Epigenetically deregulated microRNA-375 is involved in a positive feedback loop with estrogen receptor alpha in breast cancer cells
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 pr...
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| Hauptverfasser: | , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
November 14 2010
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| In: |
Cancer research
Year: 2010, Jahrgang: 70, Heft: 22, Pages: 9175-9184 |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-10-1318 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/0008-5472.CAN-10-1318
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| Verfasserangaben: | 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, and Yasser Riazalhosseini |
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| 520 | |a 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. Cancer Res; 70(22); 9175-84. ©2010 AACR. | ||
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