Abstract P2-04-02: TRIB3 regulates lipophagy and drives the metastasis of triple negative breast cancer by activation of PI3K/AKT/mTOR pathway

Abstract Background: The balance of lipophagy is critical for maintaining oncogenic signaling pathways. However, the mechanisms by which lipophagy promotes progression and metastasis in triple-negative breast cancer (TNBC) are currently unknown. In this study, we investigated the clinical significance and biological involvement of the pseudokinase protein TRIB3 in TNBC. Methods: Target genes associated with lipophagy were identified by GSEA database screening and tested in tissues and cell lines. The biological functions of TRIB3 in TNBC were investigated using gain-of-function/loss-of-function assays. Western blotting, laser confocal microscopy, transmission electron microscopy and immunoprecipitation were used to detect and analyze lipophagy. ChIP and luciferase reporter gene assays were used to evaluate the relationship between TRIB3 and FOXA1. Next-generation sequencing technology was applied to screen out the possible downstream molecule MSI2 of TRIB3 and verify the regulatory relationship between the two. Results: Increased expression of TRIB3 was found in TNBC compared with paired peritumoral tissues. It was more signifcant in TNBC with metastasis and correlated with worse overall survival. Upregulation of TRIB3 accelerated TNBC cells colony formation, migration and invasion. Mechanically, RNAseq-based analysis showed enrichment of autophagy-related pathways in TRIB3 lowly-expressed TNBC. Next, TRIB3 was demonstrated to interact and stabilize MSI2, amplify PI3K/AKT/mTOR-mediated lipophagy and then promote TNBC growth and metastasis. Moreover, FOXA1 was upregulated and transcriptionally increased TRIB3 expression in TNBC cells. Furthermore, These phenotypes could be reversed by the lipophagy inhibitor chloroquine. Conclusions: Our fndings suggested that TRIB3 is a key pseudokinase molecule for tumor progression and metastasis and may be an effective target for TNBC patients. Citation Format: Zirong iang, Yushuai Yu, Qing Wang, Mingyao Huang, Shiping Luo, Xin Yu, Xiewei Huang, Chuangui Song, Jun Liu. TRIB3 regulates lipophagy and drives the metastasis of triple negative breast cancer by activation of PI3K/AKT/mTOR pathway [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-04-02.