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/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.
Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77843, USA.
Shu
S
Zhang
KyoungHyun
K
Kim
Un Ho
UH
Jin
Catherine
C
Pfent
Huojun
H
Cao
Brad
B
Amendt
Xinyi
X
Liu
Heather
H
Wilson-Robles
Stephen
S
Safe
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000172:deficiency; D055751:SOXC Transcription Factors / Q000378:metabolism
D020413:3' Untranslated Regions; D001572:Benzofurans; C556347:MIRN335 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; C054923:6-methyl-1,3,8-trichlorodibenzofuran