Emergence of glycolysis-lactate-Lactylation Axis in breast cancer: Mechanisms, tumour progression, and therapeutic implications.

Abstract

Breast cancer is a uniquely metabolically reprogrammed cancer, with increased aerobic glycolysis, excess lactate production, and the development of an excess of lysine lactylation. This glycolysis-lactate-lactylation signal has become a key player in the control of tumour growth and resistance to treatment. This review highlights the mechanisms of the glycolysis-lactate-lactylation axis and its implications in the development of breast cancer, cancer associated with the tumour microenvironment remodelling, and therapeutic applications. Aberrant glycolysis increases lactate production, while lactylation functions as a metabolic-epigenetic signalling mechanism through histone and non-histone protein lactylation. Lactylation is found to regulate protein function and gene expression, which favours tumour growth, tumour angiogenesis, E-MT, metastasis, cancer stem cells, immune evasion and chemoresistance, immune polarization, and skewing of macrophage polarization. The natural history of glycolytic enzymes, lactate transporters and enzymes involved in lactylation and their clinical utility for the dampening of tumour progression and the enhancement of treatment effectiveness has also been highlighted recently. The glycolysis-lactate-lactylation axis is a key connection between metabolic reprogramming and epigenetic regulation in breast cancer. This entangled pathway presents as a potentially encouraging possibility for creating biomarkers and developing new and better therapeutic approaches.