title: Inhibition of β-Catenin to Overcome Endocrine Resistance in Tamoxifen-Resistant Breast Cancer Cell Line.
abstract: The β-catenin signaling is important in cell growth and differentiation and is frequently dysregulated in various cancers. The most well-known mechanism of endocrine resistance is cross-talk between the estrogen receptor (ER) and other growth factor signaling, such as phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway. In the present study, we investigated whether β-catenin could be a potential target to overcome endocrine resistance in breast cancer.
  
  
  
  We established tamoxifen-resistant (TamR) cell line via long-term exposure of MCF-7 breast cancer cells to gradually increasing concentrations of tamoxifen. The levels of protein expression and mRNA transcripts were determined using western blot analysis and real-time quantitative PCR. The transcriptional activity of β-catenin was measured using luciferase activity assay.
  
  
  
  TamR cells showed a mesenchymal phenotype, and exhibited a relatively decreased expression of ER and increased expression of human epidermal growth factor receptor 2 and the epidermal growth factor receptor. We confirmed that the expression and transcriptional activity of β-catenin were increased in TamR cells compared with control cells. The expression and transcriptional activity of β-catenin were inhibited by β-catenin small-molecule inhibitor, ICG-001 or β-catenin siRNA. The viability of TamR cells, which showed no change after treatment with tamoxifen, was reduced by ICG-001 or β-catenin siRNA. The combination of ICG-001 and mTOR inhibitor, rapamycin, yielded an additive effect on the inhibition of viability in TamR cells.
  
  
  
  These results suggest that β-catenin plays a role in tamoxifen-resistant breast cancer, and the inhibition of β-catenin may be a potential target in tamoxifen-resistant breast cancer.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hye Sung
authors.initials: HS
authors.lastname: Won
authors.affiliation: Division of Hematology-Oncology, Departments of Internal Medicine, Ewha Medical Research Center, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Kyung Mee
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Departments of Internal Medicine, Ewha Medical Research Center, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Ju Eon
authors.initials: JE
authors.lastname: Oh
authors.affiliation: Division of Hematology-Oncology, Departments of Internal Medicine, Ewha Medical Research Center, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Nam
authors.affiliation: Division of Hematology-Oncology, Departments of Internal Medicine, Ewha Medical Research Center, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Kyoung Eun
authors.initials: KE
authors.lastname: Lee
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000633:toxicity*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000633:toxicity*; D006801:Humans; D061986:MCF-7 Cells; D011744:Pyrimidinones / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000633:toxicity*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004965:Estrogen Antagonists; C492448:ICG 001; D011744:Pyrimidinones; D011960:Receptors, Estrogen; D051176:beta Catenin; D013629:Tamoxifen