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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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Main Authors: De Souza Rocha Simonini, Pedro (Author) , Breiling, Achim (Author) , Gupta, Nibedita (Author) , Malekpour, Mahdi (Author) , Youns, Mahmoud (Author) , Omranipour, Ramesh (Author) , Malekpour, Fatemeh (Author) , Volinia, Stefano (Author) , Croce, Carlo M. (Author) , Najmabadi, Hossein (Author) , Diederichs, Sven (Author) , Sahin, Özgür (Author) , Mayer, Doris (Author) , Lyko, Frank (Author) , Hoheisel, Jörg D. (Author) , Riazalhosseini, Yasser (Author)
Format: Article (Journal)
Language:English
Published: November 14 2010
In: Cancer research
Year: 2010, Volume: 70, Issue: 22, Pages: 9175-9184
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-10-1318
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/0008-5472.CAN-10-1318
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Author Notes: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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Summary: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.
Item Description:Gesehen am 01.08.2023
Physical Description:Online Resource
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-10-1318

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