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Down-Regulated Xanthine Oxidoreductase Is a Feature of Aggressive Breast Cancer

Authors' Affiliations: ¹ Research Program for Developmental and Reproductive Biology and Hospital for Children and Adolescents, Biomedicum Helsinki, University of Helsinki; ² Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland; and ³ Institute of Medical Technology, University of Tampere, Tampere, Finland

Requests for reprints: Nina Linder, Research Program for Developmental and Reproductive Biology, Room B524b, Biomedicum Helsinki, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), FIN-00014 Helsinki, Finland. Phone: 358-9-4717-1976; Fax: 358-9-4717-1947; E-mail: nina.linder{at}hus.fi.

Purpose: Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA, and high-energy phosphates and also plays a role in milk lipid globule secretion. Given the strong and regulated expression of XOR in normal breast epithelium, and the previously shown alterations of its expression in experimental tumorigenesis, we hypothesized that XOR may be differentially expressed in breast cancer.

Experimental Design: XOR expression was analyzed by immunohistochemistry in tissue microarray specimens of 1,262 breast cancer patients with a median follow-up of 9.5 years.

Results: Expression of XOR was moderately decreased in 50% and undetectable in another 7% of the tumors. Decreased XOR expression was associated with poor histologic grade of differentiation, ductal and lobular histologic types, large tumor size, high number of positive axillary lymph nodes, and high cyclooxygenase-2 expression, but not with estrogen or progesterone receptor status, Ki-67, p53, or ERBB2 amplification. Absence of XOR expression was associated with unfavorable outcome, and patients with no XOR expression had more than twice the risk of distant recurrence as compared with those with a moderately decreased or normal expression (hazard ratio, 2.21; P < 0.0001). This was also true in patients with node-negative disease (hazard ratio, 2.75; P < 0.0001) as well as in patients with small (1 cm) tumors (hazard ratio, 3.09; P = 0.027). In a multivariate survival analysis, negative XOR emerged as an independent prognostic factor both in the entire series (P = 0.01) and among patients with node-negative disease (P = 0.0009).

Conclusion: Loss of XOR identifies breast cancer patients with unfavorable prognosis.

Key Words: Xanthine oxidoreductase • breast neoplasms • prognosis • survival analysis

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