Individuals inheriting the same mutation predisposing to cancer may show very different outcomes, ranging from early aggressive cancer to disease-free survival. Experimental mouse models can provide a powerful tool to identify factors in the environment and genetic background that account for such modifications. The Min mouse strain, in which the ApcMin mutation disrupts the mouse homologue of the human familial polyposis gene, develops intestinal neoplasms whose multiplicity is strongly affected by genetic background. We previously mapped a strong modifier locus, Mom1 (modifier of Min-1), to a 4-cM region on mouse chromosome 4 containing a candidate gene Pla2g2a encoding a secretory phospholipase. Here, we report that a cosmid transgene overexpressing Pla2g2a caused a reduction in tumour multiplicity and size, comparable to that conferred by a single copy of the resistance allele of Mom1. These results offer strong evidence that this secretory phospholipase can provide active tumour resistance. The association of Pla2g2a with Mom1 thus withstands a strong functional test and is likely to represent the successful identification of a polymorphic quantitative trait locus in mammals.

The Mom1 (Modi®er of Min-1) region of distal chromosome 4 was identi®ed during a screen for polymorphic modi®ers of intestinal tumorigenesis in Apc Min/+ mice. Here, we demonstrate that the Mom1 AKR allele consists of two genetic components. These include the secretory phospholipase Pla2g2a, whose candidacy as a Mom1 resistance modi®er has now been tested with several transgenic lines. A second region, distal to Pla2g2a, has also been identi®ed using ®ne structure recombinants. Pla2g2a AKR transgenic mice demonstrate a modest resistance to tumorigenesis in the small intestine and a very robust resistance in the large intestine. Moreover, the tumor resistance in the colon of Pla2g2a AKR animals is dosage-dependent, a ®nding that is consistent with our observation that Pla2g2a is expressed in goblet cells. By contrast, mice carrying the distal Mom1 modi®er demonstrate a modest tumor resistance that is con®ned to the small intestine. Thus, the phenotypes of these two modi®er loci are complementary, both in their quantitative and regional eects. The additive eects and tight linkage of these modi®ers may have been necessary for the initial identi®cation of the Mom1 region. Oncogene (2000) 19, 3182 ± 3192.

Although nonsteroidal antiinflammatory drugs (NSAIDs) show great promise as therapies for colon cancer, a dispute remains regarding their mechanism of action. NSAIDs are known to inhibit cyclooxygenase (COX) enzymes, which convert arachidonic acid (AA) to prostaglandins (PGs). Therefore, NSAIDs may suppress tumorigenesis by inhibiting PG synthesis. However, various experimental studies have suggested the possibility of PG-independent mechanisms. Notably, disruption of the mouse group IIA secretory phospholipase A 2 locus (Pla2g2a), a potential source of AA for COX-2, increases tumor number despite the fact that the mutation has been predicted to decrease PG production. Some authors have attempted to reconcile the results by suggesting that the level of the precursor (AA), not the products (PGs), is the critical factor. To clarify the role of AA in tumorigenesis, we have examined the effect of deleting the group IV cytosolic phospholipase A2 (cPLA2) locus (Pla2g4). We report that Apc Min/؉ , cPLA2 ؊/؊ mice show an 83% reduction in tumor number in the small intestine compared with littermates with genotypes Apc Min/؉ , cPLA2 ؉/؊ and Apc Min/؉ , cPLA2 ؉/؉ . This tumor phenotype parallels that of COX-2 knockout mice, suggesting that cPLA 2 is the predominant source of AA for COX-2 in the intestine. The protective effect of cPLA2 deletion is thus most likely attributed to a decrease in the AA supply to COX-2 and a resultant decrease in PG synthesis. The tumorigenic effect of sPLA2 mutations is likely to be through a completely different pathway.