Elevated ΔNp63α Levels Facilitate Epidermal and Biliary Oncogenic Transformation

Unlike its family member p53, TP63 is rarely mutated in human cancer. However, Delta Np63 alpha protein levels are often elevated in tumors of epithelial origin, such as squamous cell carcinoma and cholangiocarcinoma. To study the oncogenic properties of Delta Np63 alpha in vivo, we generated transgenic mice overexpressing Delta Np63 alpha from the Rosa26 locus promoter controlled by keratin 5-Cre. We found that these mice spontaneously develop epidermal cysts and ectopic Delta Np63 alpha expression in the bile duct epithelium that leads to dilatation of the intrahepatic biliary ducts, to hepatic cyst formation and bile duct adenoma. Moreover, when subjected to models of 7,12-dimethylbenz[a]anthracene-based carcinogenesis, tumor initiation was increased in Delta Np63 alpha transgenic mice in a gene dosage-dependent manner although Delta Np63 alpha overexpression did not alter the sensitivity to 7,12-dimethylbenz[a] anthracene-induced cytotoxicity in vivo. However, keratinocytes isolated from Delta Np63 alpha transgenic mice displayed increased survival and delayed cellular senescence compared with wild-type keratinocytes, marked by decreased p16 Ink4a and p19 Arf expression. Taken together, we show that increased Delta Np63 alpha protein levels facilitate oncogenic transformation in the epidermis as well as in the bile duct.