Functional role of miR-10b in tamoxifen resistance of ER-positive breast cancer cells through down-regulation of HDAC4

BMC Cancer

Research Article

Aliccia Bollig-Fischer¹  Aamir Ahmad²  Kaladhar B. Reddy²  Kevin R. Ginnebaugh²  Shuping Yin²  Fazlul H. Sarkar³ 

[1] Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, 48201, Detroit, MI, USA;Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, 48201, Detroit, MI, USA;Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, 48201, Detroit, MI, USA;Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, 48201, Detroit, MI, USA;

关键词: Tamoxifen resistance;    miR-10b;    HDAC4;    ER-positive breast cancers;   

DOI  :  10.1186/s12885-015-1561-x

 received in 2015-01-02, accepted in 2015-07-16,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundFor breast cancer patients diagnosed with estrogen receptor (ER)-positive tumors, treatment with tamoxifen is the gold standard. A significant number of patients, however, develop resistance to tamoxifen, and management of such tamoxifen-resistant patients is a major clinical challenge. With an eye to identify novel targets for the treatment of tamoxifen-resistant tumors, we observed that tamoxifen-resistant cells derived from ER-positive MCF-7 cells (MCF7TR) exhibit an increased expression of microRNA-10b (miR-10b). A role of miR-10b in drug-resistance of breast cancer cells has never been investigated, although its is very well known to influence invasion and metastasis.MethodsTo dileneate a role of miR-10b in tamoxifen-resistance, we over-expressed miR-10b in MCF-7 cells and down-regulated its levels in MCF7TR cells. The mechanistic role of HDAC4 in miR-10b-mediated tamoxifen resistance was studied using HDAC4 cDNA and HDAC4-specific siRNA in appropriate models.ResultsOver-expression of miR-10b in ER-positive MCF-7 and T47D cells led to increased resistance to tamoxifen and an attenuation of tamoxifen-mediated inhibition of migration, whereas down-regulation of miR-10b in MCF7TR cells resulted in increased sensitivity to tamoxifen. Luciferase assays identified HDAC4 as a direct target of miR-10b. In MCF7TR cells, we observed down-regulation of HDAC4 by miR-10b. HDAC4-specific siRNA-mediated inactivation of HDAC4 in MCF-7 cells led to acquisition of tamoxifen resistance, and, moreover, reduction of HDAC4 in MCF7TR cells by HDAC4-specific siRNA transfection resulted in further enhancement of tamoxifen-resistance.ConclusionsWe propose miR-10b-HDAC4 nexus as one of the molecular mechanism of tamoxifen resistance which can potentially be expolited as a novel targeted therapeutic approach for the clinical management of tamoxifen-resistant breast cancers.

【 授权许可】

Unknown   
© Ahmad et al. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.