Progressive Tumor Formation in Mice with Conditional Deletion of TGF- Signaling in Head and Neck Epithelia Is Associated with Activation of the PI3K/Akt Pathway

¹Functional Genomics Section, Laboratory of Cell and Developmental Biology, ²Oral and Pharyngeal Cancer Branch, ³Mucosal Immunity Section, Oral Immunity and Infection Branch, National Institute of Dental and Craniofacial Research and ⁴Cancer Biology of TGF- Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland

^* To whom correspondence should be addressed. E-mail: ak40m{at}nih.gov.

	Abstract

The precise role of transforming growth factor (TGF)- signaling in head and neck squamous cell carcinoma (SCC) is not yet fully understood. Here, we report generation of an inducible head- and neck-specific knockout mouse model by crossing TGF- receptor I (Tgfbr1) floxed mice with K14-CreER^tam mice. By applying tamoxifen to oral cavity of the mouse to induce Cre expression, we were able to conditionally delete Tgfbr1 in the mouse head and neck epithelia. On tumor induction with 7,12-dimethylbenz(a)anthracene (DMBA), 45% of Tgfbr1 conditional knockout (cKO) mice (n = 42) developed SCCs in the head and neck area starting from 16 weeks after treatment. However, no tumors were observed in the control littermates. A molecular analysis revealed an enhanced proliferation and loss of apoptosis in the basal layer of the head and neck epithelia of Tgfbr1 cKO mice 4 weeks after tamoxifen and DMBA treatment. The most notable finding of our study is that the phosphoinositide 3-kinase (PI3K)/Akt pathway was activated in SCCs that developed in the Tgfbr1 cKO mice on inactivation of TGF- signaling through Smad2/3 and DMBA treatment. These observations suggest that activation of Smad-independent pathways may contribute cooperatively with inactivation of Smad-dependent pathways to promote head and neck carcinogenesis in these mice. Our results revealed the critical role of the TGF- signaling pathway and its cross-talk with the PI3K/Akt pathway in suppressing head and neck carcinogenesis. [Cancer Res 2009;69(14):5918–26]

Key Words: TGF-, PI3K/Akt, Head and Neck Squamous Cell Carcinoma (HNSCC), Conditional Knockout, Cancer Mouse Model