HER2 Expression and Nuclear Localization in Clear Cell Renal Cell Carcinoma: Implications for Prognosis and Therapeutic Targeting

Background/Aim: The HER2 oncoprotein is a membrane-associated receptor with tyrosine kinase activity that is overexpressed in several solid tumors and is associated with poor prognosis. However, its role in renal cancer remains unclear. This study aimed to evaluate HER2 expression in renal cell carcinoma and its relationship with prognostic factors. Materials and Methods: A total of 110 renal epithelial tumor samples were analyzed. Immunohistochemistry and immunofluorescence were performed using antibodies against HER2, hypoxia-inducible factor α (HIF1α), and EPAS1. Associations with clinicopathological parameters were evaluated using the Chi-square test. Results: Renal cell carcinoma occurred predominantly in males and was associated with larger tumor size. HER2 expression was detected specifically in the clear cell renal cell carcinoma (ccRCC) subtype. Membranous HER2 expression was positive (3+) in 32% of cases and equivocal (2+) in 47%. Nuclear HER2 localization was observed in 33% of tumors. Membranous HER2 expression was associated with EPAS1/HIF2 expression, whereas nuclear HER2 expression was associated with higher Fuhrman nuclear grades (III-IV). Membranous HER2 was detected in both early (stage I) and advanced clinical stages (III-IV). Conclusion: HER2 expression in ccRCC occurs in both membranous and nuclear compartments. Membranous HER2 is associated with EPAS1/HIF2 signaling, whereas nuclear HER2 localization correlates with higher Fuhrman nuclear grades. These findings suggest that HER2 may represent a potential therapeutic target and that its nuclear localization may serve as a marker of poor prognosis.