Protein networking in bladder cancer: immunoreactivity for FGFR3, EGFR, ERBB2, KAI1, PTEN, and RAS in normal and malignant urothelium.

A panel of markers, selected for the suspected bladder cancer relevance of their corresponding genes, were explored for their expression and subcellular location in urinary bladder tissue. The expression in normal urothelium, in non-metastasised transitional cell carcinomas (TCC), and in primary metastasised TCC with corresponding metastases was mapped. Potential associations between the proteins were identified. The observations were then combined in a set of hypotheses aimed at further hypothesis testing. Membranous ERBB4 and cytoplasmic p21RAS were downregulated in carcinoma cells compared with normal urothelium cells. FGFR3 was translocated from the cytoplasm to the nucleus. ERBB2 was translocated to the membrane and seemingly upregulated in one subgroup and conversely downregulated in another. EGFR, KAI1 and possibly PTEN revealed increased membranous immunoreactivity in non-metastasised tumours. The metastases showed decreased nuclear FGFR3 and membranous PTEN staining compared with corresponding primary tumours. EGFR expression was positively correlated with the expression of PTEN and FGFR3. The expression of ERBB2 was negatively correlated with p21RAS expression. According to our results, bladder carcinogenesis comprises FGFR3 translocation to the nucleus, upregulation of EGFR, ERBB2, KAI1 and PTEN; downregulation of p21RAS; and translocation of EGFR, ERBB2, and possibly PTEN to the membrane. Our results support the hypotheses regarding PTEN and KAI1 functioning as tumour suppressors in bladder cancer. EGFR and KAI1 may discriminate between non-metastasised and metastasised cancers. A complex network of associations between the factors is suggested.