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 cross-talk is mediated. Following PRL stimulation, we show that a complex between the transmembrane glycoprotein signal regulatory protein-α (SIRPα) and the PRLr, β(1) integrin, and Jak2 in estrogen receptor-positive (ER(+)) and ER(-) breast cancer cells is formed. Overexpression of SIRPα 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 SIRPα 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 SIRPα (SIRPα-4YF) prevented the signaling and phenotypic effects mediated by wild-type SIRPα. Furthermore, overexpression of a phosphatase-defective mutant of Shp-2 or pharmacologic inhibition of Shp-2 produced effects comparable with that of SIRPα-4YF. However, the tyrosine phosphorylation of SIRPα was unaffected in the presence or absence of collagen 1. These data suggest that SIRPα modulates PRLr-associated signaling as a function of integrin occupancy predominantly through the alteration of Shp-2 activity. This PRLr-SIRPα-integrin complex may therefore provide a basis for integrin-PRLr cross-talk and contribute to the biology of breast cancer.
Galbaugh
Traci
T
Department of Pathology, Northwestern University,Chicago, Illinois 60611, USA. t-galbaugh@northwestern.edu.
Feeney
Yvonne B
YB
Clevenger
Charles V
CV
D000943:Antigens, Differentiation / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D020239:Receptor Cross-Talk / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D011981:Receptors, Prolactin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D000943:Antigens, Differentiation; D019012:Integrin beta1; D011971:Receptors, Immunologic; D011981:Receptors, Prolactin; C501920:SIRPA protein, human
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