Do microRNAs Mediate Estrogen-Dependent Repression of Genes

Estrogen receptor alpha (ERa) mediates transcriptional effects of estrogen. Estrogen inducible proteins c-Myc and E2F family are required for optimal ERa activity and secondary estrogen response, respectively. The purpose of this study was to investigate whether estrogen regulates its target gene expression through microRNAs. We show that estrogen induces 21 and represses 7 microRNAs, which potentially control 420 estrogen-regulated and 757 non-estrogen regulated mRNAs at post-transcriptional level. Estrogen induced the expression of eight Let-7 family microRNAs, miR-98 and miR-21, which by reducing c-Myc and E2F2 proteins level, may attenuate estrogen response. Consistent with the role of Let-7 in differentiation of cancer stem cells, estrogen reduced ALDH1-positive breast cancer stem subpopulation of MCF-7 cells. The protein kinase AKT reduced estrogen-inducible expression of Let-7 microRNAs and may disrupt attenuation of estrogen response. Significance: Luminal subtype A breast cancers contain functional ERa, are well differentiated and display favorable prognosis. Estrogen:ERa-mediated differentiation pathway in these cancers is yet to be elucidated. We propose that estrogen-regulated Let-7 family microRNAs contribute to differentiated phenotype of ERa-positive breast cancers. The phenotype and the clinical course of ERa-positive breast cancers, particularly response to anti-estrogen therapy, may be dependent on the balance between estrogen-induced tumor suppressor (let-7 family) and oncogenic (miR-21) microRNAs. Our studies also reveal a negative regulatory loop controlling estrogen response through microRNAs and highlights differences in estrogen-induced transcriptome and proteome.