MicroRNA-191, an estrogen-responsive microRNA, functions as an oncogenic regulator in human breast cancer

Abstract

Estrogen- and microRNA-mediated gene regulation play a crucial role in breast cancer biology. However, a functional link between the two major players remains unclear. This study reveals miR-191 as an estrogen-inducible onco-miR in breast cancer, which promotes several hallmarks of cancer including enhanced cell proliferation, migration, chemoresistance and survival in tumor microenvironment. miR-191 is a direct estrogen receptor (ER) target and our results suggest existence of a positive regulatory feedback loop. We show miR-191 as critical mediator of estrogen-mediated cell proliferation. Investigations of mechanistic details of miR-191 functions identify several cancer-related genes like BDNF, CDK6 and SATB1 as miR-191 targets. miR-191 and SATB1 show inverse correlation of expression. miR-191-mediated enhanced cell proliferation and migration are partly dependent on targeted downregulation of SATB1. Further, functional validation of estrogen:miR-191:SATB1 link suggests a cascade initiated by estrogen that induces miR-191 in ER-dependent manner to target SATB1, a global chromatin remodeler, thereby contributing to estrogen-specific gene signature to regulate genes like ANXA1, PIWIL2, CASP4, ESR1/ESR2, PLAC1 and SOCS2 involved in breast cancer progression and migration. Overall, the identification of estrogen/ER/miR-191/SATB1 cascade seems to be a significant pathway in estrogen signaling in breast cancer with miR-191 as oncogenic player.