title: Functional role of miR-10b in tamoxifen resistance of ER-positive breast cancer cells through down-regulation of HDAC4.
abstract: BACKGROUND
  For 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  Over-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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, Detroit, MI, 48201, USA. ahmada@karmanos.org.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, Detroit, MI, 48201, USA. ginneba3@gmail.com.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Ginnebaugh
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, Detroit, MI, 48201, USA. syin@med.wayne.edu.
authors.forename: Shuping
authors.initials: S
authors.lastname: Yin
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, Detroit, MI, 48201, USA. bollig@karmanos.org.
authors.forename: Aliccia
authors.initials: A
authors.lastname: Bollig-Fischer
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, Detroit, MI, 48201, USA. kreddy@med.wayne.edu.
authors.forename: Kaladhar B
authors.initials: KB
authors.lastname: Reddy
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, Detroit, MI, 48201, USA. fsarkar@med.wayne.edu.|Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC Bldg, 4100 John R. Street, Detroit, MI, 48201, USA. fsarkar@med.wayne.edu.
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D020413:3' Untranslated Regions; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D020413:3' Untranslated Regions; D018931:Antineoplastic Agents, Hormonal; C547183:MIRN10 microRNA, human; D035683:MicroRNAs; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D013629:Tamoxifen; C400300:HDAC4 protein, human; D006655:Histone Deacetylases