Prolactin receptor-integrin cross-talk mediated by SIRPα in breast cancer cells.
Prolactin receptor-integrin cross-talk mediated by SIRPα in breast cancer cells.
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DOI：
10.1158/1541-7786.mcr-10-0130
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Clevenger CV
中科院分区：
文献类型：
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作者：
Galbaugh T;Feeney YB;Clevenger CV
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-α (SIRPα) and the PRLr, β1 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.
