Epigenetically Deregulated microRNA-375 Is Involved in a Positive Feedback Loop with Estrogen Receptor α in Breast Cancer Cells

Estrogen receptor alpha (ER alpha) 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 ER alpha-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 hypo-methylation, dissociation of the transcriptional repressor CTCF from the miR-375 promoter, and interactions of ER alpha with regulatory regions of miR-375. Inhibiting miR-375 in ER alpha-positive MCF-7 cells resulted in reduced ERa 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 ER alpha expression. Our findings define a forward feedback pathway in control of ER alpha expression, highlighting new strategies to treat ER alpha-positive invasive breast tumors. Cancer Res; 70(22); 9175-84. (C) 2010 AACR.