Expression of resistance factors (P-glycoprotein, glutathione S-transferase-π, and topoisomerase II) and their interrelationship to proto-oncogene products in renal cell carcinomas

Abstract

Background. This study investigates whether or not an interrelationship exists between the expression of resistance-related proteins (P-glycoprotein, glutathione S-transferase, topoisomerase II) and proto-oncogene products (c-fos, c-myc, c-K-ras, epidermal growth factor receptor [EGF-R], and c-neu proteins). Methods. Thirty-eight human renal cell carcinomas of previously untreated patients were analyzed for expression of P-glycoprotein (P-170), glutathione S-transferase-π (GST-π), topoisomerase II (Topo II) and proto-oncogene proteins by means of immunohistochemistry. Because of significant heterogeneity in most tumor biopsies, all analyses were done on tumor-derived primary cell culture lines on the third or fourth passage. Results. An interrelationship between increased expression of P-170 and GST-π and down-regulation of Topo II was found. Expression of the c-fos protein was seen in 66% of the tumors; expression of the c-myc protein, in 50%; of the c-K-ras protein, in 16%; of the EGF-R protein, in 61%; and of the c-neu protein, in 54% of the tumors. A significant correlation between the resistance factors and the c-fos, EGF-R, and c neu-proteins was observed (GST/c-fos, P=0.012; Topo II/c-fos, P = 0.024; P-170/EGF-R, P < 0.001; GST/EGF-R, P = 0.018; Topo II/EGF-R, P = 0.027; P-170/c-neu, P = 0.005; GST/c-neu, P = 0.018; Topo II/EGF-R, P = 0.027; P-170/c-neu, P = 0.005; GST/c-neu, P = 0.008; Topo II/c-neu, P = 0.05). In contrast, interrelationships between resistance proteins and c-myc and c-K-ras proteins were not found. A significant interrelationship between the investigated resistance-related proteins or proto-oncogene proteins and the stage or grading of the tumors was not observed. Conclusions. The results demonstrate that in renal cell carcinomas a significant relationship exists between resistance-related proteins, such as P-170, GST-π, or Topo II, and proto-oncogenes, such as c-fos, c-erbB1, and c-neu.