Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients.
Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients.
复制标题
磷酸化BRD4的表达与PP2A通路的激活状态显著相关，并在三阴性乳腺癌患者中显示出强预后价值。
DOI：
10.3390/cancers13061246
复制
发表时间：
2021-03-12
期刊：
影响因子：
5.2
通讯作者：
Rojo F
中科院分区：
文献类型：
--
作者：
Sanz-Álvarez M;Cristóbal I;Luque M;Santos A;Zazo S;Madoz-Gúrpide J;Caramés C;Chiang CM;García-Foncillas J;Eroles P;Albanell J;Rojo F
BRD4抑制剂的使用已经成为包括三阴性乳腺癌在内的多种肿瘤的一种新的治疗方法。此外，PP2A被认为是参与调节BRD4磷酸化和稳定的磷酸酶。我们的目的是首次评估BRD4磷酸化在三阴性乳腺癌患者中的临床影响，以及它与该疾病中PP2A激活状态的潜在联系。我们的研究结果具有特殊的相关性，因为它们表明BRD4磷酸化水平的预后价值，以及PP2A抑制标志物在预测BRD4抑制剂反应方面的潜在临床用途。含溴结构域蛋白4 （BRD4）是溴结构域和外末端结构域（BET）蛋白家族的一员，近年来作为包括乳腺癌在内的许多肿瘤的有前途的分子靶点而出现。三阴性乳腺癌（TNBC）代表了预后最差的分子亚型和当前的治疗挑战，据报道，TNBC细胞对BET抑制剂表现出优先敏感性。有趣的是，BRD4磷酸化（pBRD4）被发现是一种改变，赋予对BET抑制的抗性，PP2A被认为是负责调节pBRD4水平的磷酸酶。然而，pBRD4的潜在临床意义及其与TNBC中PP2A通路的潜在相关性仍有待研究。在这里，我们评估了pBRD4在132例TNBC患者中的表达水平。我们发现34.1%的病例中pBRD4水平较高（45/132），并且发现这种改变与患者复发的发展有关（p = 0.007）。有趣的是，BRD4过度磷酸化预测总体（p < 0.001）和无事件生存期（p < 0.001）显著缩短。此外，我们还进行了多变量分析，以证实其在我们的队列中的独立预后影响。总之，我们的研究结果表明，BRD4过度磷酸化是一种与PP2A抑制相关的改变，它定义了一个预后不良的TNBC患者亚组，这表明PP2A/BRD4轴作为克服基于BRD4抑制的治疗耐药的新分子靶点具有潜在的临床和治疗价值。
The use of BRD4 inhibitors has emerged as a novel therapeutic approach in a wide variety of tumors including the triple negative breast cancer. Moreover, PP2A has been proposed as the phosphatase involved in regulating BRD4 phosphorylation and stabilization. Our aim was to evaluate for the first time the clinical impact of BRD4 phosphorylation in triple negative breast cancer patients and as well as its potential linking with the PP2A activation status in this disease. Our findings are special relevant since they suggest the prognostic value of BRD4 phosphorylation levels, and the potential clinical usefulness of PP2A inhibition markers to anticipate response to BRD4 inhibitors. The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.
登录
查看更多内容
DOI：
10.1016/j.breast.2015.07.009
发表时间：
2015-11
期刊：
Breast (Edinburgh, Scotland)
影响因子：
--
作者：
Lehmann BD;Pietenpol JA
通讯作者：
Pietenpol JA
影响因子：
--
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
通讯作者：
Rojo F
固定过表达与接受他莫昔芬辅助治疗的原发性乳腺癌患者的无复发生存率较差有关。
影响因子：
3.9
作者：
Huang YH;Chu PY;Chen JL;Huang CT;Lee CH;Lau KY;Wang WL;Wang YL;Lien PJ;Tseng LM;Liu CY
通讯作者：
Liu CY
影响因子：
--
作者：
Hammond, M. Elizabeth H.;Hayes, Daniel F.;Temin, Sarah
通讯作者：
Temin, Sarah
影响因子：
5
作者：
Obuchowski, NA
通讯作者：
Obuchowski, NA