Crosstalk among p53 family members in cutaneous carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with a frequency increasing worldwide. The risk of developing cSCC has been strongly associated with chronic sun exposure, especially in light skin people. The aim of this viewpoint is to discuss the contribution of the tumor suppressor p53 and its homologues p63 and p73 in the formation and progression of cSCC. Mutations in the p53 gene are early and frequent events in skin carcinogenesis mainly as a consequence of UV light exposure, often followed by loss of function of the second allele. Although rarely mutated in cancer, p63 and p73 play key roles in human cancers, with their truncated isoforms lacking the N-terminal transactivating domain (∆N) being often upregulated as compared to normal tissues. ∆Np63 is abundantly expressed in cSCC, and it is likely to favour tumor initiation and progression. The function of p73 in cSCC is more enigmatic and awaits further studies. Interestingly, an intimate interplay exists between both p53 and p63, and the Notch signalling pathway, often inactivated in cSCC. Here, we summarize our current knowledge about the biological activities of p53 family members in cSCC and propose that integration of their signalling with Notch is key to cSCC formation and progression.