Aryl hydrocarbon receptor agonists inhibit breast cancer cell growth and modulate microRNA expression

Abstract

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MDA-MB-468 and BT474 are estrogen receptor (ER)-negative and ER-positive breast cancer cell lines, respectively, that also express the aryl hydrocarbon receptor (AhR). Treatment of these cell lines with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), 3,3’,4,4’,5-pentachlorobiphenyl (PCB), and the selective AhR modulator (SAhRM) 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) induced CYP1A1 expression, a typical AhR-responsive gene. In addition, treatment with 40 nM TCDD, PCDD, TCDF and PCDF, 100 nM PCB and 5 uM MCDF resulted in a >30-80% and 25-50% decreased in MDA-MB-468 and BT474 cell proliferation, respectively. Moreover, in cells treated with the halogenated aromatic TCDD, PCDD, TCDF, PCDF and PCB congeners, the growth inhibitory effects were completely abrogated after cotransfection with a small inhibitory RNA for the AhR (iAhR). In contrast, iAhR only partially reversed the antiproliferative effects of 6-MCDF, suggesting that this compound activates both AhR-dependent and AhR-independent growth inhibitory pathways. The potential role of microRNAs in mediating the effects of these compounds was investigated using a System Biosciences QuantiMir Cancer MicroRNA qPCR Array. The results show that 6-MCDF and the five halogenated aromatics modulate expression of several common microRNAs including let-7-family, miR-103, miR-198 and miR-373. However, it was also evident that 6-MCDF and the five halogenated aromatics differentially modulated microRNA expression, and current studies are focused on identifying and characterizing structure-dependent activation of microRNAs via AhR-dependent and independent pathways. [Supported by the Dow Chemical Company and National Institutes of Health (ES09106 and ES04917)]