Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit.
Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit.
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DOI：
10.1007/s10549-012-2376-y
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发表时间：
2013-01
影响因子：
3.8
通讯作者：
Stal, Olle
中科院分区：
文献类型：
--
作者：
Bostner, Josefine;Karlsson, Elin;Pandiyan, Muneeswaran J.;Westman, Hanna;Skoog, Lambert;Fornander, Tommy;Nordenskjold, Bo;Stal, Olle
PI3K/Akt/ mtor生长信号通路的频繁改变被认为是乳腺癌内分泌治疗耐药的机制，部分通过调节雌激素受体α (ER)活性。改善个体化治疗需要可靠的治疗预测生物标志物。我们对912名绝经后淋巴结阴性乳腺癌患者的原发肿瘤进行了回顾性免疫组织化学分析，这些患者随机接受他莫昔芬治疗或无辅助治疗。磷酸化(p) akt -丝氨酸(s) 473、p- mtor -s2448和内质网磷酸化-s167和-s305作为预后和他莫昔芬治疗效果的潜在生物标志物进行评估。p-mTOR的高表达表明对他莫昔芬的反应降低，在ER+/孕激素受体(PgR) +亚组中最为明显(他莫昔芬vs.无他莫昔芬：危险比（HR）， 0.86；95%置信区间（CI）， 0.31-2.38；P = 0.78)，而低P - mtor表达预测他莫昔芬的益处（HR, 0.29; 95% CI, 0.18-0.49; P = 0.000002）。此外，核p-Akt-s473以及-s167和/或-s305的p-ER与他莫昔芬的疗效表现出相互作用，具有临界统计学意义。包括P - akt、P - mtor和P - er在内的阳性通路标记物的联合评分显示与他莫昔芬的获益显著相关（相互作用检验；P = 0.029）。生长信号通路和er信号通路之间的交叉对话被认为会影响激素受体阳性乳腺癌患者对他莫昔芬的反应。结果支持这一假设，因为过度活跃的通路与对他莫昔芬的反应降低显著相关。对串扰标志物的临床治疗前测试将是个性化辅助内分泌治疗的一步，无论是否添加PI3K/Akt/mTOR途径抑制剂。本文的在线版本（doi:10.1007/s10549-012-2376-y）包含补充材料，仅供授权用户使用。
The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor α (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31–2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18–0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors. The online version of this article (doi:10.1007/s10549-012-2376-y) contains supplementary material, which is available to authorized users.
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影响因子：
8.8
作者：
Perez-Tenorio, G;Stal, O
通讯作者：
Stal, O
影响因子：
45.3
作者：
Bachelot, Thomas;Bourgier, Celine;Pujade-Lauraine, Eric
通讯作者：
Pujade-Lauraine, Eric
影响因子：
28.2
作者：
Rodrik-Outmezguine VS;Chandarlapaty S;Pagano NC;Poulikakos PI;Scaltriti M;Moskatel E;Baselga J;Guichard S;Rosen N
通讯作者：
Rosen N
影响因子：
168.9
作者：
Davies, C.;Godwin, J.;Gray, R.;Clarke, M.;Darby, S.;McGale, P.;Wang, Y. C.;Peto, R.;Pan, H. C.;Cutter, D.;Taylor, C.;Ingle, J.
通讯作者：
Ingle, J.
影响因子：
11.5
作者：
Bostner, Josefine;Skoog, Lambert;Stal, Olle
通讯作者：
Stal, Olle