Abstract 2014: SHP2 stabilizes EGFR and beta-catenin to promote the transformation and tumorigenic potential of basal-like and triple-negative breast cancer cells

Abstract

Abstract Basal-like and triple-negative breast cancer (BTBC) causes disproportionately high mortalities in women. One of the major reasons is lack of targeted therapy, and the other is the highly aggressive and metastatic nature of the disease. The primary complication in finding viable drug targets has been the dysregulation of multiple signaling pathways, making one pathway inhibition an unlikely strategy to lead to effective treatment for BTBC. Therefore, targeting multiple pathways or finding proteins that control multiple signaling pathways and targeting them remain to be the only hope. In line with this, we have discovered that the Src homology phosphotyrosyl phosphatase 2 (SHP2) controls EGFR and Wnt/β-catenin signaling, major pathways known to be dysregulated in BTBC. We show that SHP2 overexpression in BTBC tumors is associated with elevated EGFR expression and cytoplasmic and nuclear accumulation of β-catenin. Silencing SHP2 expression in BTBC cells destabilizes EGFR and β-catenin and inhibits respective downstream signaling, confirming that SHP2 overexpression is essential for dysregulation of EGFR and β-catenin in this subtype of breast cancer. Furthermore, we demonstrate that inhibition of SHP2 in BTBC cells induces luminal epithelial morphology, suppresses cell proliferation, reverses transformation, blocks invasiveness in 3D matrigel, and abolishes tumorigenesis and metastasis. These findings suggest that SHP2 controls the EGFR and the Wnt/β-catenin signaling pathways to promote BTBC. Citation Format: Hua Zhao, Yehenew M. Agazie. SHP2 stabilizes EGFR and beta-catenin to promote the transformation and tumorigenic potential of basal-like and triple-negative breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2014. doi:10.1158/1538-7445.AM2014-2014