Solar ultraviolet (UV) radiation is the primary cause of skin cancer. Non-melanoma skin cancer, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is the most common form of skin cancer and accounts for 2-3 million worldwide cases of cancer each year. The transcription factor Smad4 is a central mediator in the transforming growth factor β (TGFβ), activin, and bone morphogenetic protein (BMP) signaling pathways. Smad4 loss occurs frequently in human skin squamous cell carcinoma (SCC), but it is unknown if this event is causal to ultraviolet-induced (UV) carcinogenesis, a major etiological factor in human skin cancer. In the present study, we exposed mice with keratinocyte-specific Smad4 deletion (K14.Smad4−/) and wildtype (WT) mice to chronic UV irradiation. Compared to WT littermates, K14.Smad4−/ mice exhibited increased susceptibility to UV-induced skin cancer. Histological examination revealed that UV-induced Smad4−/ tumors were all SCCs. Moreover K14.Smad4−/ skin shows increased DNA damage due to reduced expression of DNA repair genes compared to WT skin. We have identified a novel mechanism by which Smad4 suppresses skin cancer by promoting repair of UV-induced DNA lesions.

Citation Format: Doyel Mitra, Pamela Fernandez, Bian Li, Ningjing Song, Gangwen Han, Xiao-Jing Wang. Smad4 loss leads to reduced DNA repair and skin cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1285. doi:10.1158/1538-7445.AM2013-1285