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Molecular Mechanisms and Application of Ah Receptor-MicroRNA Interactions

Ah受体-MicroRNA相互作用的分子机制及应用

基本信息

批准号：
8269955
负责人：
Stephen H. Safe
金额：
$ 25.92万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269955
关键词：
7-ketocholesterol Adverse effects Affinity Agonist Aromatic Amines Aromatic Compounds Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Benzo(a)pyrene Bilirubin Binding Biochemical Breast Cancer Cell CYP1A1 gene Cancer cell line Cell Line Cell Proliferation Cells Chemopreventive Agent Chemoprotective Agent Cleft Palate Cytotoxic agent Development Dioxins Disease Disease-Free Survival Elements Endometrial Carcinoma Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptors Estrogen receptor negative Estrogens Exhibits Family Flavonoids Food Genes Growth Indole-3-Carbinol Ink Laboratories Ligands Malignant neoplasm of prostate Mammary Neoplasms Mediating Metabolism MicroRNAs Molecular Mus Nuclear Receptors Nude Mice Patients Pharmaceutical Preparations Pharmacologic Substance Phytochemical Porphyrias Protein Binding Regulation Research Role Staging Tetrachlorodibenzodioxin Tissues Toxic Environmental Substances Xenograft procedure chemotherapy clinical application immunotoxicity in vivo malignant breast neoplasm member migration outcome forecast pancreatic cancer cells receptor receptor binding response transcription factor tumor growth

项目摘要

PROJECT SUMMARY The aryl hydrocarbon receptor (AhR) was initially discovered as an intracellular protein that binds to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related chlorinated aromatic compounds. In recent years, it has been demonstrated that the AhR binds with structurally and functionally diverse compounds including chemoprotective phytochemicals such as flavonoids, polyphenolics and indole-3-carbinol. Not surprisingly, these compounds exhibit tissue-specific AhR agonist and antagonist activities and can be classified as selective AhR modulators (SAhRMs). Previous studies in this laboratory have taken advantage of the potential applications of SAhRMs for treatment of diseases, and 6-methyl-1,3,8- trichlorodibenzofuran (MCDF) was initially characterized as an AhR antagonist but, like TCDD, MCDF exhibited antiestrogenic activity in estrogen-responsive breast cancer cells and mammary tumors, and MCDF is a potent antiestrogen that acts through inhibitory AhR-estrogen receptor (ER) crosstalk. Results of preliminary studies now show that AhR agonists such as TCDD and MCDF inhibit growth of a large number of ER-negative breast cancer cells including highly invasive MDA-MB-231 and MDA-MB-468 cells that are classified as basal or triple negative cells. MCDF also inhibits tumor growth in vivo in athymic nude mice bearing ER-negative cells as xenografts. Moreover, the antitumorigenic activity of MCDF and TCDD is accompanied by AhR-dependent induction of two antimetastatic microRNAs (miRs), namely miR-335 and miR- 205. The proposed studies will further investigate the molecular mechanisms and potential clinical applications of MCDF and structurally-related SAhRMs for treatment of ER-negative breast cancer. Aim 1 will focus on SAhRM-induced modulation of miR-335 and miR-205 and the role of the AhR in decreasing the proliferation, migration and invasion of a panel of ER-negative breast cancer cell lines. In Aim 2, the mechanism of AhR- dependent regulation of miR-335 and miR-205 expression will be determined ER-negative breast cancer cell lines and the functional dioxin responsive elements (DREs) regulating miR expression will be identified. In addition, genes regulated by AhR-miR-335 and AhR-miR-205 interactions will also be investigated. Aim 3 will confirm the role of the AhR, miR-335 and miR-205 in regulating orthotopic mammary tumor growth in athymic nude mice using cell lines in which expression of the AhR, miR-335 and miR-205 is regulated. The proposed studies will be the first to characterize the molecular mechanisms of AhR-miR interactions and development of SAhRMs for clinical applications in the treatment of ER-negative breast cancer.

项目总结