Role of the WWOX fragile gene in cancer

LB-107 The WW domain-containing oxidoreductase (WWOX) encodes a 46kDa protein that contains two N-terminal WW domains and central short-chain dehydrogenase/reductase (SDR) -like domain. The WWOX gene spans the second most active common fragile site, FRA16D; a region that shows frequent loss-of heterozygosity, and is associated with homozygous deletions in various adenocarcinomas and with chromosomal translocations in multiple myeloma. Indeed, WWOX expression is altered in a large fraction of many cancer types including breast, prostate, lung, stomach and pancreatic carcinomas. Therefore, it has been suggested that loss of WWOX expression in several cancer types is due mainly to its location within FRA16D and might be a secondary event not associated with tumorigenesis. Our recent observations, however, indicate that loss of WWOX expression in human tumors contributes to their pathogenesis. Early evidence that WWOX might be capable of suppressing tumor growth came from overexpression studies. Restoration of WWOX in cancer cells lacking expression of endogenous WWOX results in significant growth inhibition and prevents the development of tumors in athymic nude mice. To provide direct in vivo evidence that WWOX is a tumor suppressor, we generated mice carrying a targeted deletion of the Wwox gene. The murine Wwox locus is similar to its human homolog, spans the Fra8E1 common fragile site, and is highly conserved. We demonstrate that the loss of both alleles of Wwox results in osteosarcomas in some early postnatal mice, while loss of one allele significantly increases the incidence of spontaneous lung papillary carcinomas. In addition, higher incidence and multiplicity of ethyl nitrosourea (ENU) and N-nitrosomethylbenzylamine (NMBA)-induced tumors were formed in Wwoxheterozygous mice compared to wild type mice. Intriguingly, some of these tumors still express Wwox protein, suggesting haploinsuffiency of Wwox itself is cancer predisposing. Our findings indicate that WWOX is a bona fide tumor suppressor and that inactivation of one Wwox allele, a condition that frequently occurs due to the fragility of the WWOX locus and the high incidence of LOH observed in WWOX gene in many human cancer types, is sufficient for tumorigenesis.