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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cancer+Res 2016 ; 76 (11): 3376-86 Nephropedia Template TP
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Ly6E/K signaling to TGF-? promotes breast cancer progression, immune escape and drug resistance #MMPMID27197181
Cancer Res 2016[Jun]; 76 (11): 3376-86 PMID27197181show ga
Stem cell antigen Sca-1 is implicated in murine cancer stem cell biology and breast cancer models, but the role of its human homologues Ly6K and Ly6E in breast cancer are not established. Here we report increased expression of Ly6K/E in human breast cancer specimens correlates with poor overall survival, with an additional specific role for Ly6E in poor therapeutic outcomes. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells and decreased natural killer (NK) cell activation. Mechanistically, Ly6K/E were required for TGF-? signaling and proliferation in breast cancer cells where they contributed to phosphorylation of Smad1/5 and Smad2/3. Further, Ly6K/E promoted cytokine-induced PDL1 expression and activation and binding of NK cells to cancer cells. Lastly, we found that Ly6K/E promoted drug resistance and facilitate immune escape in this setting. Overall, our results establish a pivotal role for a Ly6K/E signaling axis involving TGF-? in breast cancer pathophysiology and drug response, and highlight this signaling axis as a compelling realm for therapeutic invention.