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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008258-06
Application #
6627072
Study Section
Special Emphasis Panel (ZRG1-REB (01))
Program Officer
Balshaw, David M
Project Start
1996-09-01
Project End
2005-02-28
Budget Start
2003-01-01
Budget End
2005-02-28
Support Year
6
Fiscal Year
2003
Total Cost
$275,686
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
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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
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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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