Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cancerología, Av. San Fernando No. 22, Sección XVI, Tlalpan, 14080, Ciudad de México, Mexico.
Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados (CINVESTAV-IPN), 07360, Ciudad de México, Mexico.
BMC Cancer. 2018 Jul 3;18(1):709. doi: 10.1186/s12885-018-4613-1.
HER2 over-expression is related with a poor prognosis in patients with invasive breast cancer tumors. Clinical associations have reported that somatic mutations of p53 more frequently detected in cases of sporadic breast cancer of the HER2 subtypes, besides a high percentage of HER2-amplifying tumors carry germline mutations of p53. The mechanisms responsible for the acquisition of oncogenic functions of p53 mutant proteins (mtp53), known as Gain of Function (GOF), over HER2 expression have not been reported. The objective of this study was to evaluate a possible relationship between p53 mutants and HER2 regulation.
HER2 expression (transcription and protein), as well as HER2 protein stabilization have been evaluated after inducing or silencing of p53 mutants' expression in cell lines. Finally, we evaluated the interaction of the p53 mutants over the HER2 receptor promoter.
Higher HER2 expression in cell lines harboring endogenous mtp53 compared with wt or null expression of p53 cell lines. Transfection of p53 mutants (R248Q and R273C) in cell lines increased the expression of HER2. Silencing of p53 mutants, decrease HER2 expression. The p53 mutants R248Q and R273C significantly increase the luciferase activity on the HER2 promoter, and both mutants also promote acetylation of H3 and H4 histones binding in it.
These findings show for the first time that p53 mutants induce over-expression of HER2 at transcriptional level of the HER2 protein. Our results could have clinical implications in breast cancer and other types of cancer where HER2 is over-expressed and used as a therapy target.
HER2 过表达与浸润性乳腺癌患者的预后不良有关。临床关联报告称，在 HER2 亚型的散发性乳腺癌病例中，p53 的体细胞突变更频繁地被检测到，除了高比例的 HER2 扩增肿瘤携带 p53 的种系突变。导致 p53 突变蛋白（mtp53）获得致癌功能的机制，称为功能获得（GOF），与 HER2 表达的关系尚未报道。本研究的目的是评估 p53 突变体与 HER2 调节之间可能存在的关系。
在细胞系中诱导或沉默 p53 突变体的表达后，评估 HER2 表达（转录和蛋白）以及 HER2 蛋白稳定性。最后，我们评估了 p53 突变体对 HER2 受体启动子的相互作用。
与 wt 或 p53 缺失表达的细胞系相比，内源性 mtp53 存在的细胞系中 HER2 表达更高。p53 突变体（R248Q 和 R273C）转染到细胞系中会增加 HER2 的表达。沉默 p53 突变体可降低 HER2 表达。p53 突变体 R248Q 和 R273C 显著增加了 HER2 启动子上的荧光素酶活性，并且这两种突变体还促进了结合在其上的 H3 和 H4 组蛋白的乙酰化。
这些发现首次表明，p53 突变体在 HER2 蛋白的转录水平诱导 HER2 的过表达。我们的研究结果可能对 HER2 过表达并用作治疗靶点的乳腺癌和其他类型的癌症具有临床意义。
