p53 loss before or after exposure to ionizing radiation accelerates BCC carcinogenesis in Ptch1+/- mice

Abstract

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p53 is an important tumor suppressor that is mutated in 40-100% of basal cell carcinomas (BCCs). Since Ptch1^+/- p53^-/- mice all develop fatal early onset medulloblastomas, we tested the effects of p53 loss on experimental BCC formation in mice by breeding mice in which basal keratinocyte (floxed) p53 could be deleted by tamoxifen (tam)-activation of K14-Cre-ER. Ptch1^+/-mice develop multiple microscopic BCCs after exposure to IR at age 8 weeks, and about 50% (depending on genetic background) of these mice develop macroscopic BCCs. Basal keratinocyte specific deletion of p53 by tam administration at age 6 weeks (2 weeks before IR) or at age 9 weeks (1 week after IR) produces rapid and equivalent acceleration of BCC carcinogenesis. Thus, keratinocyte p53 deleted mice develop multiple visible BCCs as early as age 5 months, in contrast to their IR-treated Ptch1^+/-non-p53 deleted siblings, which developed one or two visible BCCs no earlier than age 10 months. Furthermore, visible BCC tumors were seen by age 9 months in Ptch1^+/- p53 deleted mice even without IR treatment. CGH analysis indicated that global genome changes were similar in BCCs irrespective of keratinocyte p53 status. Cell lines could be established from BCCs from p53 deleted Ptch1^+/- irrespective of whether or not IR had been given. These studies indicate (i) that p53 functions to restrain the effect of epithelial carcinogenesis AFTER repair of acute DNA damage, consistent with recent publications that have suggested a role of p53 in opposing “oncogene stress” (ii) that the mechanism of BCC acceleration by p53 loss does not involve marked changes in DNA copy number (iii) that acceleration of carcinogenesis in Ptch1^+/- mice by p53 loss is not limited to the previously reported cerebellar tumors and (iv) that p53 loss plus hemizygosity for functioning PTCH1 is sufficient for the development of BCCs even without further imposed mutagenic insult.