Fujii Teruhiko, Kawahara Akihiko, Basaki Yuji, Hattori Satoshi, Nakashima Kazutaka, Nakano Kenji, Shirouzu Kazuo, Kohno Kimitoshi, Yanagawa Takashi, Yamana Hideaki, Nishio Kazuto, Ono Mayumi, Kuwano Michihiko, Kage Masayoshi
Center for Innovative Cancer Therapy of the 21st Century Center of Excellence Program for Medical Science, Department of Surgery, Kurume University School of Medicine, Kurume, Japan.
Cancer Res. 2008 Mar 1;68(5):1504-12. doi: 10.1158/0008-5472.CAN-07-2362.
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.
在我们目前的研究中，我们检测了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）、激素受体以及其他影响乳腺癌预后的分子的表达相关。采用免疫组织化学方法分析核YB-1的表达、临床病理特征以及分子标志物[EGFR、HER2、雌激素受体（ER）α、ERβ、孕激素受体、趋化因子（C-X-C基序）受体4（CXCR4）、磷酸化Akt以及主要穹窿蛋白/肺耐药蛋白]。利用微阵列、定量实时PCR和蛋白质免疫印迹分析，检测乳腺癌细胞系中核YB-1表达与分子标志物之间的关联。用小干扰RNA（siRNA）敲低YB-1可显著降低ERα阳性而非ERα阴性乳腺癌细胞系中EGFR、HER2和ERα的表达。在人乳腺癌临床标本中，核YB-1表达与HER2呈正相关（P = 0.0153），与ERα（P = 0.0122）和CXCR4（P = 0.0166）呈负相关，但与EGFR表达无相关性。核YB-1表达是总生存（P = 0.0139）和无进展生存（P = 0.0280）的独立预后因素。总之，核YB-1表达可能通过HER2-Akt依赖途径对乳腺癌患者获得恶性特征至关重要。YB-1的核定位不仅可能是抗多药耐药的重要治疗靶点，也是抗依赖HER2和ERα的肿瘤生长的重要治疗靶点。
