Fini Mehdi A, Orchard-Webb David, Kosmider Beata, Amon Jeremy D, Kelland Robert, Shibao Gayle, Wright Richard M
Webb-Waring Institute for Cancer, Aging and Antioxidant Research, 4200 East 9th Ave, Denver, Colorado 80262, USA.
J Cell Biochem. 2008 Nov 1;105(4):1008-26. doi: 10.1002/jcb.21901.
Xanthine oxidoreductase (XOR) may exert an important, but poorly defined, role in the pathogenesis of breast cancer (BC). Loss of XOR expression was linked to aggressive BC, and recent clinical observations have suggested that decreasing XOR may be functionally linked to BC aggressiveness. The goal of the present investigation was to determine whether the decreased XOR observed in clinically aggressive BC was an intrinsic property of highly invasive mammary epithelial cells (MEC). Expression of XOR was investigated using HC11 mouse MEC, HB4a and MCF-10A normal human MEC, and several human mammary tumor cells including MCF-7 and MDA-MB-231. Consistent with clinical observations, data shown here revealed high levels of XOR in normal HC11 and MCF-10A cells that was markedly reduced in highly invasive mammary tumor cells. The contribution of XOR to tumor cell migration in vitro was investigated using MDA-MB-231 and MCF-7 cells and clonally selected derivatives of HC11 that exhibit either weak or strong migration in vitro. We observed that over-expression of an XOR cDNA in MDA-MB-231 and in HC11-C24, both possessing weak XOR expression and high migratory capacity, inhibited their migration in vitro. Conversely, pharmacological inhibition of XOR in MCF-7 and HC11-C4, both possessing high XOR expression and weak migratory capacity, stimulated their migration in vitro. Further experiments suggested that XOR derived ROS mediated this effect and also modulated COX-2 and MMP levels and function. These data demonstrate a functional link between XOR expression and MEC migration and suggest a potential role for XOR in suppressing BC pathogenesis.
黄嘌呤氧化还原酶（XOR）可能在乳腺癌（BC）的发病机制中发挥重要但尚未明确的作用。XOR表达缺失与侵袭性乳腺癌相关，最近的临床观察表明，XOR的减少可能在功能上与乳腺癌的侵袭性有关。本研究的目的是确定在临床侵袭性乳腺癌中观察到的XOR减少是否是高侵袭性乳腺上皮细胞（MEC）的固有特性。使用HC11小鼠MEC、HB4a和MCF-10A正常人MEC以及包括MCF-7和MDA-MB-231在内的几种人乳腺肿瘤细胞研究了XOR的表达。与临床观察一致，此处显示的数据表明正常HC11和MCF-10A细胞中XOR水平较高，而在高侵袭性乳腺肿瘤细胞中明显降低。使用MDA-MB-231和MCF-7细胞以及在体外表现出弱或强迁移能力的HC11克隆选择衍生物研究了XOR对体外肿瘤细胞迁移的贡献。我们观察到，在MDA-MB-231和HC11-C24中过表达XOR cDNA（两者均具有弱XOR表达和高迁移能力）可抑制它们在体外的迁移。相反，在MCF-7和HC11-C4中对XOR进行药理抑制（两者均具有高XOR表达和弱迁移能力）可刺激它们在体外的迁移。进一步的实验表明，XOR衍生的活性氧介导了这种作用，还调节了COX-2和MMP的水平及功能。这些数据证明了XOR表达与MEC迁移之间的功能联系，并表明XOR在抑制乳腺癌发病机制中可能发挥潜在作用。
