Abstract PS2-11-10: Mct4 drives triple-negative breast cancer progression via lactate-induced histone lactylation and mapk pathway activation

Abstract Background: Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype with limited therapeutic options and poor prognosis. Monocarboxylate transporter 4 (MCT4) is a key lactate efflux transporter involved in cancer metabolism. However, the mechanistic role of MCT4 in TNBC progression and its potential as a therapeutic target remain unclear. Methods: MCT4 expression was analyzed in TNBC patient tissues and correlated with clinical outcomes. MDA-MB-231 cells were subjected to hypoxia treatment and paclitaxel (PTX) exposure. MCT4 was knocked down using siRNA. Cell proliferation, invasion, migration, and PTX sensitivity were assessed. In vivo xenograft experiments were performed to evaluate tumor growth and drug response. RNA-sequencing and KEGG pathway analysis were conducted. Lactate secretion and glucose uptake were measured. Western blot analysis examined MAPK pathway proteins and histone modifications. CUT&Tag sequencing analyzed histone H3K9 lactylation changes and associated gene transcription. Results: MCT4 was significantly overexpressed in TNBC tissues and high expression correlated with poor patient prognosis. Both hypoxia and PTX treatment upregulated MCT4 expression in MDA-MB-231 cells. MCT4 knockdown markedly inhibited cell proliferation, invasion, and migration while enhancing PTX sensitivity. In vivo xenograft studies confirmed that MCT4 knockdown significantly retarded tumor growth and increased PTX sensitivity. RNA-sequencing revealed that MCT4 knockdown dramatically downregulated MAPK signaling pathway. Metabolically, MCT4 knockdown reduced both lactate secretion and glucose uptake. Western blot analysis confirmed that MCT4 knockdown decreased MAPK pathway-related proteins. Under hypoxic conditions, RNA-sequencing showed MAPK pathway activation, which was accompanied by increased histone lactylation levels and H3K9 lactylation. MCT4 knockdown reversed these histone modifications. CUT&Tag analysis revealed that hypoxia-induced H3K9 lactylation promoted transcription of MAPK pathway genes. Notably, MCT4 was not identified among the genes with increased H3K9 lactylation-mediated transcription, suggesting that MCT4 functions as an upstream regulator of histone lactylation rather than a downstream target, establishing a direct mechanistic link between lactate metabolism and gene regulation. Conclusions: This study demonstrates that MCT4 promotes TNBC progression through a novel lactate-histone lactylation-MAPK axis. MCT4 facilitates lactate production and efflux, which drives histone H3K9 lactylation and subsequent activation of MAPK signaling genes, ultimately enhancing cancer cell aggressiveness and chemoresistance. Our findings are validated both in vitro and in vivo, providing strong mechanistic evidence for MCT4 as a therapeutic target in TNBC. Clinical Relevance: MCT4 represents a promising biomarker for TNBC prognosis and a novel therapeutic target. Targeting MCT4-mediated lactate metabolism could enhance chemotherapy efficacy and improve clinical outcomes in TNBC patients. This metabolic-epigenetic crosstalk mechanism opens new avenues for combination therapy strategies. Citation Format: Y. Peng, Q. Luo, S. Liu. Mct4 drives triple-negative breast cancer progression via lactate-induced histone lactylation and mapk pathway activation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-10.