Abstract 2054: In pancreatic cancer, MUC1 regulates function of TGF-β and thus enhances metastasis

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background Pancreatic Cancer (PC) is the 4th leading cause of cancer-related deaths in the United States with 94% of PC patients dying within 5 years of diagnosis. Pancreatic Ductal Adenocarcinoma (PDA) characterizes 90% of PC. Over 80% of PDA overexpresses tumor associated Mucin-1 (MUC1), a membrane bound glycoprotein that is hypoglycosylated compared to normally expressed MUC1. Overexpression of MUC1 is associated with increased metastasis and poor prognosis. However the mechanism remains elusive. Transforming growth factor-β (TGF-β) is similarly overexpressed in most PDA. TGF-β is a cytokine with dual functionality. In normal cells, TGF-β functions as a tumor suppressor and induces apoptosis. This effect is mediated by activation of the canonical Smad pathway via engagement of TGF-β Receptor 1 (TGF-βRI). However, during cancer development, TGF-β becomes a tumor promoter and stimulates epithelial to mesenchymal transition, migration, and invasion of tumor cells thus enhancing metastasis. This effect of TGF-β is mediated by activation of the noncanonical Erk1/2 pathway through the engagement of TGF-β Receptor 2 (TGF-βRII). Therefore, we hypothesize that overexpression of MUC1 in PDA transforms the function of TGF-β from a tumor suppressor to a tumor promoter. Further, we postulate that signaling through the MUC1 cytoplasmic tail (CT) is necessary to activate the noncanonical Erk1/2 pathway via phosphorylation of the TGF-βRII, thus leading to enhanced metastasis. Methods We first assessed the ability of TGF-β to induce apoptosis versus invasiveness in PDA cell lines that express variable levels of MUC1 with gain of function (forced expression) and loss of function (knock down using specific MUC1 siRNA) studies. We determined the levels of TGF-βRI, RII, MUC1, and Smad 4 proteins in these PDA cell lines. We evaluated the activation status of the Erk1/2 and Smad pathways. Since c-Src is known to phosphorylate the 6th tyrosine residue of MUC1 CT and is essential for oncogenic signaling, we determined if c-Src is associated with MUC1 and is phosphorylated upon treatment with exogenous TGF-β in PDA cells. Results In MUC1-high expressing PDA cells, TGF-β acts as a tumor promoter while in MUC1-low expressing PDA cells, TGF-β induces apoptosis and acts as a tumor suppressor. We show a clear association between the expression of MUC1 and TGF-βRI and RII activation. In MUC1-high expressing cells, TGF-βRII is over expressed while in MUC1-low expressing cells, TGF-βRI is over expressed and this correlates with the activation status of Erk1/2 and Smad 4. Finally, we show that MUC1 specifically associates with c-Src and without this association, downstream oncogenic signaling is impeded. Conclusion MUC1 expression is directly correlated with TGF-β function and expression of TGF-βRII, while being negatively correlated with TGF-βRI expression. This has high clinical significance for patients with PDA. Citation Format: Priyanka Grover, Sritama Nath, Mohammad Ahmad, Pinku Mukherjee. In pancreatic cancer, MUC1 regulates function of TGF-β and thus enhances metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2054. doi:10.1158/1538-7445.AM2015-2054