Abstract
Medulloblastoma (MD) is the most common malignant brain tumor in children. These invasive neuroectodermal tumors arise from cerebellar granule cell-like precursors. In the developing cerebellum, estrogen influences growth and viability of granule cell precursors that transiently express elevated levels estrogen receptor-beta (ERbeta) during differentiation. Immunoanalysis revealed that ERbeta was expressed in the maturing human cerebellum, in all 22 primary MD tumors analyzed, and in two MD-derived cell lines (D283Med and Daoy). Very low levels of ERalpha-like proteins were detected in each cell line and 41% of tumor samples. Physiological concentrations of the 17beta-estradiol- or the ERbeta-selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile diarylpropionitrile dose-dependently increased MD growth and cellular migration. In contrast, the ERalpha-selective agonist (4-propyl-[1H]pyrazole-1,3,5-triyl) trisphenol did not influence MD growth. Similar to previous studies in normal cerebellar granule cell precursors, these studies demonstrate that the physiological actions of estrogens in MD are mediated by ERbeta. Preclinical studies assessing the therapeutic efficacy of antiestrogen chemotherapeutics for treating human MD were performed. It was found that pharmacological inhibition of ER-mediated signaling with the ER antagonist drug Faslodex (ICI182,780) blocked all estrogen-mediated effects in both cell culture and xenograft models of human MD. These studies have revealed that functional ERbeta expression is a fundamental aspect of MD biology and has defined antiestrogen therapy as a potentially efficacious clinical approach to improve the long-term outcomes for MD patients.