Recovery of Anoikis in Src-Transformed Cells and Human Breast Carcinoma Cells by Restoration of the SIRPα1/SHP-2 Signaling System

Src kinase dysregulation contributes to cancer progression but mechanistic understanding for this contribution remains incomplete. Signal regulatory protein alpha 1 (SIRP alpha 1) is a tumor suppressor that is constitutively suppressed in v-Src-transformed cells, where restoration of SIRP alpha 1 expression inhibits anchorage-independent growth. In this study, we investigated the role of the protein tyrosine phosphatase-2 (SHP-2) in SIRP alpha 1 activity. SHP-2 suppression resulted in a blockade of SIRP alpha 1-mediated inhibition of anchorage-independent growth. Notably, we found that SIRP alpha 1 did not act in v-Src-transformed cells by triggering cell growth arrest but by eliciting a suspension-selective apoptosis (anoikis), and that SHP-2 was required for this effect. Furthermore, we found that SHP-2 was crucial for recovery of stress fiber and focal contact formation by SIRP alpha 1 in v-Src-transformed cells. Finally, we found that SIRP alpha 1/SHP-2 signaling regulates anoikis in human breast carcinoma cells with activated c-Src. Taken together, our findings define SHP-2 as an essential component of tumor suppression and anoikis mediated by SIRP alpha 1 in human breast carcinoma cells as well as in v-Src-transformed cells. Cancer Res; 71(4); 1229-34. (c) 2011 AACR.