The role of miR-206 in the epidermal growth factor (EGF) induced repression of estrogen receptor-alpha (ERalpha) signaling and a luminal phenotype in MCF-7 breast cancer cells.
Epidermal growth factor (EGF) receptor (EGFR)/MAPK signaling can induce a switch in MCF-7 breast cancer cells, from an estrogen receptor (ER)alpha-positive, Luminal-A phenotype, to an ERalpha-negative, Basal-like phenotype. Although mechanisms for this switch remain obscure, Basal-like cancers are typically high grade and confer a poorer clinical prognosis. We previously reported that miR-206 and ERalpha repress each other's expression in MCF-7 cells in a double-negative feedback loop. We show herein that miR-206 coordinately targets mRNAs encoding the coactivator proteins steroid receptor coactivator (SRC)-1 and SRC-3, and the transcription factor GATA-3, all of which contribute to estrogenic signaling and a Luminal-A phenotype. Overexpression of miR-206 repressed estrogen-mediated responses in MCF-7 cells, even in the presence of ERalpha encoded by an mRNA lacking a 3'-untranslated region, suggesting miR-206 affects estrogen signaling by targeting mRNAs encoding ERalpha-associated coregulatory proteins. Furthermore, EGF treatments enhanced miR-206 levels in MCF-7 cells and ERalpha-negative, EGFR-positive MDA-MB-231 cells, whereas EGFR small interfering RNA, or PD153035, an EGFR inhibitor, or U0126, a MAPK kinase inhibitor, significantly reduced miR-206 levels in MDA-MB-231 cells. Blocking EGF-induced enhancement of miR-206 with antagomiR-206 abrogated the EGF-inhibitory effect on ERalpha, SRC-1, and SRC-3 levels, and on estrogen response element-luciferase activity, indicating that EGFR signaling represses estrogenic responses in MCF-7 cells by enhancing miR-206 activity. Elevated miR-206 levels in MCF-7 cells ultimately resulted in reduced cell proliferation, enhanced apoptosis, and reduced expression of multiple estrogen-responsive genes. In conclusion, miR-206 contributes to EGFR-mediated abrogation of estrogenic responses in MCF-7 cells, contributes to a Luminal-A- to Basal-like phenotypic switch, and may be a measure of EGFR response within Basal-like breast tumors.
Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030-3505, USA.
Brian D
BD
Adams
Danielle M
DM
Cowee
Bruce A
BA
White
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D008954:Models, Biological; D008957:Models, Genetic; D016366:Open Reading Frames; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D014343:Trypan Blue / Q000494:pharmacology
D047628:Estrogen Receptor alpha; C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D004815:Epidermal Growth Factor; D014343:Trypan Blue