UBE2C Overexpression Aggravates Patient Outcome by Promoting Estrogen-Dependent/Independent Cell Proliferation in Early Hormone Receptor-Positive and HER2-Negative Breast Cancer

Yu-Jin Kim,Gyunghwa Lee,Young Kee Shin,Jinil Han,Joon-Seok Choi,Kyoung Song,Yoon-La Choi

doi:10.3389/fonc.2019.01574

Abstract

We previously showed that UBE2C mRNA expression is significantly associated with poor prognosis only in patients with hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)– breast cancer. In this study, we further reanalyzed the correlation between UBE2C mRNA expression and clinical outcomes in patients with HR+/HER2– breast cancer, and we investigated the molecular mechanism underlying the role of UBE2C modulation in disease progression in this subgroup of patients. Univariate and multivariate analyses showed that high UBE2C expression was associated with significantly shorter survival of breast cancer patients with pN0 and pN1 tumors but not pN2/N3 tumors (P < 0.05). In vitro functional experiments in HR+/HER2– breast cancer cells showed that UBE2C expression is a tumorigenic factor, and that estrogen upregulated UBE2C mRNA and protein by directly binding to the UBE2C promoter region. UBE2C knockdown inhibited cell proliferation by affecting cell cycle progression, and UBE2C overexpression was associated with estrogen-independent growth. UBE2C depletion markedly increased the cytotoxicity of tamoxifen by inducing apoptosis. The present findings suggest that UBE2C overexpression is correlated with relapse and promotes estrogen-dependent/independent proliferation in early HR+/HER2– breast cancer.

Highlights

Breast cancer is classified according to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression status into hormone receptor HR+/HER2– (ER+ or PR+/HER2–), HR+/HER2+ (ER+ or PR+/HER2+), HR–/HER2+ (ER–/PR–/HER2+), or triple-negative breast cancer (TNBC; ER–/PR–/HER2–); the HR+/HER2– subtype accounts for 25–40% of breast cancers [1, 2]
We previously showed that high ubiquitinconjugating enzyme E2C (UBE2C) mRNA expression is significantly associated with poor Disease-free survival (DFS), Distant metastasis-free survival (DMFS), and Overall survival (OS) only in patients with HR+/HER2– breast cancer among the four subtypes [10]
This finding indicated that the association between UBE2C overexpression and the survival of patients with HR+/HER2– breast cancer might be estrogen related; in this study, we assessed the effect of estrogen on UBE2C expression using HR+/HER2– breast cancer cells

Summary

Introduction

Breast cancer is classified according to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression status into hormone receptor HR+/HER2– (ER+ or PR+/HER2–), HR+/HER2+ (ER+ or PR+/HER2+), HR–/HER2+ (ER–/PR–/HER2+), or triple-negative breast cancer (TNBC; ER–/PR–/HER2–); the HR+/HER2– subtype accounts for 25–40% of breast cancers [1, 2]. Because gene expression provides significant prognostic or predictive information for patients with HR+ breast cancer, several commercial assays such as Oncotype DX, MammaPrint, and EndoPredict, which are based on the expression of multiple genes in frozen or formalin-fixed, paraffin-embedded (FFPE) samples, have been developed [6,7,8]. These assays predict the risk of distant recurrence after hormone therapy and help to identify patients who may benefit from adjuvant chemotherapy by discriminating between high- and low-risk patients with early HR+ breast cancer. Six genes were selected to develop a prognostic model for predicting the risk of distant recurrence or distant metastasis, and the performance of the model was compared with that of classical clinicopathological risk factors [10,11,12,13]

Methods

Results

Conclusion