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Cancer Res. 2010 Nov 15;70(22):9175-84. doi: 10.1158/0008-5472.CAN-10-1318. Epub 2010 Oct 26.

Epigenetically deregulated microRNA-375 is involved in a positive feedback loop with estrogen receptor alpha in breast cancer cells.

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  • 1Division of Functional Genome Analysis, Helmholtz-University-Young Investigator Group Molecular RNA Biology and Cancer, German Cancer Research Center (DKFZ) & Institute of Pathology, University of Heidelberg, Heidelberg, Germany.

Abstract

Estrogen receptor α (ERα) upregulation causes abnormal cell proliferation in about two thirds of breast cancers, yet understanding of the underlying mechanisms remains incomplete. Here, we show that high expression of the microRNA miR-375 in ERα-positive breast cell lines is a key driver of their proliferation. miR-375 overexpression was caused by loss of epigenetic marks including H3K9me2 and local DNA hypomethylation, dissociation of the transcriptional repressor CTCF from the miR-375 promoter, and interactions of ERα with regulatory regions of miR-375. Inhibiting miR-375 in ERα-positive MCF-7 cells resulted in reduced ERα activation and cell proliferation. A combination of expression profiling from tumor samples and miRNA target prediction identified RASD1 as a potential miR-375 target. Mechanistic investigations revealed that miR-375 regulates RASD1 by targeting the 3' untranslated region in RASD1 mRNA. Additionally, we found that RASD1 negatively regulates ERα expression. Our findings define a forward feedback pathway in control of ERα expression, highlighting new strategies to treat ERα-positive invasive breast tumors.

Copyright © 2010 AACR.

PMID:
20978187
[PubMed - indexed for MEDLINE]
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