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Vaginal cancer is rare and largely unexplored. We found here that kallikrein-related peptidase 5 (KLK5) is coordinately expressed along with other KLKs in all stratified epithelia, including vagina, pointing to potential role(s) in differentiation. Further, we propose that KLK5 could be implicated in vaginal cancer development based on the fact that Klk5−/− mice are prone to develop vaginal tumors when exposed to 7,12-dimethylbenz[a]anthracene. Nf-κb activation is markedly enhanced in Klk5−/−, leading to increased resistance to apoptosis of mutated vaginal cells. This explains the higher tumor numbers observed in Klk5−/− compared to wildtype. Thus, KLK5 may represent a putative suppressor of vaginal cancer.