Expression of HER2 and estrogen receptor α depends upon nuclear localization of Y-box binding protein-1 in human breast cancers
Expression of HER2 and estrogen receptor α depends upon nuclear localization of Y-box binding protein-1 in human breast cancers
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DOI：
10.1158/0008-5472.can-07-2362
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发表时间：
2008-03-01
期刊：
影响因子：
11.2
通讯作者：
Kage, Masayoshi
中科院分区：
文献类型：
--
作者：
Fujii, Teruhiko;Kawahara, Akihiko;Kage, Masayoshi
在我们目前的研究中，我们研究了Y盒结合蛋白-1（YB-1）的核定位是否与表皮生长因子受体（EGFR）、激素受体和其他影响乳腺癌预后的分子的表达相关。对细胞核YB-1的表达、临床病理结果和分子标志物[EGFR、HER 2、雌激素受体（ER）α、ER β、孕激素受体、趋化因子（C-X-C基序）受体4（CXCR 4）、磷酸化Akt和主要穹窿蛋白/肺耐药蛋白]进行化学分析。使用微阵列、定量实时PCR和Western印迹分析，在乳腺癌细胞系中检查核YB-1表达和分子标记的关联。用siRNA敲低YB-1显著降低ER α阳性乳腺癌细胞系中EGFR、HER 2和ER α的表达，但不降低ER α阴性乳腺癌细胞系中的表达。在乳腺癌临床标本中，YB-1表达与HER 2表达呈正相关（P = 0.0153），与ER α表达呈负相关（P = 0.0122），与CXCR 4表达呈负相关（P = 0.0166），与EGFR表达无相关性。核YB-1表达是总体（P = 0.0139）和无进展生存（P = 0.0280）的独立预后因素。总之，核YB-1表达可能是必要的收购恶性特征，通过HER 2-Akt依赖性途径在乳腺癌患者。YB-1的核定位可能是一个重要的治疗靶点，不仅针对多药耐药，而且针对依赖于HER 2和ER α的肿瘤生长。
In our present study, we examined whether nuclear localization of Y-box binding protein-1 (YB-1) is associated with the expression of epidermal growth factor receptors (EGFR), hormone receptors, and other molecules affecting breast cancer prognosis. The expression of nuclear YB-1, clinicopathologic findings, and molecular markers [EGFR, HER2, estrogen receptor (ER)alpha, ER beta, progesterone receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), phosphorylated Akt, and major vault protein/lung resistance protein] were immunohistochemically analyzed. The association of the expression of nuclear YB-1 and the molecular markers was examined in breast cancer cell lines using microarrays, quantitative real-time PCR, and Western blot analyses. Knockdown of YB-1 with siRNA significantly reduced EGFR, HER2, and ER alpha expression in ER alpha-positive, but not ER alpha-negative, breast cancer cell lines. Nuclear YB-1 expression was positively correlated with HER2 (P = 0.0153) and negatively correlated with ER alpha (P = 0.0122) and CXCR4 (P = 0.0166) in human breast cancer clinical specimens but was not correlated with EGFR expression. Nuclear YB-1 expression was an independent prognostic factor for overall (P = 0.0139) and progression-free (P = 0.0280) survival. In conclusion, nuclear YB-1 expression might be essential for the acquisition of malignant characteristics via HER2-Akt-dependent pathways in breast cancer patients. The nuclear localization of YB-1 could be an important therapeutic target against not only multidrug resistance but also tumor growth dependent on HER2 and ER alpha.