KLHL1 suppresses triple-negative breast cancer progression by promoting M1 macrophage polarization via APOC2 degradation.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by an immunosuppressive tumor microenvironment and resistance to chemotherapy. Previous studies have indicated that apolipoprotein C-II (APOC2) is involved in the immune microenvironment of several malignancies and is upregulated in breast cancer; however, the molecular mechanisms through which APOC2 regulates the immune microenvironment in TNBC remain poorly understood. In the present study, we found that APOC2 was upregulated in TNBC tissues and was negatively correlated with M1 macrophage infiltration. APOC2 overexpression in 4 T1 cells promoted tumor progression by enhancing cell proliferation, migration, and invasion, while suppressing M1 macrophage polarization. In addition, KLHL1, a substrate adaptor for the Cullin3-RING E3 ubiquitin ligase complex, was found to interact with APOC2, and KLHL1 overexpression reversed the biological effects induced by APOC2. Mechanistically, KLHL1 promoted APOC2 protein degradation through the ubiquitin-proteasome pathway, thereby enhancing M1 macrophage polarization and suppressing the malignant behavior of tumor cells. Finally, in vivo xenograft experiments demonstrated that APOC2 reduced M1 macrophage polarization and increased tumor weight and volume, whereas KLHL1 overexpression counteracted the oncogenic effects of APOC2. Collectively, these findings reveal that activation of the KLHL1/APOC2 axis enhances M1 macrophage polarization and inhibits TNBC progression, providing novel insights into the immune regulatory mechanisms underlying TNBC development.