Sanz-Álvarez Marta, Cristóbal Ion, Luque Melani, Santos Andrea, Zazo Sandra, Madoz-Gúrpide Juan, Caramés Cristina, Chiang Cheng-Ming, García-Foncillas Jesús, Eroles Pilar, Albanell Joan, Rojo Federico
Pathology Department, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS-FJD, UAM)-CIBERONC, E-28040 Madrid, Spain.
Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain.
Cancers (Basel). 2021 Mar 12;13(6):1246. doi: 10.3390/cancers13061246.
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 ( = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall ( < 0.001) and event-free survival ( < 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.
含溴结构域蛋白4（BRD4）是溴结构域和额外末端结构域（BET）蛋白家族的成员，近年来已成为包括乳腺癌在内的许多肿瘤中有前景的分子靶点。三阴性乳腺癌（TNBC）是预后最差且当前面临治疗挑战的分子亚型，据报道TNBC细胞对BET抑制剂表现出优先敏感性。有趣的是，发现BRD4磷酸化（pBRD4）是一种赋予对BET抑制耐药性的改变，并且提出蛋白磷酸酶2A（PP2A）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途径的潜在相关性仍有待研究。在此，我们评估了132例TNBC患者中pBRD4的表达水平。我们发现34.1%的病例（45/132）中pBRD4水平较高，并且发现这种改变与患者复发的发生相关（P = 0.007）。有趣的是，BRD4过度磷酸化显著预测了更短的总生存期（P < 0.001）和无事件生存期（P < 0.001）。此外，进行了多变量分析以确认其在我们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，它定义了一组预后不良的TNBC患者，提示PP2A/BRD4轴作为克服基于BRD4抑制的治疗耐药性的新型分子靶点具有潜在的临床和治疗价值。
