Huntingtin interacting protein 1 is a novel brain tumor marker that associates with epidermal growth factor receptor

Huntingtin interacting protein I (HIPI) is a multidomain oncoprotein whose expression correlates with increased epidermal growth factor receptor (EGFR) levels in certain tumors. For example, HIP1-transformed fibroblasts and HIP1-positive breast cancers have elevated EGFR protein levels. The combined association of HIPI with huntingtin, the protein that is mutated in Huntington's disease, and the known overexpression of EGFR in glial brain tumors prompted us to explore HIPI expression in a group of patients with different types of brain cancer. We report here that HIPI is over-expressed with high frequency in brain cancers and that this overexpression correlates with EGFR and platelet-derived growth factor receptor expression. Furthermore, serum samples from patients with brain cancer contained anti-HIP1 antibodies more frequently than age-matched brain cancer-free controls. Finally, we report that HIP I physically associates with EGFR and that this association is independent of the lipid, clathrin, and actin interacting domains of HIPI. These findings suggest that HIPI may up-regulate or maintain EGFR overexpression in primary brain tumors by directly interacting with the receptor. This novel HIPI-EGFR interaction may work with or independent of HIPI modulation of EGFR degradation via clathrin-mediated membrane trafficking pathways. Further investigation of HIPI function in brain cancer biology and validation of its use as a prognostic or predictive brain tumor marker are now warranted.