Abstract Objective: Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer due to its high heterogeneity, aggressive metastatic potential, and lack of effective targeted therapies and predictive biomarkers. Although btg2 has been implicated as a tumor suppressor in tumorigenesis and cancer progression, its specific role in TNBC invasion and metastasis remains unclear. This study aims to elucidate the mechanism through which btg2 regulates the invasion and metastasis of TNBC by modulating the degradation of becn1. Methods: Using the TCGA database, we analyzed btg2 expression levels and their prognostic significance in TNBC, which we further validated through IHC staining of clinical TNBC samples. Functional assays, including cell viability, colony formation, transwell assays, as well as mouse xenograft experiments, were performed to assess the impact of btg2 on TNBC cell proliferation, migration, and invasion. To elucidate the underlying mechanism, we employed mass spectrometry (MS), co-immunoprecipitation (Co-IP), and immunofluorescence confocal microscopy to examine the interaction between btg2 and becn1. Additionally, Western blotting, qPCR, cycloheximide chase, and ubiquitination assays were conducted to determine how btg2 regulates becn1 protein stability and ubiquitination, including the potential involvement of rnf123 in btg2-mediated becn1 degradation. Results: btg2 was significantly downregulated in TNBC tissues, and this downregulation correlated with poor prognosis. Functional studies demonstrated that btg2 suppressed TNBC cell proliferation, colony formation, migration, and invasion, findings further corroborated by xenograft tumor models. Mechanistically, btg2 increased becn1 levels by inhibiting its proteasomal degradation. Specifically, btg2 expression reduced becn1 ubiquitination, prolonged its half-life, and activated autophagy. Furthermore, we discovered that btg2 stabilizes becn1 by binding to rnf123, thereby blocking rnf123-mediated ubiquitination of becn1. Conclusions: Our findings demonstrate that btg2 interacts with the E3 ligase rnf123 to suppress becn1 ubiquitination and proteasomal degradation, leading to autophagy activation and inhibition of TNBC invasion and metastasis. These results highlight btg2 as a potential diagnostic marker and therapeutic target for TNBC. Citation Format: H. H. Li, J. L. Zhang, D. D. Zhou, S. J. Sun, Y. S. Gao. Trial in progress: A phase 2/3 trial of iza-bren (BMS986507/BL-B01D1), an EGFRxHER3 antibody-drug conjugate, vs standard-of-care chemotherapy in patients with previously untreated, locally advanced, recurrent inoperable, or metastatic triple negative breast cancer ineligible for anti-PD-(L)1 treatment (IZABRIGHT-Breast01) 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 PS5-03-09.
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