MGP is downregulated due to promoter methylation in chemoresistant ER+ breast cancer and high MGP expression predicts better survival outcomes.

Abstract

Objective: In this study, we aimed to investigate the underlying mechanisms of MGP downregulation in chemoresistant ER+ breast cancer cells and its association with survival outcomes in breast cancer patients.

Materials and methods: Microarray data of dysregulated genes in chemoresistant ER+ breast cancer cells were searched in GEO datasets. MGP expression in breast cancer patients and its DNA methylation status were analyzed in TCGA database. MGP promoter methylation was assessed using Methylation-Specific PCR (MSP) assay. The association between MGP expression and survival outcomes in different sub-types of breast cancer patients after systemic therapy was analyzed by data mining in Kaplan Meier plotter and in Breast Cancer Gene-Expression Miner Version 4.0 (bc-GenExMiner 4.0).

Results: MGP is significantly downregulated in MCF-7/ADR cells compared to the parental MCF-7 cells. MCF-7/ADR cells had a significantly higher level of methylation in MGP promoter than MCF-7 cells. Demethylation treatment significantly restored MGP expression at both mRNA and protein levels. High MGP expression is associated with better relapse-free survival (RFS) in luminal A and luminal B breast cancer patients, but the association was not observed in HER2+ and basal-like subtype breast cancer patients. High MGP expression was associated with significantly lower risk of any event (AE) and also lower risk of metastatic relapse (MR). Survival curve showed that high MGP expression was associated to both better AE-free survival and MR-free survival.

Conclusions: MGP is downregulated due to promoter hypermethylation in chemoresistant ER+ breast cancer cells. High MGP expression may predict better survival outcomes among ER+ breast cancer patients.