Abstract

Abstract Basal cell carcinoma (BCC), the most commonly diagnosed human cancer, is driven by aberrant activation of hedgehog (HH) signaling. In addition, we have found that p53 is a potent inhibitor of HH-driven BCC carcinogenesis - ablation of p53 in Ptch1+/- K14CreER2 p53fl/fl (PF mice) dramatically accelerates BCC formation with a shorter tumor latency and a 10 fold increase of tumor burden. To begin to determine how p53 is activated in this Ptch1+/- murine BCC model, we investigated the role of p19ARF in translating oncogene-induced stress (OIS) into p53 activation. We bred Ptch1+/- mice with ARFGFP/GFP to generate Ptch1+/- ARFGFP/GFP (ARF mice), lacking functional ARF. In addition, we crossed ARF mice and PF mice to generate ARF/p53 double deletion mice (DD mice), treated ARF, PF and DD mice as well as Ptch1+/- (ARF+/+, p53+/+) with IR at mouse age 8w, and quantified BCC formation. .As assessed in age 5m skin biopsies, PF and DD mice had a significantly higher microscopic BCC tumor burden than did ARF and Ptch1+/- mice. There was no significant difference between PF and DD or between ARF and Ptch1+/-. ARF and PF mice developed visible BCC starting at 5-6 m. By contrast, DD mice had visible BCCs as early as age 4m, a statistically different age of onset. Consistent with our previous findings, Ptch1+/- mice did not form any visible BCCs until age 9 m or later. These data indicate that loss of functional ARF or of p53 promotes malignant conversion of microscopic BCCs to visible BCCs. However, only loss of p53, but not loss of ARF, enhances tumor initiation. To gain further insights in the molecular mechanisms differentiating these tumors, we examined the whole genome expression analysis by RNA-seq. Taken together, our findings suggest that both ARF-dependent and -independent activation of p53 is involved in BCC carcinogenesis. ARF-mediated p53 activation, presumably via the OIS pathway, appears to be crucial in regulating malignant transformation of BCC, while ARF-independent p53 activation inhibits tumor initiation. Citation Format: Grace Y. Wang, Carla Wood, Hiroe Hu, John Dolorito, Eileen Libove, Ervin H. Eptein. Dependent and independent tumor suppression function of ARF and p53 in murine BCC carcinogenesis in Ptch1+/- mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-86. doi:10.1158/1538-7445.AM2014-LB-86

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