Abstract 1091: ShcA-mediated ERK signaling contributes to the tumor-promoting activity of TGF-beta in the presence of mutant p53

Abstract

Abstract Transforming growth factor-beta (TGF-β) signaling has been shown to inhibit tumorigenesis at the early stage and promote metastasis at the late stage. However, biomarkers for identifying the complicated molecular alterations mediating the switch of TGF-β from a tumor suppressor to a tumor promoter still remain obscure. Published studies have shown that the presence of mutated tumor p53 can switch TGF-β to becoming tumor-promoting. However, we found that in the p53-null PC-3 prostate cancer cell line, the ectopic expression of the mutant p53 R175H (mp53) enhanced the Smad-dependent signaling, but inhibited TGF-β-induced cell migration by downregulating the active ERK. Since TGF-β is known to activate MAPK/ERK pathway to induce cell migration, EMT and survival through direct phosphorylation of adaptor protein ShcA isoform p52, we investigated how the expression of the mp53 inhibited ERK activation. We found that the expression of mp53 led to downregulation of phospho-p52ShcA and upregulation of ERK antagonist p66ShcA isoform. Interestingly, we found partial depletion of p52ShcA by using siRNA enhanced the TGF-β/Smad signaling and inhibited the TGF-β/ERK signaling in PC-3 cells and spontaneously immortalized and non-tumorigenic human mammary epithelial MCF-10A cell line, suggesting ShcA may act as an additional switcher of the TGF-β. Furthermore, reactivation of ERK by the expression of its activator, MEK1, restored active ERK level and TGF-β-induced cell migration in PC-3/mp53 cell. Those findings show that mp53 expression alone is not sufficient to promote the malignant phenotype of TGF-β in certain cells and the cooperation of mp53 and ShcA-mediated ERK signaling may switch TGF-β to be a tumor promoter. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1091. doi:10.1158/1538-7445.AM2011-1091