Abstract B19: An integrative in vivo analysis of PIK3CA, PTEN and AKT alterations in head and neck squamous cell carcinoma

Abstract

Abstract In vitro studies indicate that deregulation of the PI3K/AKT pathway is important in head and neck squamous cell carcinoma (HNSCC) tumorigenesis, as has been observed in several other cancers. However, the in vivo role of PI3K/AKT pathway deregulation in HNSCC remains unknown. The objective of this study was to investigate the in vivo roles of PIK3CA, PTEN and AKT alterations in head and neck tumorigenesis. To this end, we developed inducible head and neck specific transgenic PIK3CA and AKT mice, and inducible head and neck specific knockout PTEN mice under the control of an RU486-responsive Keratin 5 promoter. Both PIK3CA or AKT transgene expression was induced in mouse head and neck epithelia, i.e. buccal mucosa, tongue, and esophagus, upon RU486 application in a dose- and time- dependent manner. PTEN deletion was also achieved in mouse head and neck epithelia after five consecutive RU486 applications. The PIK3CA and AKT inducible transgenic mice exhibited severe head and neck epithelial hyperplasia, dysplasia, and carcinoma in situ, but no visible tumor formation after one year of observation. Further, the inducible head and neck specific PTEN knockout mice developed oral, but not esophageal SCCs. To investigate whether the inducible PIK3CA or AKT mice harbored higher cancer susceptibility upon tobacco carcinogen exposure, we applied a subcarcinogenic dose of 4NQO, a surrogate of a tobacco carcinogen, to the PIK3CA and AKT mice. Both PIK3CA and AKT mice developed oral and/or esophageal SCCs as early as one month after 4NQO exposure, and by 4 months, all PIK3CA and AKT transgenic mice developed oral and/or esophageal SCCs. Interestingly, a higher incidence of esophageal in comparison with oral SCC (93% versus. 19% of mice) was observed in the AKT transgenic mice, while a higher incidence of oral versus esophageal SCC (74% vs. 44% of mice) was found in the PIK3CA mice, suggesting a tissue specificity of AKT and PIK3CA in head and neck tumorigenesis. Studies investigating the underlying molecular mechanism of each molecule in head and neck tumorigenesis are currently underway. In conclusion, our data demonstrate an oncogenic role of PIK3CA and AKT, and a tumor suppressive role of PTEN in head and neck tumorigenesis in vivo. Our inducible head and neck specific mouse models are powerful tools to evaluate the roles of PIK3CA, PTEN, and AKT during each stage and site involved in head and neck tumorigenesis, and to test novel therapeutics targeting this important signaling pathway. Citation Information: Cancer Res 2009;69(23 Suppl):B19.