Aryl hydrocarbon receptor agonists induce microRNA-335 expression and inhibit lung metastasis of estrogen receptor negative breast cancer cells.

Abstract

The aryl hydrocarbon receptor (AHR) was initially identified as a receptor that bound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related environmental toxicants; however, there is increasing evidence that the AHR is an important new drug target for treating multiple diseases including breast cancer. Treatment of estrogen receptor (ER)-negative MDA-MB-231 and BT474 breast cancer cells with TCDD or the selective AHR modulator 6-methyl-1,3,-trichlorodibenzofuran (MCDF) inhibited breast cancer cell invasion in a Boyden chamber assay. These results were similar to those previously reported for the antimetastic microRNA-335 (miR-335). Both TCDD and MCDF induced miR-335 in MDA-MB-231 and BT474 cells and this was accompanied by downregulation of SOX4, a miR-335-regulated (inhibited) gene. The effects of TCDD and MCDF on miR-335 and SOX4 expression and interactions of miR-335 with the 3'-UTR target sequence in the SOX4 gene were all inhibited in cells transfected with an oligonucleotide (iAHR) that knocks down the AHR, thus confirming AHR-miR-335 interactions. MCDF (40 mg/kg/d) also inhibited lung metastasis of MDA-MB-231 cells in a tail vein injection model, showing that the AHR is a potential new target for treating patients with ER-negative breast cancer, a disease where treatment options and their effectiveness are limited.

• Authors: Shu Zhang, KyoungHyun Kim, Un Ho Jin, Catherine Pfent, Huojun Cao, Brad Amendt, Xinyi Liu, Heather Wilson-Robles, Stephen Safe
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 1 Pg. 108-18 (Jan 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22034498 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• 3' Untranslated Regions
• Benzofurans
• MIRN335 microRNA, human
• MicroRNAs
• Oligonucleotides
• Polychlorinated Dibenzodioxins
• RNA, Messenger
• RNA, Small Interfering
• Receptors, Aryl Hydrocarbon
• Receptors, Estrogen
• SOX4 protein, human
• SOXC Transcription Factors
• 6-methyl-1,3,8-trichlorodibenzofuran

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Benzofurans (pharmacology)
• Breast Neoplasms (pathology)
• Cell Line, Tumor
• Female
• Humans
• Lung Neoplasms (secondary)
• Mice
• Mice, Nude
• MicroRNAs (metabolism)
• Oligonucleotides (genetics, pharmacology)
• Polychlorinated Dibenzodioxins (pharmacology)
• RNA Interference
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering
• Receptors, Aryl Hydrocarbon (agonists, genetics, metabolism)
• Receptors, Estrogen (deficiency)
• SOXC Transcription Factors (metabolism)