Xanthine oxidoreductase expression is diminished in breast cancer as a response to uric acid mediated chelation of redox active iron.

Breast cancer patients with diminished xanthine oxidoreductase (XOR) expression have a greater risk for metastases and diminished survival; however, the mechanisms underpinning this phenomenon are unknown. Under normal growth conditions, neither triple negative MDA-MB-231 nor ER-positive MCF-7 cells demonstrated detectable expression of XOR mRNA, protein and enzymatic activity, which was confirmed using archived in silico data. Enforced expression of XOR did not yield viable cells with significant increases in XOR protein and activity. In addition, exposing breast cancer cells to clinically relevant concentrations of UA diminished growth, migratory capacity, and clonogenic cell survival. Parallel experiments with iron chelators (e.g., DTPA or DFO) produced similar effects, suggesting a potential link between UA and iron chelation. Consistent with this hypothesis, the breast cancer cell growth inhibition seen with UA was inhibited by supplementing iron (2.0 μM). Electron paramagnetic resonance (EPR) spectrometry confirmed that UA loosely chelated iron by diminishing Fe-mediated redox reactions with ascorbate (e.g., Fe + AscH → Fe + Asc). Importantly the anti-proliferative effect of UA was not observed in normal cell counterparts (e.g., MCF10A and HMEC), suggesting a cancer cell-specific effect supporting the hypothesis that greater labile iron pools were required for breast cancer cells. In addition, inhibition of the breast cancer resistance protein (BCRP), a known UA export protein, concomitant with UA treatment exacerbated the impact of UA alone. Overall, these data support the hypothesis that breast cancer cells lose expression of XOR to avoid cancer cell-specific, Fe-dependent growth inhibitory effects of UA and suggest that UA and XOR activity may represent a target for inhibiting breast cancer progression.