Estrogen Receptor-α Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer
Estrogen Receptor-α Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer
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DOI：
10.1158/1078-0432.ccr-09-1733
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发表时间：
2010-03-01
影响因子：
11.5
通讯作者：
Stal, Olle
中科院分区：
文献类型：
--
作者：
Bostner, Josefine;Skoog, Lambert;Stal, Olle
目的：在体外，p21活化激酶1 （Pak1）磷酸化雌激素受体α (ER α)丝氨酸305残基，影响乳腺癌细胞对他莫昔芬的反应。我们研究了Pak1和pER α (ser305)对乳腺癌预后和他莫昔芬治疗结果的影响。实验设计：我们通过免疫组织化学检测了912例随机接受他莫昔芬或无辅助内分泌治疗的淋巴结阴性乳腺癌患者肿瘤中的Pak1和pER α (ser305)蛋白。结果：胞质Pak1与大肿瘤和ER阴性相关，核Pak1和pER α (ser305)与小肿瘤和ER阳性相关。Pak1和pER α (ser305)的核表达预测ER α阳性肿瘤患者对他莫昔芬的反应降低(他莫昔芬与无他莫昔芬：风险比（HR）， 1.33；95%置信区间（95% CI）， 0.42-4.2；P = 0.63)，而缺乏这种组合的患者从他莫昔芬中获益显著（HR, 0.43; 95% CI, 0.30-0.62; P < 0.0001）。在对蛋白质的单独分析中也发现了类似的不显著趋势。细胞质中Pak1是一个独立的预后指标，表明随机接受无辅助治疗的患者复发率（HR, 1.79; 95% CI, 1.17-2.74; P = 0.0068）和乳腺癌死亡率（HR, 1.98; 95% CI, 1.14-3.46; P = 0.016）增加。结论：我们的研究结果表明，Pak1和pER α (ser305)联合表达的肿瘤患者是他莫昔芬治疗不足的群体。此外，该途径可能作为乳腺癌的药物靶点。此外，这些发现支持了先前的研究，表明Pak1在细胞质和细胞核中具有不同的作用。临床癌症研究；16 (5);1624 - 33所示。(c) 2010年aacr。
Purpose: In vitro, p21-activated kinase 1 (Pak1) phosphorylates the serine 305 residue of the estrogen receptor alpha (ER alpha) and influences the response of breast cancer cells to tamoxifen. We investigated the influence of Pak1 and pER alpha(ser305) on breast cancer prognosis and results of tamoxifen therapy.Experimental Design: We examined Pak1 and pER alpha(ser305) protein by immunohistochemistry in a series of 912 tumors from node-negative breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment.Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity, whereas nuclear Pak1 and pER alpha(ser305) correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pER alpha(ser305) predicted reduced response to tamoxifen in patients with ER alpha-positive tumors (tamoxifen versus no tamoxifen: hazard ratio (HR), 1.33; 95% confidence interval (95% CI), 0.42-4.2; P = 0.63), whereas patients lacking this combination benefitted significantly from tamoxifen (HR, 0.43; 95% CI, 0.30-0.62; P < 0.0001). Similar nonsignificant trends were detected in analyses of the proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR, 1.79; 95% CI, 1.17-2.74; P = 0.0068) and breast cancer mortality (HR, 1.98; 95% CI, 1.14-3.46; P = 0.016) for patients randomized to no adjuvant treatment.Conclusion: Our results suggest that patients with tumors expressing Pak1 and pER alpha(ser305) in combination are a group in which tamoxifen treatment is insufficient. In addition, the pathway may be of interest as a drug target in breast cancer. Furthermore, the findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus. Clin Cancer Res; 16(5); 1624-33. (C) 2010 AACR.