HER-2 gene amplification correlates with higher levels of angiogenesis and lower levels of hypoxia in primary breast tumors
HER-2 gene amplification correlates with higher levels of angiogenesis and lower levels of hypoxia in primary breast tumors
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DOI：
10.1158/1078-0432.ccr-03-0695
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发表时间：
2004-06-15
影响因子：
11.5
通讯作者：
Harris, LN
中科院分区：
文献类型：
--
作者：
Blackwell, KL;Dewhirst, MW;Harris, LN
目的：研究HER-2基因扩增、HER-2蛋白表达与肿瘤血管生成和氧合指标在可手术、浸润性乳腺癌患者中的关系。实验设计：1988年至1995年，425例转移性乳腺癌患者接受大剂量化疗联合自体移植。取原代瘤块，用von Willebrand因子抗体对血管进行免疫组织化学(IHC)染色。平均微血管密度(MVD)通过图像分析对三个不同的“血管热点”中的von Willebrand因子染色的细胞进行计数。采用免疫组织化学方法检测肿瘤组织中HER-2的表达，荧光原位杂交方法检测HER-2基因扩增产物，免疫组织化学方法检测碳酸氢酶9，免疫组织化学方法检测血管内皮生长因子。结果：HER-2基因扩增与最大MVD和平均MVD呈显著正相关(Spearman系数分别为0.51和0.50，P=0.03和0.05)。HER-2基因扩增与肿瘤缺氧标志物CA-9表达呈负相关(x~(2)，P=0.02)。HER-2基因扩增水平与血浆D-二聚体水平呈正相关(Spearman系数=0.43，P=0.021)。有趣的是，免疫组化检测到HER-2阳性的肿瘤组织中的VEGF染色减少(X_(2)=5.81；P=0.01)。免疫组化检测HER-2与MVD、D-二聚体无相关性。在所有被检测的变量中，只有平均(P=0.0016)和最大微血管密度(P=0.0128)预测无病生存率(COX单变量模型)。结论：HER-2扩增的乳腺癌增加了血管生成，减少了缺氧，增加了纤维蛋白降解的标志物。这些发现对乳腺癌的治疗具有预后、预测和治疗意义。
Purpose: This study investigated the connection among HER-2 gene amplification, HER-2 protein expression, and markers of tumor angiogenesis and oxygenation in patients with operable, invasive breast tumors.Experimental Design: From 1988 to 1995, 425 patients with metastatic breast cancer were enrolled in a study of high-dose chemotherapy with autologous transplant. Primary tumor blocks were obtained and evaluated using immunohistochemistry (IHC) staining of vessels with von Willebrand factor antibody. Mean microvessel densities (MVD) were determined by counting von Willebrand factor stained cells in three separate "vascular hot spots" using image analysis. Tumor samples were also stained for HER-2 by IHC, HER-2 gene amplification by fluorescence in situ hybridization, carbonic anhydrase 9 by IHC, and vascular endothelial growth factor (VEGF) by IHC. Plasma from 36 patients with primary tumor samples had VEGF (R&D Systems, MN) and D-dimer (American Diagnostica, Greenwich, CT) levels determined.Results: There was a significant positive correlation between HER-2 gene amplification and both maximum and average MVD (Spearman coefficient = 0.51 and 0.50; P = 0.03 and 0.05, respectively). There was an inverse correlation with HER-2 gene amplification and expression of the tumor hypoxia marker CA-9 (chi(2) P = 0.02). The level of HER-2 gene amplification correlated with plasma D-dimer levels (Spearman coefficient = 0.43; P = 0.021). Interestingly, tumors with HER-2 by IHC had decreased amounts of VEGF staining (chi(2) = 5.81; P = 0.01). There was no correlation between HER-2 by IHC and MVD or D-dimer. Of all of the variables examined, only average (P = 0.0016) and maximum MVD (P = 0.0128) predicted disease-free survival (Cox univariate model).Conclusions: HER-2-amplified breast cancers have increased amounts of angiogenesis, decreased amounts of hypoxia, and increased markers of fibrin degradation. These findings have prognostic, predictive, and therapeutic implications in breast cancer treatment.