PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects.
PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects.
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DOI：
10.18632/oncotarget.3012
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发表时间：
2015-02-28
期刊：
影响因子：
--
通讯作者：
Rojo F
中科院分区：
文献类型：
--
作者：
Rincón R;Cristóbal I;Zazo S;Arpí O;Menéndez S;Manso R;Lluch A;Eroles P;Rovira A;Albanell J;García-Foncillas J;Madoz-Gúrpide J;Rojo F
蛋白磷酸酶2A （protein phosphatase 2A, PP2A）是一种关键的肿瘤抑制因子，已成为一些人类癌症的新分子靶点。在这里，我们发现PP2A抑制在乳腺癌中是一个常见的事件，并确定PP2A磷酸化和去调控SET和CIP2A是PP2A失活的分子机制。有趣的是，FTY720处理后，PP2A活性的恢复减少了细胞生长，诱导凋亡，降低了AKT和ERK的激活。此外，FTY720可激活PP2A，从而增强阿霉素诱导的体外和体内抗肿瘤作用。27%的病例（62/230）检测到PP2A抑制（CPscore: PP2A磷酸化和/或CIP2A过表达），并与分级（p = 0.017）、复发（p < 0.001）、雌激素（p < 0.001）和孕激素受体表达（p < 0.001）、her2阳性肿瘤（p = 0.049）、Ki-67表达（p < 0.001）以及AKT （p < 0.001）和ERK （p < 0.001）磷酸化升高相关。此外，PP2A抑制缩短了总生存期（p = 0.006）和无事件生存期（p = 0.003），多变量分析证实了其独立的预后影响。总之，我们的研究结果表明，PP2A在乳腺癌中经常失活，并决定了更糟糕的结果，使用PP2A激活剂恢复PP2A代表了这种疾病的另一种治疗策略。
The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease.
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