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

Pedro de Souza Rocha Simonini, Achim Breiling, Nibedita Gupta, Mahdi Malekpour, Mahmoud Youns, Ramesh Omranipour, Fatemeh Malekpour, Stefano Volinia, Carlo M Croce, Hossein Najmabadi, Sven Diederichs, Ozgür Sahin, Doris Mayer, Frank Lyko, Jörg D Hoheisel, Yasser Riazalhosseini
Cancer Research 2010 November 15, 70 (22): 9175-84
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.

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