Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 110, Taiwan.
Breast Cancer Res Treat. 2012 Aug;134(3):989-1004. doi: 10.1007/s10549-012-1986-8. Epub 2012 Mar 21.
The extracellular matrix (ECM) plays a critical role in the development and invasion of primary breast tumors. Lysyl oxidase (LOX), which is an ECM remodeling enzyme, appears to play roles in promoting cancer cell motility and invasion. To ascertain whether LOX overexpression in breast tumor tissues from Asian patients is associated with decreases in metastasis-free and overall survival in breast cancer patients, the mRNA levels of LOX were examined in paired tumor/normal tissue samples using real-time RT-PCR analysis (n = 246 pair-matched samples). To test whether specifically targeting LOX by inhibiting its activity (using beta-aminopropionitrile (β-APN), a LOX inhibitor), mRNA expression (using siRNA), or protein expression (using 25 μM magnolol) attenuates the invasion of MDA-MB-231 breast cancer cells, a cancer cell migration assay was performed. Interestingly, only 78.5% (n = 193) of the breast cancer tumors displayed detectable LOX expression. Nearly 60% (n = 120) of the cases fell into Group 1 (tumor > normal, T > N); in this group, the mean LOX expression in the tumor cells was 20.2-fold greater than in normal cells. However, in Group 2 (normal > tumor, N > T), the LOX expression level in most of the normal tissues examined (80%, 59/73) was less than fivefold greater than in the tumor tissues. The increased level of active LOX in the invasive breast cancer cell line MDA-MB-231 was accompanied by the increased phosphorylation of focal adhesion kinase at Tyr-576 and of paxillin at Tyr-118. We also found that the addition of β-APN (300 μM) and magnolol (25 μM), synergistically inhibited the migration and invasion of MDA-MB-231 cells. In this article, we describe, for the first time, higher expression of a LOX protein in breast tumors compared with normal tissues from Asian patients. Moreover, the results indicate that the inhibition of LOX using magnolol may represent a more desirable strategy for breast cancer therapy than the use of β-APN.
细胞外基质 (ECM) 在原发性乳腺癌的发展和浸润中起着关键作用。赖氨酰氧化酶 (LOX) 是一种 ECM 重塑酶，似乎在促进癌细胞运动和浸润方面发挥作用。为了确定亚洲患者乳腺癌组织中 LOX 的过度表达是否与乳腺癌患者无转移和总生存率的降低有关，使用实时 RT-PCR 分析检查了 LOX 的 mRNA 水平（n = 246 对配对肿瘤/正常组织样本）。为了测试通过抑制其活性（使用 LOX 抑制剂 β-氨基丙腈 (β-APN)）、mRNA 表达（使用 siRNA）或蛋白表达（使用 25 μM 厚朴酚）特异性靶向 LOX 是否会减弱 MDA-MB-231 乳腺癌细胞的侵袭，进行了癌细胞迁移测定。有趣的是，只有 78.5%（n = 193）的乳腺癌肿瘤显示可检测到的 LOX 表达。近 60%（n = 120）的病例属于第 1 组（肿瘤>正常，T>N）；在该组中，肿瘤细胞中的 LOX 表达平均比正常细胞高 20.2 倍。然而，在第 2 组（正常>肿瘤，N>T）中，大多数检查的正常组织中的 LOX 表达水平（80%，59/73）小于肿瘤组织的五倍。侵袭性乳腺癌细胞系 MDA-MB-231 中活性 LOX 水平的增加伴随着粘着斑激酶 Tyr-576 磷酸化和桩蛋白 Tyr-118 磷酸化的增加。我们还发现，添加 300 μM β-APN 和 25 μM 厚朴酚协同抑制 MDA-MB-231 细胞的迁移和侵袭。在本文中，我们首次描述了亚洲患者乳腺癌肿瘤中 LOX 蛋白的表达高于正常组织。此外，结果表明，使用厚朴酚抑制 LOX 可能代表一种比使用 β-APN 更理想的乳腺癌治疗策略。
