Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, BCM:600, Room N1110, Houston, TX 77030, USA.
Breast Cancer Res Treat. 2010 Oct;123(3):651-60. doi: 10.1007/s10549-009-0632-6. Epub 2009 Nov 19.
Insulin receptor substrate-1 (IRS-1) is a cytoplasmic scaffolding protein that is phosphorylated by insulin-like growth factor-I receptor and recruits downstream effectors. Recent evidence suggests that IRS-1 has a nuclear localization and function. Here we investigated whether nuclear and cytoplasmic IRS-1 levels are associated with clinico-pathological characteristics and clinical outcome in breast cancer patients. Tissue microarrays from 1,097 patients with stage I-II breast cancer were stained by immunohistochemistry for IRS-1. Nuclear and cytoplasmic IRS-1 were scored separately according to the Allred score. Nuclear IRS-1 showed a positive association with estrogen receptor (ER) (r = 0.09, P = 0.003) and progesterone receptor (PR) (r = 0.08, P = 0.008) status and a negative correlation with lymph node involvement (r = -0.10, P = 0.001). Cytoplasmic IRS-1 did not correlate with ER or PR but showed a positive correlation with tumor size (r = 0.10, P = 0.001) and S-phase fraction (r = 0.16, P < 0.001). In univariate analysis, tamoxifen-treated patients with tumors showing positive nuclear IRS-1 had a better recurrence-free survival (RFS) (P = 0.009) and overall survival (OS) (P = 0.0007), while no association was shown between cytoplasmic IRS-1 and RFS or OS in the same group of patients. In multivariate analysis of patients receiving tamoxifen, negative nuclear IRS-1 showed a significantly reduced RFS (P = 0.046) and OS (P = 0.018). Combining both PR and nuclear IRS-1, tamoxifen-treated patients with PR+/IRS-1+ tumors had a better RFS (P = 0.0003) and OS (P < 0.0001) when compared with patients with PR-/IRS-1- tumors. In conclusion, nuclear IRS-1 may be a useful marker to predict tamoxifen response in patients with early breast cancer, particularly when assessed in combination with PR.
胰岛素受体底物-1（IRS-1）是一种细胞质支架蛋白，可被胰岛素样生长因子-I 受体磷酸化，并募集下游效应物。最近的证据表明，IRS-1 具有核定位和功能。在这里，我们研究了核内和细胞质 IRS-1 水平是否与乳腺癌患者的临床病理特征和临床结局相关。用免疫组织化学法对来自 1097 例 I 期-II 期乳腺癌患者的组织微阵列进行 IRS-1 染色。根据 Allred 评分，分别对核内和细胞质 IRS-1 进行评分。核 IRS-1 与雌激素受体（ER）（r = 0.09，P = 0.003）和孕激素受体（PR）（r = 0.08，P = 0.008）状态呈正相关，与淋巴结受累呈负相关（r = -0.10，P = 0.001）。细胞质 IRS-1 与 ER 或 PR 不相关，但与肿瘤大小呈正相关（r = 0.10，P = 0.001）和 S 期分数呈正相关（r = 0.16，P <0.001）。在单因素分析中，接受他莫昔芬治疗且肿瘤核 IRS-1 阳性的患者无复发生存率（RFS）（P = 0.009）和总生存率（OS）（P = 0.0007）更好，而同一组患者中，细胞质 IRS-1 与 RFS 或 OS 之间没有关联。在接受他莫昔芬治疗的患者的多因素分析中，阴性核 IRS-1 显示 RFS（P = 0.046）和 OS（P = 0.018）显著降低。将 PR 和核 IRS-1 相结合，与 PR-/IRS-1-肿瘤患者相比，接受他莫昔芬治疗且 PR+/IRS-1+肿瘤的患者具有更好的 RFS（P = 0.0003）和 OS（P <0.0001）。总之，核 IRS-1 可能是预测早期乳腺癌患者他莫昔芬反应的有用标志物，尤其是在与 PR 联合评估时。
