Aberrant cell cycle progression contributes to the early-stage accelerated carcinogenesis in transgenic epidermis expressing the dominant negative TGFβRII

Mutations in the transforming growth factor beta type II receptor (TGF beta RII) have been found in various malignant tumors, suggesting that loss of TGF beta signaling plays a causal role in late-stage cancer development, To test whether loss of TGF beta RII is involved in early-stage carcinogenesis, ne have generated transgenic mice expressing a dominant negative TGF beta RII (Delta beta RII) in the epidermis, These mice exhibited an increased susceptibility to chemical carcinogenesis protocols at both early and late stages. In the current study, parameters for cell cycle progression and chromosome instability were analysed in Delta beta RII tumors. Delta beta RII papillomas showed an increased S phase in flow cytometry. Bromodeoxyuridine (BrdU) labeling and mitotic indices in Delta beta RII papillomas also showed a threefold increase compared to papillomas developing in non-transgenic mice, When papillomas further progressed to squamous cell carcinomas (SCC), both control and Delta beta RII SCC showed similar BrdU labeling indices and percentages of S phase cells. However, Delta beta RII SCC cells showed a sixfold increase in the G2/M population. Mitotic indices in Delta beta RII SCC also showed a threefold increase compared to non-transgenic SCC, Consistent with a perturbed cell cycle, Delta beta RII papillomas and SCC showed reduced expression of the TGF beta target genes p15 (INK4b), p21 (WAF-1) and p27 (Kip1), inhibitors of cyclin-dependent kinases (cdks). However, most Delta beta RII papilloma cells exhibited normal centrosome numbers, and Delta beta RII SCC exhibited a similar extent of centrosome abnormalities compared to control SCC (35-40% cells). Most of Delta beta RII SCC exhibited diploid chromosome profiles. These data indicate that inactivation of TGF beta RII accelerates skin tumorigenesis at early stages by the acceleration of loss of cell cycle control, but not by increased chromosome instability.