Many industrial and environmental chemicals mimic, antagonize, or indirectly alter the activity of hormones, particularly steroid hormones. It is commonly thought that these chemicals bind to the estrogen receptor or androgen receptor, either imitating the action of the hormones or blocking their activity. However, it is also possible that some of these compounds may act in an indirect fashion by either inhibiting aromatase activity or inducing aromatase expression, resulting in a change in the level of estrogen in women. Aromatase is a cytochrome P450 enzyme that converts androgen to estrogen. During the previous grant period, this laboratory has made important accomplishments in three areas. It has been demonstrated that computer modeling, aromatase site-directed mutagenesis, and inhibition profile analyses are useful tools for evaluating the molecular basis of the inhibition of aromatase by endocrine disrupters such as flavone and isoflavone phytoestrogens. Furthermore, the laboratory has developed a yeast screen system that can be adapted for use as a high throughput method to screen endocrine disrupters with anti- aromatase activity. In addition, the orphan receptor ERRalpha-1 was identified as a target of endocrine disrupters.
The specific aims for this grant period are: (1) to refine the yeast screening system as a high throughput approach to identify endocrine disrupters for aromatase inhibitors and ligands for androgen receptors; (2) determine the binding nature of endocrine disrupters that have anti-aromatase activity; and (3) to investigate the molecular basis of the interaction of endocrine disrupters with ERRalpha-1.
|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|
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