Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Breast Cancer Res Treat. 2011 Aug;128(3):713-23. doi: 10.1007/s10549-010-1058-x. Epub 2010 Oct 16.
The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.
哺乳动物雷帕霉素靶蛋白（mTOR）及其底物 S6K1 和 S6K2 通过翻译控制调节细胞生长、增殖和代谢。RPS6KB1（S6K1）和 RPS6KB2（S6K2）位于共同扩增的 17q21-23 和 11q13 区域。S6K1 扩增和蛋白过表达先前与乳腺癌预后不良相关，但关于 S6K2 的信息很少。本研究旨在评估 S6K1/S6K2 基因扩增以及乳腺癌中 S6K2 蛋白表达的预后和治疗预测相关性。在 207 例 II 期乳腺癌中通过实时 PCR 确定 S6K1/S6K2 基因拷贝数，在 792 例淋巴结阴性乳腺癌中通过免疫组化检测 S6K2 蛋白表达。在 10.7%/21.4%和 4.3%/21.3%的肿瘤中检测到 S6K1 扩增/增益，在 4.3%/21.3%的肿瘤中检测到 S6K2 扩增/增益。S6K2 蛋白在肿瘤细胞的核（38%）和细胞质（76%）中均有检测到。S6K1 扩增与 HER2 基因扩增和蛋白表达显著相关。S6K2 扩增与高 S6K2 mRNA 水平、ER+状态和 CCND1 扩增显著相关。S6K1 和 S6K2 基因扩增与 HER2 和 CCND1 无关的不良预后相关。S6K2 增益和核 S6K2 表达与 ER+、分别为 ER+/PgR+肿瘤中接受他莫昔芬治疗的获益增加相关。在 ER+/PgR-亚组中，核 S6K2 反而提示他莫昔芬反应性降低。S6K1 扩增预测放疗获益减少。这是第一项表明 S6K2 扩增和过表达与 S6K1 扩增一样，在乳腺癌中具有预后和治疗预测意义的研究。
