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Xanthine Oxidoreductase Expression is Diminished in Breast Cancer as a Response to Uric Acid Mediated Chelation of Redox Active Iron
Journal article   Peer reviewed

Xanthine Oxidoreductase Expression is Diminished in Breast Cancer as a Response to Uric Acid Mediated Chelation of Redox Active Iron

M.G. Chapa, R.D. King, Z.W. Dean, A. Maskey, R.M. Park, M. Velayutham, E.N. Pugacheva, O.M. Woodward, B.A. Webb, D.R. Spitz, …
Free radical biology & medicine, Vol.238, pp.329-343
10/2025
DOI: 10.1016/j.freeradbiomed.2025.06.019
PMCID: PMC12750285
PMID: 40523540
url
https://pmc.ncbi.nlm.nih.gov/articles/PMC12750285/View
Open Access

Abstract

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., Fe3+ + AscH- → Fe2+ + 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 liable 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. [Display omitted] •Low XOR expression breast cancer patient’s tumors is associated with increased metastasis and diminished survival.•Breast cancer cell lines demonstrate little if any detectable XOR expression; yet it remains unclear why?•Exposure of breast cancer cells to the XOR product, uric acid (UA) decreases proliferation and migration whereas it does not affect normal cell counterparts.•Antiproliferative effects of UA on breast cancer cells are rescued by Fe supplementation because UA binds and limits access to Fe.•Inhibition of the breast cancer resistance protein (BCRP), a known UA export protein, concomitant with UA treatment exacerbated the impact of UA alone.•We hypothesize that breast cancer cells down-regulate XOR to avoid growth inhibitory effects of UA and that UA and XOR activity may be a target for inhibiting breast cancer progression.
 Iron ABCG2 Breast Cancer Resistance Protein HMEC MCF-7 MCF10A MDA-MB-231 Urate Transporter Uric Acid XDH XOR

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