Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation

Pinho, Filipa G., Frampton, Adam E., Nunes, Joao, Krell, Jonathan, Alshaker, Heba, Jacob, Jimmy, Pellegrino, Loredana, Roca-Alonso, Laura, de Giorgio, Alexander, Harding, Victoria, Waxman, Jonathan, Stebbing, Justin, Pchejetski, Dmitry and Castellano, Leandro (2013) Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation. Cancer Research, 73 (19). pp. 5936-5948. ISSN 0008-5472

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Abstract

Sphingosine kinase 1 (SK1) plays an important role in estrogen-dependent breast tumorigenesis, but its regulation is poorly understood. A subset of microRNAs (miRNA, miR) is regulated by estrogen and contributes to cellular proliferation and cancer progression. Here, we describe that miR-515-5p is transcriptionally repressed by estrogen receptor α (ERα) and functions as a tumor suppressor in breast cancer. Its downregulation enhances cell proliferation and estrogen-dependent SK1 activity, mediated by a reduction of miR-515-5p posttranscriptional repression. Enforced expression of miR-515-5p in breast cancer cells causes a reduction in SK1 activity, reduced cell proliferation, and the induction of caspase-dependent apoptosis. Conversely, opposing effects occur with miR-515-5p inhibition and by SK1 silencing. Notably, we show that estradiol (E2) treatment downregulates miR-515-5p levels, whereas the antiestrogen tamoxifen causes a decrease in SK1, which is rescued by silencing miR-515-5p. Analysis of chromatin immunoprecipitation sequencing (ChIP-Seq) data reveals that miR-515-5p suppression is mediated by a direct interaction of ERα within its promoter. RNA-sequencing (RNA-Seq) analysis of breast cancer cells after overexpressing miR-515-5p indicates that it partly modulates cell proliferation by regulating the Wnt pathway. The clinical implications of this novel regulatory system are shown as miR-515-5p is significantly downregulated in ER-positive (n = 146) compared with ER-negative (n = 98) breast cancers. Overall, we identify a new link between ERα, miR-515-5p, proliferation, and apoptosis in breast cancer tumorigenesis. Cancer Res; 73(19); 5936–48. ©2013 AACR.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 01 Aug 2014 15:14
Last Modified: 26 Jul 2018 10:02
URI: https://ueaeprints.uea.ac.uk/id/eprint/49309
DOI: 10.1158/0008-5472.CAN-13-0158

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