Cancer esearch cular and Cellular Pathobiology enetically Deregulated microRNA-375 Is Involved in a itive Feedback Loop with Estrogen Receptor α in R ast Cancer Cells

acrjourna ogen receptor α (ERα) upregulation causes abnormal cell proliferation in about two thirds of breast s, yet understanding of the underlying mechanisms remains incomplete. Here, we show that high sion of the microRNA miR-375 in ERα-positive breast cell lines is a key driver of their proliferation. 75 overexpression was caused by loss of epigenetic marks including H3K9me2 and local DNA hypolation, dissociation of the transcriptional repressor CTCF from the miR-375 promoter, and interacof ERα with regulatory regions of miR-375. Inhibiting miR-375 in ERα-positive MCF-7 cells resulted uced ERα activation and cell proliferation. A combination of expression profiling from tumor samnd miRNA target prediction identified RASD1 as a potential miR-375 target. Mechanistic investigarevealed that miR-375 regulates RASD1 by targeting the 3′ untranslated region in RASD1 mRNA. onally, we found that RASD1 negatively regulates ERα expression. Our findings define a forward Additi feedback pathway in control of ERα expression, highlighting new strategies to treat ERα-positive invasive breast tumors. Cancer Res; 70(22); 9175–84. ©2010 AACR.

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