title: WBP2 modulates G1/S transition in ER+ breast cancer cells and is a direct target of miR-206.
abstract: OBJECTIVE
  The mechanisms underlying the oncogenic properties of WW domain binding protein 2 (WBP2) in breast cancer have not been fully understood. In this study, we explored the role of WBP2 in cell cycle regulation in ER+ breast cancer cells and how it is regulated in the cancer cells.
  
  
  METHODS
  The association between WBP2 expression and prognosis in ER+ breast cancer was assessed by data mining in Breast Cancer Gene-Expression Miner v4.0. Cell cycle was assessed by PI staining and flow cytometry. EdU staining was applied to visualize cells in S phase. The binding between miR-206 and WBP2 were verified by dual luciferase assay. CCK-8 assay and flow cytometric analysis were applied to assess the functional role of WBP2 and miR-206 in the cancer cells.
  
  
  RESULTS
  High WBP2 expression correlates with higher risk of any events (AE) and metastatic relapse (MR) and also indicates shorter AE-free survival and MR-free survival in ER+ breast cancer patients. In both MCF-7 and BT474 cells, WBP can influence the expression of G1/S-related cell cycle proteins, including p21, CDK4, and cyclin D1. In addition, WBP2 overexpression resulted in facilitated G1/S transition, while WBP2 knockdown impaired the transition. The 3'UTR of WBP2 has a conserved miR-206 binding site. Functionally, miR-206 knockdown decreased tamoxifen sensitivity in tamoxifen-sensitive (TamS) MCF-7 cells, while miR-206 overexpression and WBP2 knockdown enhanced the sensitivity in tamoxifen-resistant (TamR) MCF-7 cells.
  
  
  CONCLUSIONS
  Based on these findings, we infer that the miR-206/WBP2 axis can modulate tamoxifen sensitivity via regulating G1/S progression in ER+ breast cancer.
authors.affiliation: Clinical Laboratory, Linyi Central Hospital, Linyi, 276400, Shandong, China.
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Ren
authors.affiliation: Department of Breast and Thyroid Surgery, People's Hospital of Rizhao, Rizhao, 276800, Shandong, China.
authors.forename: Hui-Jun
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Breast Surgery, Weifang People's Hospital, Weifang, 261041, Shandong, China.
authors.forename: Yong-Qing
authors.initials: YQ
authors.lastname: Zhang
authors.affiliation: Breast Center, Shandong Cancer Hospital and Institute, Jinan, 250017, Shandong, China. yqz80@outlook.com.
authors.forename: Yan-Bing
authors.initials: YB
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D016193:G1 Phase / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics*; D016196:S Phase / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology; D015534:Trans-Activators
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; D018797:Cell Cycle Proteins; C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D011960:Receptors, Estrogen; D015534:Trans-Activators; C106908:WBP2 protein, human; D013629:Tamoxifen
keywords: Breast cancer; ER+; G1/S; MiR-206; WBP2