The IER5L–AK2 axis drives aggressive behavior in triple-negative breast cancer

Breast cancer is the most frequently diagnosed malignancy in women worldwide. Triple-negative breast cancer (TNBC) has particularly poor outcomes, largely due to the lack of effective therapeutic targets. Here, we investigated the expression pattern, functional relevance, and potential molecular mechanisms of Immediate Early Response 5-Like gene (IER5L) in breast cancer by integrating public database analyses, clinical tissue validation, in vitro assays, and in vivo xenograft experiments. IER5L was significantly upregulated in breast cancer tissues, with the highest levels observed in TNBC, and elevated IER5L expression was associated with unfavorable prognosis. Silencing IER5L suppressed proliferation and migration of breast cancer cells, increased apoptosis, and inhibited tumor growth in nude mouse xenograft models. Mechanistically, proteomic profiling identified adenylate kinase 2 (AK2) as a key downstream effector of IER5L. IER5L depletion led to reduced AK2 expression and attenuation of STAT3/mTOR-related signaling. Importantly, rescue experiments demonstrated that ectopic AK2 expression partially reversed the inhibitory effects of IER5L knockdown on cell proliferation and migration. Together, these findings suggest that IER5L contributes to breast cancer progression through an AK2-associated STAT3/mTOR signaling program and support IER5L as a potential prognostic biomarker and therapeutic target, particularly in TNBC.