Ding Xiao-Fei, Yin Dong-Qing, Chen Qian, Zhang Hua-Yuan, Zhou Jun, Chen Guang
School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China.
Tumour Biol. 2015 Mar;36(3):1463-9. doi: 10.1007/s13277-014-2580-y. Epub 2015 Mar 7.
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.
阻断哺乳动物雷帕霉素靶蛋白（mTOR）是乳腺癌治疗中一个很有前景的领域。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并不高。旨在识别雷帕霉素类药物反应者的生物标志物研究越来越受到关注。我们验证了p27KIP1表达水平作为对雷帕霉素类药物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出的细胞对雷帕霉素敏感，而从表达低水平p27KIP1的组织中分离出的细胞对雷帕霉素具有抗性。在患者来源的乳腺肿瘤异种移植模型中也观察到了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在两个样本中均显著降低了磷酸化的p70S6K1和磷酸化的4EBP1。肿瘤细胞对雷帕霉素的不同敏感性似乎并非归因于其对mTOR活性的不同效力。我们进一步提出，p27KIP1表达水平可能也是乳腺癌治疗中雷帕霉素类药物的候选预测生物标志物，这需要更多的临床验证。
