening method) be confirmed through both in vitro and in vivo experiments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008258-11
Application #
7579007
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Balshaw, David M
Project Start
1996-09-01
Project End
2012-02-29
Budget Start
2009-03-01
Budget End
2012-02-29
Support Year
11
Fiscal Year
2009
Total Cost
$298,371
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Kanaya, Noriko; Nguyen, Duc M; Lu, Hannah et al. (2015) AroER tri-screen™ is a novel functional assay to estimate both estrogenic and estrogen precursor activity of chemicals or biological specimens. Breast Cancer Res Treat 151:335-45
Chen, Zhike; Yuan, Yate-Ching; Wang, Yuanzhong et al. (2015) Down-regulation of programmed cell death 4 (PDCD4) is associated with aromatase inhibitor resistance and a poor prognosis in estrogen receptor-positive breast cancer. Breast Cancer Res Treat 152:29-39
Chen, Zhike; Wang, Yuanzhong; Warden, Charles et al. (2015) Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells. J Steroid Biochem Mol Biol 149:118-27
Chen, Zhike; Wang, Ou; Nie, Min et al. (2015) Aromatase deficiency in a Chinese adult man caused by novel compound heterozygous CYP19A1 mutations: effects of estrogen replacement therapy on the bone, lipid, liver and glucose metabolism. Mol Cell Endocrinol 399:32-42
Twardowski, Przemyslaw; Kanaya, Noriko; Frankel, Paul et al. (2015) A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced prostate-specific antigen responses. Cancer 121:2942-50
Kai, Masaya; Kanaya, Noriko; Wu, Shang V et al. (2015) Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin. Breast Cancer Res Treat 151:281-94
Kanaya, Noriko; Vonderfecht, Steven; Chen, Shiuan (2013) Androgen (dihydrotestosterone)-mediated regulation of food intake and obesity in female mice. J Steroid Biochem Mol Biol 138:100-6
Kubo, Makoto; Kanaya, Noriko; Petrossian, Karineh et al. (2013) Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat). Breast Cancer Res Treat 137:93-107
Wong, Cynthie; Wang, Xin; Smith, David et al. (2012) AKT-aro and HER2-aro, models for de novo resistance to aromatase inhibitors; molecular characterization and inhibitor response studies. Breast Cancer Res Treat 134:671-81
Wong, Cynthie; Chen, Shiuan (2012) The development, application and limitations of breast cancer cell lines to study tamoxifen and aromatase inhibitor resistance. J Steroid Biochem Mol Biol 131:83-92

Showing the most recent 10 out of 68 publications