Exportin-T Promotes Breast Cancer Progression via PI3K/AKT/mTOR Signaling Pathway

Zhichao Hou,1 Wenxia Ma,2 Dongliang Ren,1 Ningning Shen,2 Weilin Bi,1 Meiqin Guo,1 Xinzheng Li,1 Yanhong Wang,3 Hongyan Jia4 1Department of Breast Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Pathology, The Second Hospital of ShanXi Medical University, Tai Yuan, People’s Republic of China; 3Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, People’s Republic of China; 4Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Hongyan Jia, Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China, Email [email protected]: Breast cancer (BC) is the most common malignant tumor in women. Exportin-T (XPOT) which is a member of the karyopherin -β family has been identified as a prognostic biomarker in various cancers, but its role in BC remains inadequately understood. This study aims to investigate the clinical characterization and molecular mechanism of XPOT in BC.Material and Methods: A retrospective RNA-seq data analysis based on a cohort of 966 BC patients from The Cancer Genome Atlas database (TCGA) and 1904 patients from the Molecular Taxonomy of Breast Cancer International Consortium database was conducted for analyzing the correlation between XPOT expression and BC clinical pathological features. In addition, small interfering RNA transfection was used to downregulate XPOT expression in MDA-MB-468/231 cell lines followed by cell proliferation assessed via Cell Counting Kit-8 assays, meanwhile, BC cell migration and invasion capabilities were measured using Transwell test. Expression levels of CDK4/6 and key proteins in the PI3K/Akt/mTOR signaling pathway were assessed using Western blotting.Results: We found that XPOT was enriched in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, larger tumor size, and cases with increased lymph node metastasis BC. XPOT was identified as a potential biomarker for the basal subtype of BC and a prognostic factor for the overall survival of patients with BC. Furthermore, XPOT promoted the proliferation and invasion of BC cells, likely through activation of the PI3K/AKT/mTOR signaling pathway, which in turn to upregulate cyclin D and CDK4/6 to drive tumor progression.Conclusion: Our findings indicate that XPOT overexpression is associated with poor clinical characteristics and poor prognosis in BC, promoting disease progression by activating PI3K/AKT/mTOR pathway. These findings highlight XPOT as a potential therapeutic target in BC.Keywords: breast cancer, exportin-T, cell proliferation, PI3K/AKT/mTOR signaling, prognosis biomarkers