Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/β-catenin signaling in HER2 overexpressing human breast cancer cells

  • Authors:
    • Ke Wang
    • Qingyong Ma
    • Yu Ren
    • Jianjun He
    • Yong Zhang
    • Yunfeng Zhang
    • Wuke Chen
  • View Affiliations

  • Published online on: January 1, 2007     https://doi.org/10.3892/or.17.1.89
  • Pages: 89-96
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

HER2 (also known as ErbB2) is a transmembrane tyrosine kinase whose surface overexpression is linked to tumorigenesis and poor prognosis in breast cancer patients. β-catenin is a substrate of this kinase, and HER2-dependent phosphorylation of tyrosine 654 leads to dissociation of the E-cadherin-β-catenin membrane complex and increased Wnt signaling. β-catenin-mediated Wnt signaling promotes proliferation and invasion of breast cancer cells. In this study, we show that HER2 binds to β-catenin and that geldanamycin (GA), a drug that destabilizes HER2 protein, causes rapid depletion of HER2, thereby disrupting its association with β-catenin in SKBr3 human breast cancer cells. Interestingly, GA did not affect the stability of β-catenin protein, but altered its subcellular localization, driving it out of the nucleus and increasing its association with E-cadherin. Importantly, the change in subcellular localization of β-catenin was also associated with a significant decrease in proliferation and motility of GA-treated breast cancer cells. Moreover, GA treatment led to reduced expression of the Wnt signaling target and cell cycle-promoting gene cyclin D1, providing a potential mechanism for the reduced proliferation. In conclusion, GA treatment suppressed tumorigenicity in the human breast cancer cell line SKBr3, at least in part through destabilization of the HER2 oncoprotein and repression of the Wnt/β-catenin signaling pathway. These findings provide evidence for the clinical importance of GA in treatment of HER2 overexpressing breast cancers.

Related Articles

Journal Cover

January 2007
Volume 17 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wang K, Ma Q, Ren Y, He J, Zhang Y, Zhang Y and Chen W: Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/β-catenin signaling in HER2 overexpressing human breast cancer cells. Oncol Rep 17: 89-96, 2007
APA
Wang, K., Ma, Q., Ren, Y., He, J., Zhang, Y., Zhang, Y., & Chen, W. (2007). Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/β-catenin signaling in HER2 overexpressing human breast cancer cells. Oncology Reports, 17, 89-96. https://doi.org/10.3892/or.17.1.89
MLA
Wang, K., Ma, Q., Ren, Y., He, J., Zhang, Y., Zhang, Y., Chen, W."Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/β-catenin signaling in HER2 overexpressing human breast cancer cells". Oncology Reports 17.1 (2007): 89-96.
Chicago
Wang, K., Ma, Q., Ren, Y., He, J., Zhang, Y., Zhang, Y., Chen, W."Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/β-catenin signaling in HER2 overexpressing human breast cancer cells". Oncology Reports 17, no. 1 (2007): 89-96. https://doi.org/10.3892/or.17.1.89