EFNA3-mediated autophagy suppression drives breast cancer proliferation, EMT and metastasis via PI3K/AKT/mTOR axis

Breast cancer is a major contributor to cancer mortality in women, and progression, metastasis, and therapy resistance remain key clinical challenges. Ephrin-A3 (EFNA3) has been implicated in various cancers, but its role in breast cancer and underlying mechanisms remain unclear.

To investigate the clinical significance, functional role, and underlying mechanisms of EFNA3 in breast cancer progression.

EFNA3 expression was assessed in breast cancer tissues and cell lines using sequencing, GEPIA, immunohistochemistry, and western blot. Cell proliferation, apoptosis, migration, invasion, and autophagy were evaluated using standard functional assays, LC3 staining, TEM, and western blot. The xenograft model was established using BALB/c nude mice. The effect of EFNA3 knockdown was evaluated by measuring tumor volume, weight, and relevant biomarkers.

EFNA3 was upregulated in breast cancer tissues and was associated with poor prognosis. Silencing EFNA3 inhibited cell proliferation and metastasis, and induced apoptosis and autophagy. Mechanistically, our data suggest that EFNA3 activates the PI3K/AKT/mTOR pathway, which is accompanied by reduced autophagy and enhanced tumor progression. Moreover, in a xenograft model, EFNA3 knockdown reduced tumor growth, enhanced autophagy, and inhibited the PI3K/AKT/mTOR pathway.

Collectively, our findings suggest that EFNA3 may promote breast cancer progression, at least in part, by activating PI3K/AKT/mTOR signaling and suppressing autophagy. EFNA3 may represent a potential prognostic biomarker and therapeutic target, pending further clinical validation.