Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
Clin Epigenetics. 2021 Apr 7;13(1):72. doi: 10.1186/s13148-021-01060-2.
The development of new biomarkers with diagnostic, prognostic and therapeutic prominence will greatly enhance the management of breast cancer (BC). Several reports suggest the involvement of the histone acetyltransferases CREB-binding protein (CBP) and general control non-depressible 5 (GCN5) in tumor formation; however, their clinical significance in BC remains poorly understood. This study aims to investigate the value of CBP and GCN5 as markers and/or targets for BC prognosis and therapy. Expression of CBP, GCN5, estrogen receptor α (ERα), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in BC was analyzed in cell lines by western blot and in patients' tissues by immunohistochemistry. The gene amplification data were also analyzed for CBP and GCN5 using the publicly available data from BC patients.
Elevated expression of CBP and GCN5 was detected in BC tissues from patients and cell lines more than normal ones. In particular, CBP was more expressed in luminal A and B subtypes. Using chemical and biological inhibitors for CBP, ERα and HER2 showed a strong association between CBP and the expression of ERα and HER2. Moreover, analysis of the CREBBP (for CBP) and KAT2A (for GCN5) genes in a larger number of patients in publicly available databases showed amplification of both genes in BC patients. Amplification of CREBBP gene was observed in luminal A, luminal B and triple-negative but not in HER2 overexpressing subtypes. Furthermore, patients with high CREBBP or KAT2A gene expression had better 5-year disease-free survival than the low gene expression group (p = 0.0018 and p < 0.00001, respectively).
We conclude that the persistent amplification and overexpression of CBP in ERα- and PR-positive BC highlights the significance of CBP as a new diagnostic marker and therapeutic target in hormone-positive BC.
具有诊断、预后和治疗重要性的新型生物标志物的开发将极大地提高乳腺癌（BC）的管理水平。有几项报告表明，CREB 结合蛋白（CBP）和一般控制不可抑制 5（GCN5）的组蛋白乙酰转移酶参与肿瘤形成；然而，它们在 BC 中的临床意义仍知之甚少。本研究旨在探讨 CBP 和 GCN5 作为 BC 预后和治疗标志物和/或靶点的价值。通过 Western blot 在细胞系中分析 CBP、GCN5、雌激素受体α（ERα）、孕激素受体（PR）和人表皮生长因子受体 2（HER2）在 BC 中的表达，并通过免疫组织化学在患者组织中分析。还使用来自 BC 患者的公开可用数据分析了 CBP 和 GCN5 的基因扩增数据。
在 BC 患者的组织和细胞系中检测到 CBP 和 GCN5 的表达升高。特别是，CBP 在腔 A 和 B 亚型中表达更高。使用 CBP 的化学和生物抑制剂，ERα 和 HER2 显示 CBP 与 ERα 和 HER2 的表达之间存在很强的关联。此外，在公开可用数据库中对更多患者的 CREBBP（用于 CBP）和 KAT2A（用于 GCN5）基因进行分析显示，BC 患者的这两个基因均发生扩增。CREBBP 基因的扩增发生在腔 A、腔 B 和三阴性，但不发生在 HER2 过表达亚型中。此外，高 CREBBP 或 KAT2A 基因表达的患者的 5 年无病生存率高于低基因表达组（p=0.0018 和 p<0.00001）。
我们得出结论，CBP 在 ERα 和 PR 阳性 BC 中的持续扩增和过表达突出了 CBP 作为激素阳性 BC 新的诊断标志物和治疗靶点的重要性。
