Lethal giant larvae gene family ( and ) functions as a tumor suppressor in mouse skin epidermis.

Loss of cell polarity and tissue disorganization occurs in majority of epithelial cancers. Studies in simple model organisms identified molecular mechanisms responsible for the establishment and maintenance of cellular polarity, which play a pivotal role in establishing proper tissue architecture. The exact role of these cell polarity pathways in mammalian cancer is not completely understood. Here we analyzed the mammalian orthologs of drosophila apical-basal polarity gene lethal giant larvae ( ), which regulates asymmetric stem cell division and functions as a tumor suppressor in flies. There are two mammalian orthologs of ( and ). To determine the role of the entire lgl signaling pathway in mammals we generated mice with ablation of both and in skin epidermis using K14-Cre ( cKO mice). Surprisingly, we found that ablation of genes does not impact epidermal polarity in adult mice. However, old cKO mice present with focal skin lesions which are missing epidermal layer and ripe with inflammation. To determine the role of lgl signaling pathway in cancer we generated cKO and cKO mice. Loss of promoted squamous cell carcinoma (SCC) development in cKO and caused SCC in cKO mice, while no cancer was observed in cKO controls. Mechanistically, we show that ablation of causes activation of aPKC and upregulation of NF-kB signaling pathway, which may be necessary for SCC in cKO mice. We conclude that Lgl signaling pathway functions as a tumor suppressor in mammalian skin epidermis.