Data from Activation of NF-κB by TMPRSS2/ERG Fusion Isoforms through Toll-Like Receptor-4

Abstract

<div>Abstract<p>The <i>TMPRSS2</i>/<i>ERG</i> (<i>T</i>/<i>E</i>) fusion gene is present and thought to be an oncogenic driver of approximately half of all prostate cancers. Fusion of the androgen-regulated TMPRSS2 promoter to the <i>ERG</i> oncogene results in constitutive high level expression of ERG which promotes prostate cancer invasion and proliferation. Here, we report the characterization of multiple alternatively spliced <i>T</i>/<i>E</i> fusion gene isoforms which have differential effects on invasion and proliferation. We found that <i>T</i>/<i>E</i> fusion gene isoforms differentially increase NF-κB–mediated transcription, which may explain in part the differences in biological activities of the T/E fusion isoforms. This increased activity is due to phosphorylation of NF-κB p65 on Ser536. Tissue microarray immunochemistry revealed that p65 phospho-Ser536 is present in the majority of prostate cancers where it is associated with ERG protein expression. The <i>T</i>/<i>E</i> fusion gene isoforms differentially increase expression of a number of NF-κB associated genes including PAR1, CCL2, FOS, TLR3, and TLR4 (Toll-like receptor). TLR4 activation is known to promote p65 Ser536 phosphorylation and knockdown of TLR4 with shRNA decreases Ser536 phosphorylation in <i>T</i>/<i>E</i> fusion gene expressing cells. TLR4 can be activated by proteins in the tumor microenvironment and lipopolysacharide from Gram (−) bacteria. Our findings suggest that bacterial infection of the prostate and/or endogenous microenvironment proteins may promote progression of high-grade prostatic intraepithelial neoplasia and/or prostate cancers that express the <i>T</i>/<i>E</i> fusion gene, where the NF-κB pathway might be targeted as a rational therapeutic approach. <i>Cancer Res; 71(4); 1325–33. ©2010 AACR</i>.</p></div>