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.
Selective aryl hydrocarbon receptor (AhR) modulators (SAhRMs) bind and activate the AhR and, in estrogen receptor-negative breast cancer cells, these compounds inhibit cell proliferation and tumor growth in mouse xenografts. The proposed research will investigate the AhR-dependent induction of the antimetastatic microRNA-335 and microRNA-205 and delineate their role in the anticarcinogenic activity of SAhRMs.
|Jin, Un-Ho; Kim, Sang-Bae; Safe, Stephen (2015) Omeprazole Inhibits Pancreatic Cancer Cell Invasion through a Nongenomic Aryl Hydrocarbon Receptor Pathway. Chem Res Toxicol 28:907-18|
|Safe, Stephen; Jin, Un-Ho; Hedrick, Erik et al. (2014) Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol Endocrinol 28:157-72|
|Jin, Un-Ho; Lee, Syng-Ook; Pfent, Catherine et al. (2014) The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. BMC Cancer 14:498|
|Jin, Un-Ho; Lee, Syng-Ook; Sridharan, Gautham et al. (2014) Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Mol Pharmacol 85:777-88|
|Safe, Stephen; Lee, Syng-Ook; Jin, Un-Ho (2013) Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol Sci 135:1-16|
|Jin, Un-Ho; Lee, Syng-ook; Safe, Stephen (2012) Aryl hydrocarbon receptor (AHR)-active pharmaceuticals are selective AHR modulators in MDA-MB-468 and BT474 breast cancer cells. J Pharmacol Exp Ther 343:333-41|
|Zhang, Shu; Kim, KyoungHyun; Jin, Un Ho et al. (2012) Aryl hydrocarbon receptor agonists induce microRNA-335 expression and inhibit lung metastasis of estrogen receptor negative breast cancer cells. Mol Cancer Ther 11:108-18|
|Safe, Stephen (2010) 3-methylcholanthrene induces differential recruitment of aryl hydrocarbon receptor to human promoters. Toxicol Sci 117:1-3|