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A Nuclear Form of the Heparin-binding Epidermal Growth Factor-like Growth Factor Precursor Is a Feature of Aggressive Transitional Cell Carcinoma¹

Departments of Urology and Surgery [R. M. A., T. D., D. L. M., J. G. B., J. L., M. R. F.] and Orthopedic Surgery [D. Z.], Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115; Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115 [M. H. W.]; Cancer Research Unit, University of Newcastle upon Tyne, Newcastle NE2 4HH, United Kingdom [P. H. R.]; and Division of Urology, University of Leicester, Leicester LE5 4PW, United Kingdom [J. K. M.]

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the ErbB receptor ligand family, exists in distinct molecular forms with disparate biological activities. Previous studies have shown that the HB-EGF precursor, proHB-EGF, localizes to the cytoplasm of transitional cells of the human bladder urothelium and that the soluble form of the growth factor is an autocrine urothelial cell mitogen. In this study, we identify a potential role for proHB-EGF in transitional cell carcinoma (TCC) of the bladder. In an analysis of 33 TCC specimens and 8 normal controls, proHB-EGF, identified using an antibody directed against the cytoplasmic tail domain, localized to cell nuclei in a manner that correlated positively with tumor stage and grade (P < 0.001). The ability of proHB-EGF to localize to the nucleus was independently confirmed in a TCC cell line (TCCSUP), in which 40% of transfected proHB-EGF was found to reside in the nuclear compartment. In Kaplan-Meier survival analysis, TCC patients with >20% proHB-EGF-positive cell nuclei demonstrated markedly reduced survival compared with patients with <20% proHB-EGF-positive nuclei (P < 0.005, log-rank test). In multivariate analysis, nuclear localization of proHB-EGF of >20% was an independent prognostic indicator of disease-specific mortality. This is the first report in any cell type that HB-EGF is capable of translocating to the cell nucleus. In addition, our findings suggest that nuclear proHB-EGF may play a role in disease progression in bladder cancer and possibly other cancers.

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