Jiang Junhan, Guo Zihe, Xu Junnan, Sun Tao, Zheng Xinyu
Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.
Department of Breast Medical, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, People's Republic of China.
Onco Targets Ther. 2020 Jun 3;13:4971-4985. doi: 10.2147/OTT.S250619. eCollection 2020.
Obesity is associated both with a higher risk of developing breast cancer, particularly in postmenopausal women, and with worse disease outcome for women of all ages. Previous investigation suggested Aurora A kinase was able to partially restore the functionalities of obese adipose-derived mesenchymal stem cells by stabilizing their primary cilia and reestablishing a balance of multiple stemness-associated genes. The association between Aurora A and obesity breast cancer is still unclear. We hypothesized that overexpression of Aurora A was associated with poor survival in obesity breast cancer and the related axis mechanism was involved.
A total of 517 primary breast cancer specimens were collected from the First Affiliated Hospital of China Medical University between January 2011 and November 2016. Our independent variable was BMI at baseline, categorized as overweight (BMI ≥25 kg/m, as obesity cohort), and normal (18.5 ≤ BMI <25 kg/m, as non-obesity cohort). The immunohistochemical (IHC) staining was performed with Aurora A, Survivin, MMP11, Cyclin B1, and Cathepsin L. Kaplan-Meier curve was used to analyze overall survival in our cohorts and TCGA-BRCA data (GSE3494). Log rank test was used to calculate values. Protein-protein interaction (PPI) network analysis and MCODE model were used to analyze the Aurora-altered signal pathway from GSE78958.
Among 517 breast patients, Aurora A-positive (staining scores ≥4) was significantly higher in obesity breast carcinoma compared with non-obesity cancer carcinoma ( =9.79, =0.002), with more frequency in hormone receptor-negative (68.4% vs 77.9%, =0.015) and HER2-positive patients (28.7% vs 17.9%, =0.003). High Aurora A expression was remarkably and significantly associated with overall survival (OS) (8-year OS ratio: 69.5% vs 81.1%, OR=1.76, 95% CI: 1.033.02, =0.041) in obesity cohort. Interestingly, higher expression of Aurora A was not associated with a shorter overall survival time among the non-obesity breast cancer (8-year OS ratio: 81.4% vs 85.8%, OR=1.40, 95% CI: 0.792.45, =0.229). As for RFS, the expression levels of Aurora A expression genes have no significance with RFS statistically in non-obesity and obesity patients. Aurora A and lymph node metastases were significantly poor prognostic factors for OS, and borderline significance was noted for high BMI. Kaplan-Meier survival analysis from TCGA database confirmed that the high Aurora A expression group had worse prognosis (HR=1.47, 95% CI: 1.14-1.90, =0.003). The KEGG pathway enrichment results were consistent with GO biological process term analysis, in which CCNB1 was enriched for upregulated Aurora A. In our samples, Aurora A level on tumor cytoplasm had broad connections with Cyclin B1 by IHC correlation analysis (correlation coefficient = 0.227, =0.001).
Our finding demonstrates here for the first time that high expression of Aurora A was notably correlated with early recurrence and poor overall survival in obesity patients with early breast cancer. The Aurora A-Cyclin B1 axis could be a potential promising therapeutic target for cancer intervention and therapy.
肥胖与患乳腺癌的风险增加相关，尤其是在绝经后女性中，并且与各年龄段女性的疾病预后较差有关。先前的研究表明，极光激酶A（Aurora A kinase）能够通过稳定肥胖脂肪来源的间充质干细胞的初级纤毛并重新建立多个干性相关基因的平衡，部分恢复其功能。Aurora A与肥胖型乳腺癌之间的关联仍不清楚。我们假设Aurora A的过表达与肥胖型乳腺癌患者的不良生存相关，并且涉及相关的轴机制。
2011年1月至2016年11月期间，从中国医科大学附属第一医院收集了517例原发性乳腺癌标本。我们的自变量是基线时的体重指数（BMI），分为超重（BMI≥25kg/m²，作为肥胖队列）和正常（18.5≤BMI<25kg/m²，作为非肥胖队列）。采用免疫组织化学（IHC）法检测Aurora A、生存素（Survivin）、基质金属蛋白酶11（MMP11）、细胞周期蛋白B1（Cyclin B1）和组织蛋白酶L（Cathepsin L）。采用Kaplan-Meier曲线分析我们队列和TCGA-BRCA数据（GSE3494）中的总生存期。采用对数秩检验计算P值。利用蛋白质-蛋白质相互作用（PPI）网络分析和MCODE模型分析来自GSE78958的Aurora改变的信号通路。
在517例乳腺癌患者中，肥胖型乳腺癌中Aurora A阳性（染色评分≥4）显著高于非肥胖型癌（P=9.79，P=0.002），在激素受体阴性患者（68.4%对77.9%，P=0.015）和HER2阳性患者（28.7%对17.9%，P=0.003）中更常见。在肥胖队列中，高Aurora A表达与总生存期（OS）显著相关（8年OS率：69.5%对81.1%，OR=1.76，95%CI：1.033.02，P=0.041）。有趣的是，在非肥胖型乳腺癌中，较高的Aurora A表达与较短的总生存时间无关（8年OS率：81.4%对85.8%，OR=1.40，95%CI：0.792.45，P=0.229）。至于无复发生存期（RFS），在非肥胖和肥胖患者中，Aurora A表达基因的表达水平与RFS在统计学上无显著意义。Aurora A和淋巴结转移是OS的显著不良预后因素，高BMI具有临界显著性。来自TCGA数据库的Kaplan-Meier生存分析证实，高Aurora A表达组预后较差（HR=1.47，95%CI：1.14-1.90，P=0.003）。KEGG通路富集结果与GO生物学过程术语分析一致，其中细胞周期蛋白B1（CCNB1）因Aurora A上调而富集。在我们的样本中，通过IHC相关性分析，肿瘤细胞质上的Aurora A水平与细胞周期蛋白B1广泛相关（相关系数=0.227，P=0.001）。
我们的研究首次表明，Aurora A的高表达与肥胖早期乳腺癌患者的早期复发和不良总生存显著相关。Aurora A-细胞周期蛋白B1轴可能是癌症干预和治疗的潜在有前景的治疗靶点。
