title: MiR-148a and miR-152 reduce tamoxifen resistance in ER+ breast cancer via downregulating ALCAM.
abstract: Activated leukocyte cell adhesion molecule (ALCAM), also called CD166 is a 105-kDa transmembrane glycoprotein of the immunoglobin superfamily. In this study, we studied the association between ALCAM expression and tamoxifen resistance in ER + breast cancer and further investigated how ALCAM is regulated in the cancer cells. IHC staining data showed that the tumor tissues from non-responders (N = 20) generally had significantly stronger ALCAM staining than that from tamoxifen responders (N = 16). In vitro cell assay also confirmed ALCAM upregulation in tamoxifen resistant (TamR) MCF-7 cells than in tamoxifen sensitive (TamS) MCF-7 cells. ALCAM overexpression significantly alleviated 4-Hydroxytestosterone (4-OHT) induced cell viability inhibition and cell apoptosis in TamS MCF-7 cells, while ALCAM knockdown remarkably enhanced 4-OHT induced cell viability inhibition and cell apoptosis in TamR MCF-7 cells. Demethylation reagent treatment significantly restored miR-148a and miR-152 expression in TamR MCF-7 cells. MiR-148a and miR-152 can directly target ALCAM 3'UTR and decrease ALCAM expression. MiR-148a overexpression had similar effect as ALCAM siRNA on enhancing 4-OHT induced cell viability inhibition and cell apoptosis in TamR MCF-7 cells. MiR-152 overexpression alone caused growth inhibition and increased cell apoptosis in TamR MCF-7 cells. It also enhanced the effect of 4-OHT. Simultaneous inhibition of miR-148a and miR-152 significantly protected TamS MCF-7 cells from 4-OHT induced cell viability inhibition and cell apoptosis. Based on these findings, we infer that MiR-148a and miR-152 can sensitize TamR MCF-7 cells to tamoxifen at least via downregulating ALCAM.
authors.affiliation: Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of Sports Management, College of Leisure and Recreation Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Ming-Jenn
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ya-Min
authors.initials: YM
authors.lastname: Cheng
authors.affiliation: Department of Plastic and Reconstruction Surgery, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Gynecology and Obstetrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Gynecology and Obstetrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: chenmed.tw@yahoo.com.tw.
authors.forename: Ching-Ju
authors.initials: CJ
authors.lastname: Shen
mesh_terms: D020413:3' Untranslated Regions; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005326:Fetal Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D020413:3' Untranslated Regions; D015703:Antigens, CD; D018931:Antineoplastic Agents, Hormonal; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D035683:MicroRNAs; D011960:Receptors, Estrogen; D013629:Tamoxifen; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C550570:MIRN148 microRNA, human; C550856:MIRN152 microRNA, human
keywords: ALCAM; Breast cancer; MiR-148a; Tamoxifen; miR-152