High BMI1 Expression with Low CD8+ and CD4+ T Cell Activity Could Promote Breast Cancer Cell Survival: A Machine Learning Approach.

Yumin Chung,Seoung Wan Chae,Kyueng-Whan Min,Sung-Im Do,Dong-Hoon Kim,Mi Jung Kwon,Byoung Kwan Son

doi:10.3390/jpm11080739

Abstract

BMI1 is known to play a key role in the regulation of stem cell self-renewal in both endogenous and cancer stem cells. High BMI1 expression has been associated with poor prognosis in a variety of human tumors. The aim of this study was to reveal the correlations of BMI1 with survival rates, genetic alterations, and immune activities, and to validate the results using machine learning. We investigated the survival rates according to BMI1 expression in 389 and 789 breast cancer patients from Kangbuk Samsung Medical Center (KBSMC) and The Cancer Genome Atlas, respectively. We performed gene set enrichment analysis (GSEA) with pathway-based network analysis, investigated the immune response, and performed in vitro drug screening assays. The survival prediction model was evaluated through a gradient boosting machine (GBM) approach incorporating BMI1. High BMI1 expression was correlated with poor survival in patients with breast cancer. In GSEA and in in silico flow cytometry, high BMI1 expression was associated with factors indicating a weak immune response, such as decreased CD8+ T cell and CD4+ T cell counts. In pathway-based network analysis, BMI1 was directly linked to transcriptional regulation and indirectly linked to inflammatory response pathways, etc. The GBM model incorporating BMI1 showed improved prognostic performance compared with the model without BMI1. We identified telomerase inhibitor IX, a drug with potent activity against breast cancer cell lines with high BMI1 expression. We suggest that high BMI1 expression could be a therapeutic target in breast cancer. These results could contribute to the design of future experimental research and drug development programs for breast cancer.

Highlights

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancerrelated death among women worldwide, as reported by the GLOBOCAN 2018 database published by the International Agency for Research on Cancer
Our study showed that B-lymphoma Moloney murine leukemia virus insertion region-1 (BMI1) was highly expressed in IDC tissue compared to normal tissue
A study by Althobiti et al demonstrated that high BMI1 expression was associated with better prognosis in patients with luminal ER-positive breast cancer, but was associated with a poorer survival rate in patients with the triple-negative subtype

Summary

Introduction

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancerrelated death among women worldwide, as reported by the GLOBOCAN 2018 database published by the International Agency for Research on Cancer. GLOBOCAN 2018 provides information on the estimated incidence and mortality rates in 185 countries for a total of 36 types of cancer [1]. There are different histological types of malignancy such as ductal carcinoma, lobular carcinoma, medullary carcinoma and micropapillary carcinoma. As a mesenchymal-type, breast cancer originating from stromal cells may occur rarely [2]. Molecular/genetic studies and evaluation of targeted therapies for breast cancer have been actively conducted to improve patient survival, but these approaches are still seen as a challenge by many clinicians. It is necessary to continuously discover carcinogenic factors with the aim of developing new therapeutic approaches

Objectives

Results

Conclusion