HER2 (also known as ErbB2) is a transmembrane
tyrosine kinase whose surface overexpression is linked to
tumorigenesis and poor prognosis in
breast cancer patients.
beta-catenin is a substrate of this
kinase, and HER2-dependent phosphorylation of
tyrosine 654 leads to dissociation of the
E-cadherin-
beta-catenin membrane complex and increased Wnt signaling.
beta-catenin-mediated Wnt signaling promotes proliferation and invasion of
breast cancer cells. In this study, we show that HER2 binds to
beta-catenin and that
geldanamycin (GA), a drug that destabilizes HER2
protein, causes rapid depletion of HER2, thereby disrupting its association with
beta-catenin in SKBr3 human
breast cancer cells. Interestingly, GA did not affect the stability of
beta-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
beta-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/beta-catenin signaling pathway. These findings provide evidence for the clinical importance of GA in treatment of HER2 overexpressing breast
cancers.