Linder Nina, Lundin Johan, Isola Jorma, Lundin Mikael, Raivio Kari O, Joensuu Heikki
Research Program for Developmental and Reproductive Biology and Hospital for Children and Adolescents, Biomedicum Helsinki, University of Helsinki, Finland.
Clin Cancer Res. 2005 Jun 15;11(12):4372-81. doi: 10.1158/1078-0432.CCR-04-2280.
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.
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.
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 (< or = 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).
Loss of XOR identifies breast cancer patients with unfavorable prognosis.
黄嘌呤氧化还原酶（XOR）是DNA、RNA和高能磷酸盐降解过程中的关键酶，在乳脂肪球分泌中也发挥作用。鉴于XOR在正常乳腺上皮中表达强烈且受调控，以及先前在实验性肿瘤发生中显示的其表达改变，我们推测XOR在乳腺癌中可能存在差异表达。
通过免疫组织化学分析1262例乳腺癌患者组织微阵列标本中的XOR表达，中位随访时间为9.5年。
50%的肿瘤中XOR表达中度降低，另有7%的肿瘤中未检测到XOR表达。XOR表达降低与组织学分化差、导管和小叶组织学类型、肿瘤体积大、腋窝淋巴结阳性数目多以及环氧化酶-2高表达相关，但与雌激素或孕激素受体状态、Ki-67、p53或ERBB2扩增无关。XOR表达缺失与不良预后相关，与XOR表达中度降低或正常的患者相比，XOR无表达的患者远处复发风险高出两倍多（风险比，2.21；P < 0.0001）。在无淋巴结转移疾病患者中（风险比，2.75；P < 0.0001）以及肿瘤较小（≤1 cm）的患者中（风险比，3.09；P = 0.027）也是如此。在多因素生存分析中，XOR阴性在整个队列（P = 0.01）以及无淋巴结转移疾病患者中（P = 0.0009）均作为独立的预后因素出现。
XOR缺失可识别预后不良的乳腺癌患者。
