Apobec3a expression accelerates chemical carcinogenesis in murine skin

Summary: Dysregulated activity of the human cytidine deaminase APOBEC3A is a prevalent contributor to human cancer. Signatures of APOBEC3A activity are found in approximately 10% of cutaneous squamous cell carcinoma (cSCC) where APOBEC3A mutagenesis targets driver genes critical to pathways regulating cell state, growth, and apoptosis. Tumors with enriched APOBEC3A activity have increased heterogeneity, increased resistance to therapy and a higher risk of metastasis. To determine the contribution of APOBEC3A to DMBA/TPA chemical carcinogenesis in the skin, we utilized the A3A10 mouse model, characterized by constitutive, low copy number expression of human APOBEC3A driven by the chicken beta actin promoter. Mice positive for human APOBEC3A that received DMBA and TPA had significantly higher average tumor burden (p <0.0001) over the course of the experiment, with final average tumor burden being 8.35 times higher than their negative counterparts. APOBEC3A expression also led to a significantly higher number of tumors (p <0.0001), with the final average tumor count being 3 times higher, and increased histological and morphological features of progressive cSCC. Overall, our data demonstrates that low level, constitutive expression of human APOBEC3A accelerates chemical carcinogenesis in the skin. Lauren E. Israel^{1, 2}, Michael Alexander¹, Shiv Poojan¹, Susan Ross³, Andrew P. South^{1, 2} 1. Departments of Dermatology and Cutaneous Biology, and Pharmacology, Physiology and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, United States. 2. Department of Dermatology, University of Wisconsin-Madison, Madison, WI, United States. 3. Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, United States. UV Biology/Injury and Non-melanoma Cancers