Validation of p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs in patient-derived breast tumor xenografts
Validation of p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs in patient-derived breast tumor xenografts
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验证 p27KIP1 表达水平作为患者来源的乳腺肿瘤异种移植物中对 rapalogs 反应的候选预测生物标志物
DOI：
10.1007/s13277-014-2580-y
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Guang Chen
中科院分区：
文献类型：
--
作者：
Xiaofei Ding;D. Yin;Qian Chen;Hua;Jun Zhou;Guang Chen
阻断哺乳动物雷帕霉素靶点（mTOR）是乳腺癌治疗中一个有前景的领域。然而，在临床试验中，mTOR 抑制剂单药治疗乳腺癌的客观缓解率较低。旨在识别雷帕霉素类似物反应者的生物标志物研究越来越受到人们的关注。我们验证了 p27KIP1 表达水平作为对 rapalogs 反应的候选预测生物标志物。我们还分析了原发性乳腺癌细胞和患者来源的乳腺肿瘤异种移植模型中雷帕霉素活性与 p27KIP1 表达之间的相关性。从表达高水平p27KIP1的乳腺肿瘤组织中分离的细胞对雷帕霉素敏感，而从表达低水平p27KIP1的组织中分离的细胞对雷帕霉素表现出抗性。在患者来源的乳腺肿瘤异种移植模型中也观察到 p27KIP1 表达与雷帕霉素抗肿瘤活性之间的相关性。此外，我们还发现雷帕霉素显着降低了两个样品中的磷酸化 p70S6K1 和磷酸化 4EBP1。肿瘤细胞对雷帕霉素的不同敏感性似乎并不归因于其针对 mTOR 活性的不同效力。我们进一步提出p27KIP1表达水平也可能是rapalogs用于乳腺癌治疗的候选预测生物标志物，这需要额外的临床验证。
Blockade of mammalian target of rapamycin (mTOR) is a promising area in breast cancer therapy. However, in clinical trials, objective response rate with mTOR inhibitor monotherapy in breast cancer was modest. Biomarker studies designed to identify the responders of rapalogs are of increasing interest. We validated p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs. We also analyzed the correlation between rapamycin activity and p27KIP1 expression in the primary breast cancer cells and the patient-derived breast tumor xenograft models. The cells isolated from the breast tumor tissues expressing high levels of p27KIP1 were sensitive to rapamycin, whereas the cells from the tissues expressing low levels of p27KIP1 exhibited resistance to rapamycin. The correlation between p27KIP1 expression and rapamycin antitumor activity was also observed in the patient-derived breast tumor xenograft models. Moreover, we also found rapamycin significantly decreased phosphorylated p70S6K1 and phosphorylated 4EBP1 in both samples. It seemed that the different sensitivity of tumor cells to rapamycin did not owe to its different potency against mTOR activity. We further propose p27KIP1 expression level may be also a candidate predictive biomarker of rapalogs for breast cancer therapy, which requires additional clinical validation.
具有表型稳定，生物学和种族多样的，患者衍生的人类乳腺癌异种移植模型的可再生组织资源。
影响因子：
11.2
作者：
Zhang X;Claerhout S;Prat A;Dobrolecki LE;Petrovic I;Lai Q;Landis MD;Wiechmann L;Schiff R;Giuliano M;Wong H;Fuqua SW;Contreras A;Gutierrez C;Huang J;Mao S;Pavlick AC;Froehlich AM;Wu MF;Tsimelzon A;Hilsenbeck SG;Chen ES;Zuloaga P;Shaw CA;Rimawi MF;Perou CM;Mills GB;Chang JC;Lewis MT
通讯作者：
Lewis MT
影响因子：
16
作者：
Hong, Feng;Larrea, Michelle D.;Slingerland, Joyce M.
通讯作者：
Slingerland, Joyce M.