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

Shu Zhang, Kyoung Hyun Kim, Un Ho Jin, Catherine Pfent, Huojun Cao, Brad Amendt, Xinyi Liu, Heather Wilson-Robles, Stephen Safe

Research output: Contribution to journalArticle

46 Scopus citations

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 30-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 theAHRis a potential new target for treating patients with ERnegative breast cancer, a disease where treatment options and their effectiveness are limited. Mol Cancer Ther; 11(1); 108-18.

Original languageEnglish (US)
Pages (from-to)108-118
Number of pages11
JournalMolecular Cancer Therapeutics
Volume11
Issue number1
DOIs
StatePublished - Jan 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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