Prolactin Receptor-Integrin Cross-Talk Mediated by SIRPα in Breast Cancer Cells

The hormone prolactin (PRL) contributes to the pathogenesis of breast cancer in part through its activation of Janus-activated kinase 2 (Jak2)/signal transducer and activator of transcription 5 (Stat5), a PRL receptor (PRLr)-associated pathway dependent on cross-talk signaling from integrins. It remains unclear, however, how this crosstalk is mediated. Following PRL stimulation, we show that a complex between the transmembrane glycoprotein signal regulatory protein-alpha (SIRP alpha) and the PRLr, beta(1) integrin, and Jak2 in estrogen receptor-positive (ER+) and ER-breast cancer cells is formed. Overexpression of SIRP alpha in the absence of collagen 1 significantly decreased PRL-induced gene expression, phosphorylation of PRLr-associated signaling proteins, and PRL-stimulated proliferation and soft agar colony formation. In contrast, overexpression of SIRP alpha in the presence of collagen 1 increased PRL-induced gene expression; phosphorylation of Jak2, Stat5, and Erk; and PRL-stimulated cell growth. Interestingly, overexpression of a tyrosine-deficient SIRP alpha (SIRP alpha-4YF) prevented the signaling and phenotypic effects mediated by wild-type SIRP alpha. Furthermore, overexpression of a phosphatase-defective mutant of Shp-2 or pharmacologic inhibition of Shp-2 produced effects comparable with that of SIRP alpha-4YF. However, the tyrosine phosphorylation of SIRP alpha was unaffected in the presence or absence of collagen 1. These data suggest that SIRP alpha modulates PRLr-associated signaling as a function of integrin occupancy predominantly through the alteration of Shp-2 activity. This PRLr-SIRP alpha-integrin complex may therefore provide a basis for integrin-PRLr cross-talk and contribute to the biology of breast cancer. Mol Cancer Res; 8(10); 1413-24. (C) 2010 AACR.