Article

The Role of miR-206 in the Epidermal Growth Factor (EGF) Induced Repression of Estrogen Receptor-alpha (ER alpha) Signaling and a Luminal Phenotype in MCF-7 Breast Cancer Cells

Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030-3505, USA.
Molecular Endocrinology (Impact Factor: 4.2). 06/2009; 23(8):1215-30. DOI: 10.1210/me.2009-0062
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
142 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hormones are key drivers of cancer development. To date, interest has largely focussed on the classical model of hormonal gene regulation but there is increasing evidence for a role of hormone signalling pathways in post-translational regulation of gene expression. In particular, a complex and dynamic network of bi-directional interactions with microRNAs at all stages of biogenesis and during target gene repression is emerging. MicroRNAs, which act mainly by negatively regulating gene expression through association with 3' untranslated regions of mRNA species, are increasingly understood to be important in development, normal physiology and pathogenesis. Given recent demonstrations of altered microRNA profiles in a diverse range of cancers, their ability to function as oncogenes or tumour suppressors, and hormonal regulation of microRNAs, understanding mechanisms by which microRNAs are generated and regulated is vitally important. MicroRNAs are transcribed by RNA polymerase II then processed in the nucleus by the Drosha-containing Microprocessor complex and in the cytoplasm by Dicer, before mature microRNAs are incorporated into the RNA-induced silencing complex. It is increasingly evident that multiple cellular signalling pathways converge upon the miR biogenesis cascade, adding further layers of regulatory complexity to modulate miR maturation. This review summarises recent advances in identification of novel components and regulators of the Microprocessor and Dicer complexes, with particular emphasis on the role of hormone signalling pathways in regulating their activity. Understanding hormone regulation of microRNA production and how this is perturbed in cancer is critical for the development of microRNA-based therapeutics and biomarkers.
    Endocrine Related Cancer 07/2014; 21(5). DOI:10.1530/ERC-14-0208 · 4.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Growing evidence suggests that breast cancer cell plasticity arises due to a partial reactivation of epithelial-mesenchymal transition (EMT) programs in order to give cells pluripotency, leading to a stemness-like phenotype. A complete EMT would be a dead end program that would render cells unable to fully metastasize to distant organs. Evoking the EMT-mesenchymal-to-epithelial transition (MET) cascade promotes successful colonization of distal target tissues. It is unlikely that direct reprogramming or trans-differentiation without passing through a pluripotent stage would be the preferred mechanism during tumor progression. This review focuses on key EMT transcriptional regulators, EMT-transcription factors involved in EMT (TFs) and the miRNA pathway, which are deregulated in breast cancer, and discusses their implications in cancer cell plasticity. Cross-regulation between EMT-TFs and miRNAs, where miRNAs act as co-repressors or co-activators, appears to be a pivotal mechanism for breast cancer cells to acquire a stem cell-like state, which is implicated both in breast metastases and tumor recurrence. As a master regulator of miRNA biogenesis, the ribonuclease type III endonuclease Dicer plays a central role in EMT-TFs/miRNAs regulating networks. All these EMT-MET key regulators represent valuable new prognostic and predictive markers for breast cancer as well as promising new targets for drug-resistant breast cancers.
  • Source

Full-text

Download
43 Downloads
Available from
Jun 18, 2014