Deletion of phospholipase A{Less than}sub{Greater than}2{Less than}/sub{Greater than} group IV c induces apoptosis in rat mammary tumor cells by the nuclear factor-{kappa}B/lipocalin 2 pathway

Although some phospholipase A₂ forms, the initiator of the arachidonic acid cascade, contribute to carcinogenesis in many organs, the contribution of phospholipase A₂ group IVc (Pla2g4c) remains to be clarified and the function of the enzyme in cancer development are unknown. The Hirosaki hairless rat (HHR), a mutant rat strain with autosomal recessive inheritance, spontaneously derived from the Sprague-Dawley rat (SDR). The HHR showed the low incidence, volume of mammary tumors induced by 7,12-dimethylbenz[a]anthracene were much smaller, and markedly increased TUNEL-positive apoptotic cells were detected. Array comparative genomic hybridization and PCR analyses revealed the deletion of 50-kb genomic DNA on 1q21, including Pla2g4c, in HHRs. The Pla2g4c gene was expressed in the ductal carcinoma cells and myoepithelial cells in SDRs but not HHRs. The direct involvement of Pla2g4c in the prevention of cell death was demonstrated through the inhibition of its expression in rat mammary tumor RMT-1 cells by using siRNA. This treatment also induced expression of lipocalin 2 (Lcn2) and other NF-κB-related genes. siRNA-induced apoptosis was inhibited by Lcn2 repression or an NF-κB inhibitor. This is the first report on Pla2g4c gene-deficient rats and their low susceptibility to mammary carcinogenesis by enhancing NF-κB/Lcn2- induced apoptosis.