Coexpression of alpha6beta4 integrin and guanine nucleotide exchange factor Net1 identifies node-positive breast cancer patients at high risk for distant metastasis.
Coexpression of alpha6beta4 integrin and guanine nucleotide exchange factor Net1 identifies node-positive breast cancer patients at high risk for distant metastasis.
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DOI：
10.1158/1055-9965.epi-08-0842
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发表时间：
2009-01
期刊：
影响因子：
--
通讯作者：
Frost JA
中科院分区：
文献类型：
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作者：
Gilcrease MZ;Kilpatrick SK;Woodward WA;Zhou X;Nicolas MM;Corley LJ;Fuller GN;Tucker SL;Diaz LK;Buchholz TA;Frost JA
临床前数据表明，α6β4整合素通过Ras同源基因家族成员A的信号传导在肿瘤细胞运动中起重要作用。本研究的目的是确定α6β4整合素和神经上皮瘤转化基因1（Net 1）（Ras同源基因家族成员A特异性鸟嘌呤核苷酸交换因子）的联合表达是否与乳腺癌患者的不良临床结局相关。每种蛋白质的免疫组化表达在肿瘤组织微阵列中进行了评估，该微阵列是从94例淋巴结阳性的浸润性乳腺癌患者的原发肿瘤中制备的，这些患者接受了全乳房切除术和基于阿霉素的化疗，而没有放射治疗，中位随访时间为12.5年。染色结果和多个临床病理变量之间的关联进行了研究。虽然当单独考虑每种标志物时，α6β4整合素或Net 1表达与临床结局之间没有显著相关性，但α6β4和Net 1的共表达与无远处转移生存率降低相关（P = 0.030）。在激素受体阳性肿瘤患者亚组中，α6β4和Net 1的共表达与无远处转移和总生存率的降低相关（分别为P < 0.001和P = 0.006）。尽管人表皮生长因子受体2表达与α6β4和Net 1共表达之间存在相关性，（P = 0.008），α6β4和Net 1共表达（风险比，1.63; P = 0.02）和淋巴管浸润多因素分析显示，与远处转移发生独立相关的因素仅为（hazard ratio，2.35; P = 0.02）。这些发现表明，α6β4整合素和Net 1的共表达可能是淋巴结阳性乳腺癌患者侵袭性疾病的有用生物标志物。
Preclinical data indicate that α6β4 integrin signaling through Ras homolog gene family, member A, plays an important role in tumor cell motility. The objective of this study was to determine whether the combined expression of α6β4 integrin and neuroepithelioma transforming gene 1 (Net1), a guanine nucleotide exchange factor specific for Ras homolog gene family member A, is associated with adverse clinical outcome in breast cancer patients. Immunohistochemical expression of each protein was evaluated in a tumor tissue microarray prepared from the primary tumors of 94 node-positive patients with invasive breast carcinoma treated with total mastectomy and doxorubicin-based chemotherapy without radiation with a median follow-up of 12.5 years. Associations between staining results and multiple clinicopathologic variables were investigated. Although there was no significant association between α6β4 integrin or Net1 expression and clinical outcome when each marker was considered individually, coexpression of α6β4 and Net1 was associated with decreased distant metastasis–free survival (P = 0.030). In the subset of patients with hormone receptor–positive tumors, coexpression of α6β4 and Net1 was associated with a decrease in distant metastasis–free and overall survival (P < 0.001 and P = 0.006, respectively). Although an association between human epidermal growth factor receptor 2 expression and coexpression of α6β4 and Net1 (P = 0.008) was observed, coexpression of α6β4 and Net1 (hazard ratio, 1.63; P = 0.02) and lymphovascular invasion (hazard ratio, 2.35; P = 0.02) were the only factors independently associated with the development of distant metastasis in multivariate analysis. These findings suggest that coexpression of α6β4 integrin and Net1 could be a useful biomarker for aggressive disease in node-positive breast cancer patients.