E3 Ligase TRIM21 Deficiency-Driven GAS2L3 Accumulation Facilitates Oncogenic Progression in Breast Cancer

GAS2L3, a member of the growth arrest-specific 2 protein family, is abnormally upregulated in multiple human cancers, implying its potential oncogenic role. However, the mechanisms underlying its stabilization and accumulation during breast cancer progression remain unclear. This study aimed to clarify the regulatory mechanism and oncogenic role of GAS2L3 in breast cancer. We analyzed the expression and prognostic value of GAS2L3 and its related signaling pathways using public breast cancer databases, and conducted functional assays to assess the malignant phenotypes of breast cancer cells. Mass spectrometry and co-immunoprecipitation were performed to identify and verify TRIM21 as a binding partner of GAS2L3. Ubiquitination and cycloheximide chase assays confirmed that TRIM21 facilitates the ubiquitination and proteasomal degradation of GAS2L3, while immunohistochemical staining of clinical specimens and mouse tissues verified their negative correlation. Rescue experiments further validated this regulatory axis. High GAS2L3 expression predicted poor prognosis and promoted breast cancer cell proliferation, migration, and invasion. Loss of TRIM21-mediated GAS2L3 degradation results in aberrant GAS2L3 accumulation, and the TRIM21–GAS2L3 axis drives breast cancer malignant progression, providing potential prognostic biomarkers and therapeutic targets for breast cancer.