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

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.

UBE2C is a Potential Biomarker for Tumorigenesis and Prognosis in Tongue Squamous Cell Carcinoma

“…For example, UBE2C is involved in the tumorigenesis of colorectal cancer [23] and non-small cell lung cancer (NSCLC) [24]. UBE2C is highly expressed in breast microcalcification lesions [25] and its overexpression is correlated with relapse in early HR + /HER2 − breast cancer patients [9]. UBE2C expression is elevated and predicts poor prognosis in hepatocellular carcinoma, esophageal squamous cell carcinoma and intestinal-type gastric cancer [14,26,27].…”

“…UBE2C overexpression causes loss of mitotic spindle checkpoint activity and genomic stability [ 8 ]. The expression level of UBE2C is very high in various human cancers, such as breast cancer [ 9 ], ovarian cancer [ 10 ], head and neck squamous cell carcinoma (HNSCC) [ 11 ] and melanoma [ 12 ], suggesting that UBE2C is associated with tumorigenesis. Moreover, overexpression of UBE2C is correlated with tumor progression [ 13 ], so it acts as a potential prognostic/diagnostic biomarker in various types of tumors [ 11 , 14 , 15 ].…”

Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer

“…UBE2T and UBE2C have been previously associated with cancer progression and poor outcome in several solid tumors, although genomic evidence in BC is recent and limited [32][33][34][35][36]. Consistently, in vitro functional experiments in ER positive HER2 negative BC cells showed that UBE2C expression is a tumorigenic factor, that it is regulated by estrogen through direct binding to the UBE2C promoter region, and that its overexpression leads to estrogen-independent growth [37]. Moreover, UBE2C depletion markedly increased the cytotoxicity of letrozole, tamoxifen, doxorubicin, and the sensitivity to radiation therapy in multiple BC cell lines [37,38].…”

The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer

“…Ubiquitin-conjugating enzyme E2 C (UBE2C) has been illustrated to facilitate proliferation, survival, invasion, and EMT in cancer [ 187 , 222 , 223 ]. For example, UBE2C can stimulate EMT process by activating Wnt/β-catenin signaling, PI3K/Akt signaling, and the level of Zinc finger E-Box-binding homeobox 1 (ZEB1) and ZEB2 [ 187 , 223 ].…”