BACKGROUND alpha-actinin-4 (Actinin-4 or ACTN4), originally identified as an actin-binding protein associated with the biological function of cancer cells, appears to be highly expressed in numerous human epithelial carcinomas, including breast cancer (BC). In the present study we assessed the role of serum ACTN4 as a biomarker for BC diagnosis, as well as the association between ACTN4 levels and clinicopathological features. MATERIAL AND METHODS ACTN4 expression level was measured with quantitative real-time PCR (qRT-PCR) analysis in serum specimens of 128 BC patients and 96 healthy volunteers. χ² testing was conducted to explore the association of ACTN4 levels with clinicopathologic factors. Moreover, the diagnostic value of ACTN4 was analyzed using receiver operating characteristic (ROC) curves. RESULTS Serum ACTN4 level was obviously upregulated in patients with BC compared with healthy controls (P<0.05). High ACTN4 expression was significantly associated with clinical stage (P=0.000), tumor grade (P=0.004), and lymph node status (P=0.024). However, no association was found between ACTN4 expression and age, tumor size, ER status, PR status, or HER-2 status (all P>0.05). The ROC analysis showed that the area under the curve (AUC) of ACTN4 was 0.887 (95%CI: 0.843-0.931), with sensitivity of 80.5% and specificity of 84.4%, and the cutoff value was 1.050. CONCLUSIONS ACTN4 in serum can serve as a clinical predictor in the diagnosis or prediction of clinical outcomes of patients with BC.