KDM3A Modulates Trastuzumab Resistance in HER2- Positive Breast Cancer Cells via the PI3K/AKT/ERK Pathway

Trastuzumab (TRA) is a key therapeutic agent for HER2-positive breast cancer (HER2+BC), effectively suppressing tumor progression. However, its prolonged use has led to the development of TRA resistance in many patients, worsening their clinical outcomes. Lysine-specific histone demethylase 3A (KDM3A) is known to be overexpressed in BC cells, contributing to enhanced proliferation, invasion, and migration. However, its involvement in TRA resistance in HER2+BC remains poorly understood. This study demonstrated TRA-resistant HER2+BC cell models and knocked down the expression of KDM3A to investigate its role and underlying mechanisms. The findings revealed that KDM3A expression was markedly upregulated in TRA-resistant cells and was associated with increased levels of AKT, ERK1/2, HER2, and their phosphorylated forms (p-AKT, p-ERK1/2, and p-HER2). KDM3A silencing suppressed cell survival, invasion, and migration, induced apoptosis, and arrested the cell cycle in the G0/G1 phase. Further analysis revealed that KDM3A silencing decreased mRNA and protein levels of PI3K, AKT, ERK1/2, HER2, and BCL-2 while increasing BAX expression. Protein phosphorylation levels of AKT, ERK1/2, and HER2 were also reduced. These results indicate that KDM3A contributes to TRA resistance in HER2+BC cells via the PI3K/AKT/ERK pathway, suggesting its potential as a therapeutic target for overcoming TRA resistance in HER2+BC.