Initial Identification of UDP-Glucose Dehydrogenase as a Prognostic Marker in Breast Cancer Patients, Which Facilitates Epirubicin Resistance and Regulates Hyaluronan Synthesis in MDA-MB-231 Cells.

Daiana L Vitale,Fiorella M Spinelli,Arianna Parnigoni,Antonella Icardi,Ina Sevic,Ilaria Caon,Alberto Passi,Laura Alaniz,Davide Vigetti

doi:10.3390/biom11020246

Abstract

UDP-glucose-dehydrogenase (UGDH) synthesizes UDP-glucuronic acid. It is involved in epirubicin detoxification and hyaluronan synthesis. This work aimed to evaluate the effect of UGDH knockdown on epirubicin response and hyaluronan metabolism in MDA-MB-231 breast cancer cells. Additionally, the aim was to determine UGDH as a possible prognosis marker in breast cancer. We studied UGDH expression in tumors and adjacent tissue from breast cancer patients. The prognostic value of UGDH was studied using a public Kaplan–Meier plotter. MDA-MB-231 cells were knocked-down for UGDH and treated with epirubicin. Epirubicin-accumulation and apoptosis were analyzed by flow cytometry. Hyaluronan-coated matrix and metabolism were determined. Autophagic-LC3-II was studied by Western blot and confocal microscopy. Epirubicin accumulation increased and apoptosis decreased during UGDH knockdown. Hyaluronan-coated matrix increased and a positive modulation of autophagy was detected. Higher levels of UGDH were correlated with worse prognosis in triple-negative breast cancer patients that received chemotherapy. High expression of UGDH was found in tumoral tissue from HER2--patients. However, UGDH knockdown contributes to epirubicin resistance, which might be associated with increases in the expression, deposition and catabolism of hyaluronan. The results obtained allowed us to propose UGDH as a new prognostic marker in breast cancer, positively associated with development of epirubicin resistance and modulation of extracellular matrix.

Highlights

We evaluated the effect of silencing the UGDH gene with a specific siRNA on the EPI response using that aggressive breast cancer cell line, by studying cellular processes ranging from cell survival to modulation of extracellular matrix composition
To have an overview of UGDH expression in different solid tumors, we analyzed its expression in samples from The Cancer Genome Atlas (TCGA), which demonstrated that
Our objective was to establish whether this enzyme could be proposed as a new biomarker of prognosis in breast cancer patients according to its hormone receptor status

Summary

Introduction

An increased understanding of mechanisms that favor the aggressive behavior of tumor cells and the role of the tumor microenvironment provide insights into novel treatment strategies for breast cancer. The extracellular matrix (ECM) is one of the most important components of the tumor microenvironment that can directly modulate cell growth, survival, migration, immune response and drug resistance [1,2]. Among the main molecular components of ECM are glycosaminoglycans (GAGs) and proteoglycans (PGs), which have been shown to play fundamental roles in different physiological processes and malignancies [3,4,5].

Objectives

Methods

Results