Department of Medicine (DAME), University of Udine, Piazzale M. Kolbe 4, 33100, Udine, Italy.
Department of Oncology, ASUI Udine SMM University Hospital Udine, Udine, Italy.
J Exp Clin Cancer Res. 2019 Jul 15;38(1):309. doi: 10.1186/s13046-019-1294-9.
Triple negative breast cancer (TNBC) is a breast cancer subgroup characterized by a lack of hormone receptors' expression and no HER2 overexpression. These molecular features both drastically reduce treatment options and confer poor prognosis. Platinum (Pt)-salts are being investigated as a new therapeutic strategy. The base excision repair (BER) pathway is important for resistance to Pt-based therapies. Overexpression of APE1, a pivotal enzyme of the BER pathway, as well as the expression of NPM1, a functional regulator of APE1, are associated with poor outcome and resistance to Pt-based therapies.
We evaluated the role of NPM1, APE1 and altered NPM1/APE1 interaction in the response to Pt-salts treatment in different cell lines: APE1 knockout (KO) cells, NPM1 KO cells, cell line models having an altered APE1/NPM1 interaction and HCC70 and HCC1937 TNBC cell lines, having different levels of APE1/NPM1. We evaluated the TNBC cells response to new chemotherapeutic small molecules targeting the endonuclease activity of APE1 or the APE1/NPM1 interaction, in combination with Pt-salts treatments. Expression levels' correlation between APE1 and NPM1 and their impact on prognosis was analyzed in a cohort of TNBC patients through immunohistochemistry. Bioinformatics analysis, using TCGA datasets, was performed to predict a molecular signature of cancers based on APE1 and NPM1 expression.
APE1 and NPM1, and their interaction as well, protect from the cytotoxicity induced by Pt-salts treatment. HCC1937 cells, having higher levels of APE1/NPM1 proteins, are more resistant to Pt-salts treatment compared to the HCC70 cells. A sensitization effect by APE1 inhibitors to Pt-compounds was observed. The association of NPM1/APE1 with cancer gene signatures highlighted alterations concerning cell-cycle dependent proteins.
APE1 and NPM1 protect cancer cells from Pt-compounds cytotoxicity, suggesting a possible improvement of the activity of Pt-based therapy for TNBC, using the NPM1 and APE1 proteins as secondary therapeutic targets. Based on positive or negative correlation with APE1 and NPM1 gene expression levels, we finally propose several TNBC gene signatures that should deserve further attention for their potential impact on TNBC precision medicine approaches.
三阴性乳腺癌（TNBC）是一种乳腺癌亚组，其特征为缺乏激素受体的表达和没有 HER2 过表达。这些分子特征都极大地减少了治疗选择，并导致预后不良。铂（Pt）盐类正在被作为一种新的治疗策略进行研究。碱基切除修复（BER）途径对于铂类治疗的耐药性很重要。APE1 的过表达，BER 途径的关键酶，以及 NPM1 的表达，NPM1 是 APE1 的功能调节剂，与不良预后和铂类治疗耐药性相关。
我们评估了 NPM1、APE1 和改变的 NPM1/APE1 相互作用在不同细胞系中对 Pt 盐类治疗反应的作用：APE1 敲除（KO）细胞、NPM1 KO 细胞、具有改变的 APE1/NPM1 相互作用的细胞系模型以及 HCC70 和 HCC1937 TNBC 细胞系，具有不同水平的 APE1/NPM1。我们评估了新的针对 APE1 的内切酶活性或 APE1/NPM1 相互作用的化疗小分子在与 Pt 盐类联合治疗时对 TNBC 细胞的反应。通过免疫组织化学分析，在 TNBC 患者队列中分析 APE1 和 NPM1 之间的表达水平相关性及其对预后的影响。使用 TCGA 数据集进行生物信息学分析，基于 APE1 和 NPM1 表达预测癌症的分子特征。
APE1 和 NPM1 及其相互作用都能保护细胞免受 Pt 盐类治疗引起的细胞毒性。与 HCC70 细胞相比，具有更高 APE1/NPM1 蛋白水平的 HCC1937 细胞对 Pt 盐类治疗更具耐药性。APE1 抑制剂与 Pt 化合物联合使用具有增敏作用。NPM1/APE1 与癌症基因特征的关联突出了与细胞周期依赖性蛋白有关的改变。
APE1 和 NPM1 保护癌细胞免受 Pt 化合物的细胞毒性，这表明使用 NPM1 和 APE1 蛋白作为二级治疗靶点，可能会改善 TNBC 的 Pt 类治疗活性。基于与 APE1 和 NPM1 基因表达水平的正相关或负相关，我们最终提出了几个 TNBC 基因特征，这些特征值得进一步关注，因为它们可能对 TNBC 精准医学方法产生影响。
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