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

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/day) also inhibited lung metastasis of MDA-MB-231 cells in a tail vein injection model, demonstrating 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.

芳香烃受体（AHR）最初被鉴定为一种能结合2,3,7,8 - 四氯二苯并 - 对 - 二恶英（TCDD）及相关环境毒物的受体；然而，越来越多的证据表明，AHR是治疗包括乳腺癌在内的多种疾病的一个重要的新药物靶点。在博伊登小室实验中，用TCDD或选择性AHR调节剂6 - 甲基 - 1,3 - 三氯二苯并呋喃（MCDF）处理雌激素受体（ER）阴性的MDA - MB - 231和BT474乳腺癌细胞，可抑制乳腺癌细胞的侵袭。这些结果与先前报道的抗转移微小RNA - 335（miR - 335）的结果相似。TCDD和MCDF均可诱导MDA - MB - 231和BT474细胞中的miR - 335，同时伴有SOX4的下调，SOX4是一个受miR - 335调控（抑制）的基因。在转染了能敲低AHR的寡核苷酸（iAHR）的细胞中，TCDD和MCDF对miR - 335和SOX4表达的影响以及miR - 335与SOX4基因3' - 非翻译区靶序列的相互作用均受到抑制，从而证实了AHR - miR - 335的相互作用。在尾静脉注射模型中，MCDF（40mg/kg/天）还可抑制MDA - MB - 231细胞的肺转移，这表明AHR是治疗雌激素受体阴性乳腺癌患者的一个潜在新靶点，对于这种疾病，治疗选择及其有效性都很有限。