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.

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ligands for the nuclear receptor superfamily control many aspects of biology, including development, reproduction, and homeostasis, through regulation of the transcriptional activity of their cognate receptors. Selective receptor modulators (SRMs) are receptor ligands that exhibit agonistic or antagonistic biocharacter in a cell- and tissue context-dependent manner. The prototypical SRM is tamoxifen, which as a selective estrogen receptor modulator, can activate or inhibit estrogen receptor action. SRM-induced alterations in the conformation of the ligand-binding domains of nuclear receptors influence their abilities to interact with other proteins, such as coactivators and corepressors. It has been postulated, therefore, that the relative balance of coactivator and corepressor expression within a given target cell determines the relative agonist vs. antagonist activity of SRMs. However, recent evidence reveals that the cellular environment also plays a critical role in determining SRM biocharacter. Cellular signaling influences the activity and subcellular localization of coactivators and corepressors as well as nuclear receptors, and this contributes to gene-, cell-, and tissue-specific responses to SRM ligands. Increased understanding of the effect of cellular environment on nuclear receptors and their coregulators has the potential to open the field of SRM discovery and research to many members of the nuclear receptor superfamily.
    Endocrine Reviews 03/2004; 25(1):45-71. · 19.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A variety of coregulator proteins serve as partners for nuclear receptors orchestrating the molecular events required for receptor-dependent transcriptional regulation. Some coregulators directly interact with nuclear receptors and provide a platform for recruitment of other factors that provide distinct biochemical activities that influence transcriptional efficiency. Coregulators can influence chromatin structure and activity via direct modification of histone proteins or by facilitating ATP-dependent chromatin remodeling. They also have the capacity to impact multiple steps in the transcription process including initiation, elongation, and mRNA splicing. Genetic analysis in humans and animal models are revealing the important cell and tissue-type specific actions of nuclear receptor coregulators as well and their role in human physiology and disease.
    Journal of Cellular Biochemistry 05/2008; 104(5):1580-6. · 3.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The p160 steroid receptor coactivator (SRC) gene family contains three homologous members, which serve as transcriptional coactivators for nuclear receptors and certain other transcription factors. These coactivators interact with ligand-bound nuclear receptors to recruit histone acetyltransferases and methyltransferases to specific enhancer/promotor regions, which facilitates chromatin remodeling, assembly of general transcription factors, and transcription of target genes. This minireview summarizes our current knowledge about the molecular structures, molecular mechanisms, temporal and spatial expression patterns, and biological functions of the SRC family. In particular, this article highlights the roles of SRC-1 (NCoA-1), SRC-2 (GRIP1, TIF2, or NCoA-2) and SRC-3 (p/CIP, RAC3, ACTR, AIB1, or TRAM-1) in development, organ function, endocrine regulation, and nuclear receptor function, which are defined by characterization of the genetically manipulated animal models. Furthermore, this article also reviews our current understanding of the role of SRC-3 in breast cancer and discusses possible mechanisms for functional specificity and redundancy among SRC family members.
    Molecular Endocrinology 10/2003; 17(9):1681-92. · 4.20 Impact Factor


Available from
Jun 18, 2014