title: Downregulation of miR-221/222 enhances sensitivity of breast cancer cells to tamoxifen through upregulation of TIMP3.
abstract: Aberrantly expressed microRNAs (miRNAs) are involved in breast tumorigenesis. It is still unclear if and how miRNAs-221/222 are implicated in breast cancer and the resistance to estrogen receptor modulator tamoxifen. We investigated the roles and mechanisms of miR-221/222 in breast cancer cells, particularly in modulating response to tamoxifen therapy. MCF-7 and MDA-MB-231 breast cancer cells were transfected with antisense oligonucleotides AS-miR-221 and AS-miR-222 and their expression of miR-221 and miR-222 was assessed. The correlation of miR-221/222 with tissue inhibitor of metalloproteinase-3 (TIMP3) expression was investigated by fluorescence quantitative PCR and western blotting analysis. The therapeutic sensitivity of these cells, transfected and untransfected, to tamoxifen was determined. Transfection of AS-miR-221 and AS-miR-222 dramatically inhibited expression of miR-221 and miR-222, respectively, in both MCF-7 and MDA-MB-231 cells (P<0.05-0.01). Downregulation of miR-221/222 significantly increased the expression of TIMP3 compared with controls (P<0.05-0.01). The viability of estrogen receptor (ER)-positive MCF-7 cells transfected with AS-miR-221 or/and AS-miR-222 was significantly reduced by tamoxifen (P<0.05-0.01). We have demonstrated for the first time that suppression of miRNA-221/222 increases the sensitivity of ER-positive MCF-7 breast cancer cells to tamoxifen. This effect is mediated through upregulation of TIMP3. These findings suggest that upregulation of TIMP3 via inhibition of miRNA-221/222 could be a promising therapeutic approach for breast cancer.
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, China.
authors.forename: R
authors.initials: R
authors.lastname: Gan
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.affiliation: 1] Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, China [2] Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, China [3] Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Laboratory Medicine, The University of Texas MD Anderson Cancer, Houston, TX, USA.
authors.forename: Q H
authors.initials: QH
authors.lastname: Meng
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D013629:Tamoxifen; D019717:Tissue Inhibitor of Metalloproteinase-3; C525709:MIR221, human; C525710:MIR222, human; C088390:TIMP3 protein, human