320. Modeling Human Brain Cancer in Transgenic E2F1 Mice

Mutations disabling the retinoblastoma (Rb) pathway are among the most common in human cancers, including brain cancer. These mutations promote tumor development through deregulated control of the E2F family of transcription factors. E2F1 belongs to a class of E2F's identified as transcriptional activators and involved in the G1/S phase transition of the cell. However, E2F-1 presents with a paradox as it is considered to have membership in two gene classes, functioning as both an oncogene and a tumor suppressor. This unusual trait generates a degree of uncertainty on the role that E2F1 plays in the development or maintenance of any given tumor. Here we show that E2F1 functions as an oncogene in brain tumors through the generation of mice engineered to overexpress E2F1 specifically within glial cells and neuronal progenitors as directed by the GFAP promoter. Mice carrying the transgene develop with high penetrance a phenotype characterized by neurological deficits including paresia, ataxia, head tilt and seizures. MRI imagining of tgE2F1 mice reveal a low incidence of mild hydrocephalus, and most notably, histological analysis demonstrates that 20% of tgE2F1 mice present with the spontaneous formation of malignant brain tumors. Overall these neoplasms show histological features from a wide range of aggressive brain cancers including medulloblastoma, choroid plexus carcinoma, primary neuroectodermic tumor and malignant gliomas. Mouse age as related to tumoral type forces a comparison to the human disease with juvenile mice presenting embryonal tumors typically identified in children, and older mice revealed gliomas similar to the clinical findings in adults. In this regard, this study suggests a global role for E2F1 in the formation and maintenance of multilineage brain tumors, irrefutably establishing E2F1 as an oncogne in the brain. Further characterization of the tgE2F1 mouse should propel the development of a preclinical brain tumor model for the testing of cell-cycle or apoptosis-targetd therapies against brain cancer.