title: 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.
authors.affiliation: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, New Delhi, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Nagpal
authors.forename: Hafiz M
authors.initials: HM
authors.lastname: Ahmad
authors.forename: Bhuvan
authors.initials: B
authors.lastname: Molparia
authors.forename: Ritu
authors.initials: R
authors.lastname: Kulshreshtha
mesh_terms: D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004967:Estrogens / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004967:Estrogens; C546177:MIRN191 microRNA, human; D036961:Matrix Attachment Region Binding Proteins; D035683:MicroRNAs; D011960:Receptors, Estrogen; C076189:SATB1 protein, human; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6