Abstract:
Our previous results suggest that Wwox-deficient cells exhibit increased survival of ionizing radiation-induced double strand breaks. To determine if the IR resistance of Wwox-deficient cells persists in vivo, Wwox-induced (231/Wwox-pos) and Wwox-deficient (231/Wwox-neg) breast cancer cells were tested for tumor growth in immunocompromised mice. The rationale was that despite irradiating the same number of cells for the two groups, more 231/Wwox-neg cells would survive IR, forming tumors more quickly than 231/Wwox-pos cells. Both groups of cells were exposed to 5Gy IR, immediately harvested and injected (1 × 107 cells per mouse) subcutaneously into the flanks of athymic nude mice. Control mice from each group were unexposed to IR and exhibited mean tumor latencies (days from injection to first sign of tumor) that were not different: 11 days for 231/Wwox-neg cells and 14 days for 231/Wwox-pos cells. For mice receiving irradiated cells, 7/8 mice injected with 231/Wwox-neg cells formed tumors, whereas 6/8 mice injected with 231/Wwox-pos cells formed tumors. Of the tumor-bearing mice, those injected with 231/Wwox-neg cells had significantly shorter tumor latencies (mean 17 days) vs mice receiving 231/Wwox-pos cells (mean 28 days). Next, we sought a human cancer database with expression and clinical data for cancers treated with radiation to determine if loss of Wwox enabled tumor cell resistance to radiation and decreased overall patient survival in a human model. In cancers treated with radiation, reduced Wwox expression correlated significantly with decreased overall survival vs Wwox normal cancers, suggesting that loss of Wwox facilitates resistance to radiation therapy, disease recurrence and shorter overall survival.
