Abstract 4284: Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by v-Src.

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Abstract The signal transducer and activator of transcription-3 (Stat3) is an important signal transducer with a role in cancer etiology. Following activation of a number of growth factor or cytokine receptors or expression of oncogenes such as vSrc, Stat3 is phosphorylated at tyr705, dimerizes and migrates to the nucleus where it activates transcription from a number of genes involved in cell division and survival. We recently discovered a novel pathway of activation of Stat3: Engagement of cadherin-11 (cad11), a cell to cell adhesion protein, known to be involved in metastasis, induces a dramatic increase in the levels of the Rac and Cdc42 small GTPases, and this leads to Stat3 activation. Stat3 in turn, downregulates the p53 antioncogene and upregulates anti-apoptotic genes, thus offering a potent survival signal. A large number of oncogenes such as vSrc activate the E2F transcription factor family, which induce the expression of genes involved in cell division. However, at the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for anti-apoptotic signals. Since cad11 activates Stat3, a potent survival factor, we examined the effect of downregulation of cad11 upon transformation of mouse Balb/c3T3 fibroblasts by vSrc. Forced expression of high levels of activated Src caused a dramatic reduction in cad11 levels. However, intermediate Src levels, which are physiologically relevant, did allow cad11 expression, albeit at lower levels. Cad11 knockdown in these cells through shRNA expression with a retroviral vector caused a dramatic reduction in Stat3 activity and induced apoptosis. That is, the residual amounts of cad11 present are sufficient to activate Stat3 and prevent apoptosis induced by the Src/E2F axis. Taken together, these findings indicate that cad11, despite its presumed structural role, and in addition to its known role in promoting metastasis, is actually also necessary for full neoplastic transformation by the Src oncogene. Citation Format: Stephanie Guy, Mulu Geletu, Rozanne Arulanandam, Leda Raptis. Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by v-Src. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4284. doi:10.1158/1538-7445.AM2013-4284