HER2 and Other ErbB Receptors’ Expression and Their Involvement in the Oncogenesis of Clear Cell Renal Cell Carcinoma

Abstract

Background/Aim: Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer with poor prognosis at advanced stages. The ErbB receptor family, including HER2, EGFR, and ErbB3, is implicated in tumor progression through membrane signaling and nuclear functions, but their roles in ccRCC remain incompletely understood. Materials and Methods: We analyzed membrane and nuclear expression of HER2, EGFR, and ErbB3 in ccRCC tissue samples by immunohistochemistry. Pearson correlation analyses evaluated receptor co-expression, while in vitro assays with HEK293 and 786-O cells treated with heregulin assessed nuclear localization. Clinical relevance was investigated by correlating receptor expression with Fuhrman Nuclear Grade and clinical stage using Fisher’s exact test. Results: Membrane expression of HER2 and EGFR was positive in approximately 32% and 38% of cases, respectively, showing a significant positive correlation (r=0.3519, p=0.028). Nuclear expression was higher for EGFR and ErbB3, with HER2 nuclear presence correlating significantly with both receptors (r=0.4713 and r=0.42; p=0.001). In vitro, heregulin stimulation induced nuclear translocation of HER2 and ErbB3. Not funding that membrane and nuclear expression co-expression of HER2/EGFR was linked to clinical parameters. However, the nuclear co-expression of HER2/ErbB3 showed significant associations with higher FNG and advanced clinical stage (p<0.05). Conclusion: Nuclear co-expression of HER2 with ErbB3 is frequent in clear cell renal cell carcinoma and is significantly associated with higher Fuhrman Nuclear Grade and advanced clinical stage. These findings indicate that nuclear ErbB signaling contributes to tumor progression and dedifferentiation, highlighting nuclear HER2/ErbB3 complexes as potential prognostic biomarkers and therapeutic targets in ccRCC.