Abstract A3: Facilitating epithelial to mesenchymal transition through inhibition of senescence checkpoint functions

Transforming growth factor (TGF)‐β is a potent inducer of epithelial to mesenchymal transition (EMT). However, EMT is not a sole consequence of TGF‐β mediated stimulation. It remains unclear as to what determines the underlying cellular capacity to undergo EMT in response to TGF‐β. Overexpression of epidermal growth factor receptor (EGFR) and mutations in tumor suppressor p53 are common in the early stage of esophageal carcinogenesis and required for transformation and invasive growth of human esophageal epithelial cells. EGFR overexpression and mutant p53 appear to be key determinants in facilitating TGF‐β-induced EMT. EGFR tyrosine kinase activity was dispensable for EMT. However, EGFR overexpression fated the esophageal cells to EMT through induction of ZEB1 and ZEB2, zinc finger E‐box binding proteins which evade EGFR‐mediated oncogenic as well as the TGF‐β-activated senescence responses by inhibiting p15 INK4b and p16 INK4a . Mutant p53 limits TGF‐β-induced senescence by suppressing the p53‐dependent senescence checkpoint function. When senescence was negated, TGF‐β prompted EMT through induction of ZEB1 and ZEB2 along with concomitant downregulation of the microRNA‐200 family. Thus, genetic lesions may involve not only suppression of senescence checkpoint functions but also reactivation of the cellular EMT program in the early stages of carcinogenesis. Citation Information: Cancer Res 2009;69(23 Suppl):A3.