Abstract 779: ARF activation is responsible for the tumor-suppressing function of p53 in basal cell carcinomas (BCCs) in Ptch1+/- mice.

Abstract

Abstract Basal cell carcinomas (BCCs) are the most common cancer among people of European ancestry. Aberrant activation of hedgehog (HH) signaling plays a pivotal role in BCC carcinogenesis. Besides mutations in genes encoding HH pathway components, mutations in the p53 gene frequently are found in human BCCs. Consistently, our previous studies have found that the loss of p53 can dramatically accelerate BCC formation in ionizing radiation (IR)-treated Ptch1+/- mice. It remains elusive how p53 is activated in BCC development. DNA damage response (DDR) and oncogenic induced stress (OIS) are two essentially independent pathways leading to p53 activation although limited evidence suggests crosstalk between these pathways. In response to OIS, ARF is activated and leads to p53 activation, functioning as a tumor suppressor, in many cancers. However, the loss of ARF, unlike loss of p53, failed to affect the development of medulloblastoma in Ptch1+/- mice (Wetmore C., et al, 2001). In the present study, we investigated whether ARF affects BCC development in the same mice. To address this, we bred ARFGFP/GFP mice, in which ARF function is disabled and GFP is expressed under the control of the endogenous ARF promoter, with our Ptch1+/- mice to generate Ptch1+/- ARFGFP/GFP (designated as ARF mice) for comparison with Ptch1+/- K14CreER2 p53fl/fl (PF) mice. Following our standard protocol of tamoxifen injection at age 7.5 weeks to delete p53 specifically in K14-expressing keratinocytes (for PF mice) and treating both ARF and PF mice with ionizing radiation at age 8 weeks, we compared BCC development between the above 2 lines. We find that at age 5 months, ARF mice formed numbers of microscopic BCCs comparable to those in PF mice though the latter exhibited greater mouse-to-mouse variation. More importantly, both mouse lines developed initial visible BCCs at age 5 to 7 months, which is dramatically earlier than the age 9 to 18 months for the Ptch1+/- mice (ARF+/+ and p53+/+). In addition, ARFGFP/GFP mice responded to IR-induced DNA damage in a pattern essentially similar to ARF+/+ mice, indicating an intact DDR pathway as reported in the literature. In conclusion, our data demonstrate that ARF is involved in BCC carcinogenesis as a tumor suppressor, probably playing the major, perhaps the exclusive, role in activating p53 in this process. Citation Format: Grace Y. Wang, Carla Wood, Joy Wang, Lynn Wang, Eileen Libove, Ervin Epstein. ARF activation is responsible for the tumor-suppressing function of p53 in basal cell carcinomas (BCCs) in Ptch1+/- mice. [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 779. doi:10.1158/1538-7445.AM2013-779