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WWOX is a putative tumor suppressor gene encoded within common chromosomal fragile site region FRA16D, in chromosome band 16q23. Multiple studies have demonstrated that WWOX expression is often reduced or lost in various tumor types. WWOX tumor suppressor activity was suggested by re-expressing WWOX in breast, ovarian, and lung tumor cell lines leading to tumor growth inhibition in vivo. To determine whether loss of Wwox gene expression has a role in tumorigenesis, we generated a mouse strain containing a Wwox gene mutated by a gene-trap vector. Homozygous Wwox gene-trap mice (Wwoxgt/gt) had no detectable Wwox protein in most tissues examined, although, a low level could be detected in a minority of tissues. Because of these observations, we concluded that these mice are Wwox hypomorphs. Remarkably, Wwox hypomorphic mice are viable in contrast to the recently reported postnatal lethality of Wwox knockout mice. Testes from Wwoxgt/gt males had high numbers of atrophic seminiferous tubules and reduced fertility when compared with wild-type counterparts. We observed that the Wwoxgt/gt mice had a significantly shorter lifespan, and female hypomorphs had a higher incidence of spontaneous B-cell lymphomas. In conclusion, we describe a novel Wwox hypomorphic mouse model that overcomes postnatal lethality that was recently observed in Wwox knockout mice. Therefore, tumorigenesis studies using this model more closely recapitulates the loss of WWOX expression observed in human cancers. Importantly, our observation that Wwox hypomorphs had an increased incidence of B-cell lymphomas supports a role of Wwox as a tumor suppressor. © 2007 Wiley-Liss, Inc.

Common chromosomal fragile sites are unstable genomic loci susceptible to breakage, rearrangement, and are highly recombinogenic. Frequent alterations at these loci in tumor cells led to the hypothesis that they may contribute to cancer development. The two most common chromosomal fragile sites FRA16D and FRA3B which harbor WWOX and FHIT genes, respectively, are frequently altered in human cancers. Here we report that environmental carcinogens, ultraviolet (UV) light, and Benzo[a]pyrene diol epoxide (BPDE), significantly downregulate expression of both genes. On the other hand, we observe that ionizing radiation (IR) does not affect expression of these genes, suggesting that the effect of repression exerted by UV and BPDE is not just a consequence of DNA damage but may be a result of different signaling pathways triggered by specific DNA lesions. Such downregulation correlates with an induction of an S-phase delay in the cell cycle. Treatment of UV-irradiated cells with caffeine abrogates the S-phase delay while concomitantly overcoming the repression phenomenon. This suggests the involvement of unique cell cycle checkpoint mechanisms in the observed repression. Therefore, it is hypothesized that protracted downregulation of the putative tumor suppressor genes WWOX and FHIT by environmental carcinogens may constitute an additional mechanism of relevance in the initiation of tumorigenesis.