OncoTargets and Therapy (Jun 2020)
Identification of Aurora Kinase A as a Biomarker for Prognosis in Obesity Patients with Early Breast Cancer
Abstract
Junhan Jiang,1 Zihe Guo,1 Junnan Xu,2 Tao Sun,2 Xinyu Zheng1,3 1Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Breast Medical, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, People’s Republic of China; 3Laboratory 1, Cancer Institute, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Xinyu ZhengDepartment of Breast Surgery, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People’s Republic of ChinaTel/ Fax +86 24 8328 2741Email [email protected]: 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.Methods: 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/m2, as obesity cohort), and normal (18.5 ≤ BMI < 25 kg/m2, 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 P values. Protein–protein interaction (PPI) network analysis and MCODE model were used to analyze the Aurora-altered signal pathway from GSE78958.Results: Among 517 breast patients, Aurora A-positive (staining scores ≥ 4) was significantly higher in obesity breast carcinoma compared with non-obesity cancer carcinoma (χ2=9.79, P=0.002), with more frequency in hormone receptor-negative (68.4% vs 77.9%, P=0.015) and HER2-positive patients (28.7% vs 17.9%, P=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: 1.03∼ 3.02, P=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: 0.79∼ 2.45, P=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, P=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, P=0.001).Conclusion: 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.Keywords: early breast cancer, obesity, Aurora A, overall survival, Cyclin B1
