PROGNOSTIC-SIGNIFICANCE OF HER2 AND HER4 COEXPRESSION IN CHILDHOOD MEDULLOBLASTOMA

Recent in vitro studies of the epidermal growth factor receptor (EGFR) family have revealed complex signaling interactions involving the pro duction of ligand-mediated heterodimers synergistic for the transforma tion of cells in vitro, In a series of 70 patients with childhood medu lloblastoma, we have used immunohistochemistry and Western blotting an alysis to investigate the expression patterns of all four EGFR family members (EGFR, HER2, HER3, and HER4) and heregulin-alpha, a ligand for the HER3 and HER4 receptors. The majority of cases expressed two or m ore receptor proteins; coexpression of the HER2 and HER4 receptors occ urred in 54%, Expression of the ligand heregulin-alpha was detected in 31% of tumors, To investigate whether coexpression results in recepto r heterodimerization, we have also performed immunoprecipitation analy sis of protein extracts from primary tumors, and we demonstrate variou s patterns of receptor interaction including between HER2 and HER4. In multivariate 25-year survival analysis with clinicopathological disea se features, no individual receptor or heregulin-alpha achieved signif icance, In contrast, when considered together in the multivariate mode l, coexpression of HER2 and HER4 demonstrated independent prognostic s ignificance (P = 0.006). These data suggest the hypothesis that HER2-H ER4 receptor heterodimerization is of particular biological significan ce in this disease, and this report is the first to demonstrate potent ial clinical significance of EGFR family heterodimerization in human c ancer, Finally, we have also analyzed expression of the AP-2 transcrip tion factor implicated in the positive regulation of HER2 and HER3 gen e transcription in malignant cells and reveal an association between A P-2 expression and not only HER2 and HER3, but also HER4 levels in med ulloblastoma primary tumors.