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Loss of  WWOX  expression has been reported in many different cancers including breast cancer. Elucidating the function of this gene in adult tissues has not been possible with full  Wwox  knockout models. Here we characterize the first conditional models of  Wwox  ablation in mouse mammary epithelium utilizing two transgenic lines expressing Cre recombinase,  keratin 5-Cre  ( BK5-Cre ) and  MMTV-Cre . In the  BK5-Cre  model we observed very efficient  Wwox  ablation in  KO  mammary glands. However,  BK5-Cre Wwox KO  animals die prematurely for unknown reasons. In the  MMTV-Cre  model we observed significant ablation of  Wwox  in mammary epithelium with no effect on survival. In both of these models we found that  Wwox  deletion resulted in impaired mammary branching morphogenesis. We demonstrate that loss of  Wwox  is not carcinogenic in our  KO  models. Furthermore, no evidence of increase proliferation or development of premalignant lesions was observed. In none of the models did loss of a single  Wwox  allele (i.e. haploinsufficiency) have any observable phenotypic effect in mammary gland. To better understand the function of Wwox in the mammary gland, transcriptome profiling was performed. We observed that  Wwox  ablation results in the deregulation of genes involved in various cellular processes. We found that expression of the non-canonical Wnt ligand,  Wnt5a , was significantly upregulated in  Wwox KO  mammary epithelium. Interestingly, we also determined that components of the Jak/Stat3 signaling pathway were upregulated in  KO  mice and this correlated with a very robust increase in phospho-Stat3 signaling, which warrants further testing. Even though the loss of Wwox expression in breast and other cancers is very well documented, our findings suggest that Wwox does not act as a classical tumor suppressor as previously thought.

Conditional Wwox Deletion in Mouse Mammary Gland by Means of Two Cre Recombinase Approaches