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: 4.02). 06/2009; 23(8):1215-30. DOI: 10.1210/me.2009-0062
Source: PubMed


Epidermal growth factor (EGF) receptor (EGFR)/MAPK signaling can induce a switch in MCF-7 breast cancer cells, from an estrogen receptor (ER)α-positive, Luminal-A phenotype, to an ERα-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 ERαrepress each other's expression in MCF-7 cells in a double-negative feedback loop.Weshow 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 ERα encoded by an mRNA lacking a 3′-untranslated region, suggesting miR-206 affects estrogen signaling by targeting mRNAs encoding ERα-associated coregulatory proteins. Furthermore, EGF treatments enhanced miR-206 levels in MCF-7 cells and ERα-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 ERα, 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 EGFRmediated abrogation of estrogenic responses in MCF-7 cells, contributes to a Luminal-A- to Basallike phenotypic switch, and may be a measure of EGFR response within Basal-like breast tumors.

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Available from: Brian D Adams, Jun 18, 2014
    • "Ectopic expression of miR-206 in MCF7 cells has been shown to reduce ER level and also the basal expression levels of ER target genes such as PR, cyclin D1, and pS2, resulting in decreased cell proliferation. Furthermore, miR-206 targets two ER coactivator proteins, SRC-1 and SRC-3, and the transcriptional factor GATA-3 that cooperates with ER.[54] miR- 206 continues to suppress estrogenic responses even under the overexpression of ER encoded by mRNA lacking the 3'UTR, confirming the involvement of additional non-ER targets of miR- 206 in the suppression of estrogenic responses. Another well-studied miRNA family that targets ER is miR- 221/222.[55] "
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    ABSTRACT: MicroRNAs are small non-coding RNAs that typically inhibit the translation and stability of messenger RNAs, controlling genes involved in cellular processes such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and migration. Not surprisingly, microRNAs are also aberrantly expressed in cancer and promote tumorigenesis by disrupting these vital cellular functions. In this review, we first broadly summarize the role of microRNAs in breast cancer and Estrogen Receptor alpha signaling. Then we focus on what is currently known about the role of microRNAs in anti-hormonal therapy or resistance to endocrine agents. Specifically, we will discuss key miRNAs involved in tamoxifen (miR-221/222, 181, 101, 519a, 301, 375, 342, 451, and the let-7 family), fulvestrant (miR-221/222, miR-200 family), and aromatase inhibitor (miR-128 and the let-7 family) resistance.
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    • "In contrast to these observations, cancers of the breast and lung have been characterized as exhibiting low miR-206 expression levels, suggesting a possible tumor suppressor function [9,10,12]. Changes in the expression of KLF4 also can be site specific, being upregulated in cancers of the breast, skin, and lung, but attenuated in colon and gastric tumors [14,15,19,31]. The prior investigation of high-abundance miRNAs in rat colon tumors highlighted a role for c-Myc, Oct-3/4, and Sox2 [24], whereas the present work has implicated a fourth ‘defined factor’ for pluripotency, namely KLF4[13]. "
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    • "miR-18a/b was clustered together with miR-17-92 [44,45] according to the similar expression profiles, which were induced by c-myc and reported to promote cell differentiation and proliferation. In pattern 6, such as miR-206 [46] and miR-1 [47], miRNA expressions dramatically increased in the lymph node metastasis. It indicated that these miRNAs may play an important role in the metastasis and may be a special biomarker for the lymph node metastasis. "
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