In
medulloblastomas, which are highly malignant
cerebellar tumors of the childhood genotoxic treatments such as
cisplatin or gamma-irradiation are frequently associated with DNA damage, which often associates with unfaithful DNA repair, selection of new adaptations and possibly
tumor recurrences. Therefore, better understanding of molecular mechanisms which control DNA repair fidelity upon DNA damage is a critical task. Here we demonstrate for the first time that
estrogen receptor beta (
ERbeta) can contribute to the development of
genomic instability in
medulloblastomas. Specifically,
ERbeta was found highly expressed and active in mouse and human
medulloblastoma cell lines. Nuclear
ERbeta was also present in human
medulloblastoma clinical samples. Expression of
ERbeta coincided with nuclear translocation of
insulin receptor substrate 1 (IRS-1), which was previously reported to interfere with the faithful component of DNA repair when translocated to the nucleus. We demonstrated that
ERbeta and IRS-1 bind each other, and the interaction involves C-terminal domain of IRS-1 (aa 931-1233). Following
cisplatin-induced DNA damage, nuclear IRS-1 localized at the sites of damaged
DNA, and interacted with Rad51--an enzymatic component of homologous recombination directed DNA repair (HRR). In
medulloblastoma cells, engineered to express HRR-
DNA reporter plasmid, ER antagonist,
ICI 182,780, or IRS mutant (931-1233) significantly increased DNA repair fidelity. These data strongly suggest that both molecular and pharmacological interventions are capable of preventing
ERbeta-mediated IRS-1 nuclear translocation, which in turn improves DNA repair fidelity and possibly counteracts accumulation of malignant mutations in actively growing
medulloblastomas.