AP2M1 promotes TNBC progression by stabilizing EGFR through inhibition of lysosomal degradation

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous malignancy, with 50–80% of cases exhibiting elevated EGFR expression. Dysregulated endocytic trafficking contributes to sustained receptor signaling and tumor progression, suggesting endocytosis as a potential therapeutic target. Transcriptome analysis of paired TNBC and adjacent tissues, together with public database analyses, identified AP2M1 as an endocytosis-related gene upregulated in TNBC tissues and cell lines. Functional assays, including proliferation, migration, and xenograft tumorigenicity, demonstrated that AP2M1 promotes TNBC progression. Mechanistically, in TNBC cells, AP2M1 interacts with EGFR, and its silencing accelerates EGFR internalization, enhances K63-linked ubiquitination, promotes EGFR trafficking to late endosomes, and facilitates lysosomal degradation, thereby reducing EGFR stability. Clinically, high AP2M1 expression is associated with poor prognosis in breast cancer. These findings indicate that AP2M1 stabilizes EGFR by inhibiting its lysosomal degradation, and that targeting the AP2M1–EGFR axis may represent a promising therapeutic strategy for EGFR-high TNBC.