Estrogen receptor expression induces changes in the microRNA pool in human colon cancer cells

There is epidemiological, animal and in vitro evidence that estrogen receptor (ER) can mediate protective effects against colon cancer, but the mechanism is not completely understood. Previous research has indicated critical pathways whereby ER acts in an antitumorigenic fashion. In this study, we investigate ERs impact on the microRNA (miRNA) pool in colon cancer cells using large-scale genomic approaches, bioinformatics and focused functional studies. We detect and confirm 27 miRNAs to be significantly changed following ER expression in SW480 colon cancer cells. Among these, the oncogenic miR-1792 cluster and miR-200a/b are strongly downregulated. Using target prediction and anticorrelation to gene expression data followed by focused mechanistic studies, we demonstrate that repression of miR-17 is a secondary event following ERs downregulatory effect on MYC. We show that re-introduction of miR-17 can reverse the antiproliferative effects of ER. The repression of miR-17 also influences cell death upon DNA damage and mediates regulation of NCOA3 (SRC-3) and CLU in colon cancer cells. We further determine that the downregulation of miR-200a/b mediates increased ZEB1 while decreasing E-cadherin levels in ER-expressing colon cancer cells. Changes in these genes correspond to significant alterations in morphology and migration. Our work contributes novel data of ER and miRNA in the colon. Elucidating the mechanism of ER and biomarkers of its activity has significant potential to impact colon cancer prevention and treatment.