SHP2 potentiates the oncogenic activity of b-catenin to promote triple-negative breast cancer

Abstract

Previous studies have reported dysregulated cytoplasmic and nuclear expression of the b-catenin protein in triple-negative breast cancer (TNBC) in the absence of Wnt signaling pathway dysregulation. However, the mechanism that sustains b-catenin protein dysregulation independent of Wnt signaling is not understood. In this study, we show that Src homology phosphotyrosyl phosphatase 2 (SHP2) is essential for b-catenin protein stability and for sustaining the cytoplasmic and nuclear pools in TNBC cells. The first evidence for this possibility came from immunofluorescence (IF) and immunoblotting (IB) studies that showed that inhibition of SHP2 induces E-cadherin expression and depletion of cytoplasmic and nuclear b-catenin, which in turn confers adherence junction mediated cell–cell adhesion. We further show that SHP2 promotes b-catenin protein stability by mediating the inactivation of GSK3b through its positive effect on Akt and ERK1/2 activation, which was confirmed by direct pharmacologic inhibition of the PI3K-Akt and the MEK-ERK signaling pathway. Finally, we show that SHP2-stabilized b-catenin contributes to TNBC cell growth, transformation, cancer stem cell (CSC) properties, and tumorigenesis and metastasis. Overall, the findings in this report show that SHP2 mediates b-catenin protein stability to promote TNBC. Implications: Data presented in this article demonstrates that SHP2 positively regulates b-catenin protein stability, which in turn promotes triple-negative breast cancer (TNBC) cell transformation, tumorigenesis, and metastasis.