Author ORCID Identifier

https://orcid.org/0000-0003-2093-1868

Semester

Summer

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

Eric Kelley

Committee Member

Michael Ruppert

Committee Member

Bradley Webb

Committee Member

Ivan Martinez

Committee Member

Timothy Eubank

Abstract

Breast cancer remains the most frequently diagnosed malignancy and the leading cause of cancer related deaths in women. This is primarily due to distant metastases, which highlight the necessity to understand factors that contribute to breast cancer progression. Emerging evidence associates decreased tumor xanthine oxidoreductase (XOR) expression with a poorer prognosis, increased recurrence, and a more aggressive phenotype. While healthy liver, intestines, kidneys, and breast tissue have robust XOR expression and activity, there is a tendency for this to be ablated in carcinogenesis. This dissertation investigates XOR's role in breast cancer and identifies its product, uric acid (UA), as possessing anticancer properties. Previous studies indicate UA has antioxidant roles, including chelation of iron, an essential nutrient for cancer cell survival. Our study establishes that clinically relevant concentrations of UA decrease breast cancer cell proliferation, migration, and survival, which is restored by iron supplementation. These effects were not observed in nontumorigenic or primary mammary epithelial cells, which indicates a cancer cell specific vulnerability to UA. Additionally, inhibiting the UA efflux transporter ABCG2, also known as BCRP, sensitized the breast cancer cells to lower concentrations of UA, affirming its promise as a therapeutic target. These findings support the hypothesis that breast cancer cells downregulate XOR expression to decrease intracellular UA accumulation and mitigate iron sequestration. In addition, our work highlights the therapeutic potential of targeting ABCG2 alone or as a combination therapy. Furthermore, we have confirmed that our observations in breast cancer cells extend to hepatocellular carcinoma, where we reveal HepG2 cells lack XOR expression and activity. When taken together, this thesis reveals a novel fundamental mechanism for altering cancer cell growth by modulating intracellular UA levels.

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