Differential expression of pyruvate dehydrogenase E1A and its inactive phosphorylated form among breast cancer subtypes

Abstract

Aims: Pyruvate dehydrogenase E1A (PDH-E1A) is one of the key regulators of metabolic pathways that determines pyruvate entry into the citric acid cycle or glycolysis. When PDH-E1A is phosphorylated (P-PDH-E1A), it loses its activity, shifting the metabolism towards glycolysis. Breast cancer (BC) is a highly heterogeneous disease by which different breast cancer subtypes acquire distinct metabolic profiles. Assessing PDH-E1A and PPDH-E1A expressions among BC subtypes might reveal their association with the distinct molecular profiles of BCs.

Methods: The expressions of PDH-E1A and P-PDH-E1A were investigated in BC cell lines and 115 BC tissues using Western blot and immunohistochemistry, respectively. Besides, PDHE1A mRNA expression was assessed in 1084 BCE patients’ transcriptomics data retrieved from Cancer Genome Atlas database. Statistical analyses were performed to assess the correlation of PDH-E1A and P-PDH-E1A expressions with patients’ clinicopathological characteristics. Kaplan-Meier method was used to evaluate their prognostic value.

Key findings: Multivariate analysis revealed a significant association between PDH-E1A/P-PDH-E1A expressions and the molecular subtype, histological type, and tumor size of breast cancer tissues. The hormonal receptors (ER and PR), HER-2, and Ki67 protein expressions were significantly associated with PDH-E1A and P-PDH-E1A protein expressions. Similar findings were observed when PDHA1 mRNA expression was assessed. The increased protein expression of PDH-E1A could be an independent prognostic factor for unfavorable overall survival (OS). In contrast, high PDHA1 mRNA expression had better OS.

Significance: This study revealed the differential expression of PDH-E1A and P-PDH-E1A among breast cancer subtypes and suggested PDH-E1A expression as a prognostic factor for BC patients’ OS.