WBP2 modulates G1/S transition in ER+ breast cancer cells and is a direct target of miR-206

Cancer Chemother Pharmacol. 2017 May;79(5):1003-1011. doi: 10.1007/s00280-017-3302-0. Epub 2017 Apr 8.


Purpose: 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.

Conclusion: 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.

Keywords: Breast cancer; ER+; G1/S; MiR-206; WBP2.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adaptor Proteins, Signal Transducing / genetics*
  • Antineoplastic Agents, Hormonal / pharmacology
  • Binding Sites
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • G1 Phase / genetics*
  • Gene Knockdown Techniques
  • Humans
  • MCF-7 Cells
  • MicroRNAs / genetics*
  • Prognosis
  • Receptors, Estrogen / genetics*
  • S Phase / genetics*
  • Sincalide / drug effects
  • Tamoxifen / pharmacology
  • Trans-Activators


  • 3' Untranslated Regions
  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Hormonal
  • Cell Cycle Proteins
  • MIRN206 microRNA, human
  • MicroRNAs
  • Receptors, Estrogen
  • Trans-Activators
  • WBP2 protein, human
  • Tamoxifen
  • Sincalide