Lethal giant larvae gene family functions as a tumor suppressor in skin epidermis

Loss of cell polarity and tissue disorganization occurs in majority of epithelial tumors. The role of cell polarity mechanisms in cancer is not completely understood. Here we analyzed the mammalian orthologs of drosophila apical-basal polarity gene lethal giant larvae (lgl), which also functions as a tumor suppressor in flies. There are two mammalian orthologs of lgl (Llgl1 and Llgl2). To determine the role of the entire Lgl signaling pathway in mammals we generated mice with ablation of both Llgl1 and Llgl2 in skin epidermis (Llgl1/2-/- cKO mice). Surprisingly, we found that ablation of Llgl1/2 does not impact epidermal polarity. However, old Llgl1/2-/- cKO mice develop skin lesions which are missing epidermal layer and ripe with inflammation. To determine the role of Llgl1/2 in cancer we generated Trp53-/-/Llgl1/2-/- and Trp53-/+/Llgl1/2-/- cKO mice. Loss of Llgl1/2 promoted squamous cell carcinoma (SCC) development in Trp53-/- cKO and caused SCC in Trp53-/+ cKO mice, while no cancer was observed in Trp53-/+ cKO controls. Mechanistically, we show that ablation of Llgl1/2 activates aPKC-NF-B-RelA signaling pathway and epidermis-specific deletion of only one allele of RelA rescues SCC phenotype in Trp53-/+/Llgl1/2-/- cKO mice. We conclude that Lgl signaling pathway functions as a tumor suppressor in mammalian skin.