Abstract 1337: MUC1 facilitates BPDE-induced EGFR activation and malignant transformation in human bronchial epithelial cells

Abstract

Abstract Inflammation has emerged as an important factor for the development of lung cancer. However, the gene targets and pathways that are involved in inflammation-associated lung cancer development have not been clearly elucidated. Cigarette smoke (CS), which causes chronic pulmonary inflammation, is an established risk factor for lung cancer. MUC1 (MUC in human and Muc in animals), a mucin-like glycoprotein expressed on the surface of airway epithelial cells, is inducible during lung inflammation. MUC1 is also overexpressed as a tumor antigen in lung tumors. We found that chronic CS exposure significantly increased Muc1 expression in mouse airway epithelial cells associated with infiltration of inflammatory cells to the lung. The role of MUC1 in lung epithelial cell transformation induced by benzo[a]pyrene diol epoxide (BPDE), the active form of the CS carcinogen benzo(a)pyrene (BaP), was examined in an in vitro cell transformation assay. Knockdown of MUC1 by shRNA significantly reduced the efficacy of BPDE-induced transformation of BEAS-2B, an SV40 large T antigen immortalized human bronchial epithelial cell line. BPDE strongly activated EGFR and Akt in BEAS-2B cells. Akt activation was blocked with an EGFR inhibitor, suggesting that BPDE activates the EGFR/Akt cascade. Blocking this cascade with inhibitors for either EGFR or Akt significantly inhibited BPDE-induced cell transformation, supporting a critical role for EGFR and Akt activation in BPDE-induced cell transformation. Interestingly, the BPDE-induced activation of EGFR and Akt was attenuated when MUC1 expression was knocked down. Suppression of EGFR or Akt significantly increased BPDE's cytotoxicity. Consistently, the MUC1-suppressed BEAS-2B cells were more sensitive to BPDE-induced death. Taken together, these results suggest that MUC1 plays an oncogenic role in the early stages of inflammation-associated lung cancer development, at least partly through mediating carcinogen-induced activation of the EGFR/Akt pathway that potentiates survival in immortalized bronchial epithelial cells. This work is supported by 1R01ES017328. 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 1337. doi:10.1158/1538-7445.AM2011-1337