This led to the present investigation of the effect of pharmacological inhibition of AR in vitro and in the subcutaneous in vivo model, as well as the effect of genetic silencing of the receptor in GBM cell lines.ĪR protein expression and the presence of the ligand-independent AR splice variant 7 (AR3) in GBM samples The findings from our laboratory, some of which were previously presented, show amplification and overexpression of AR in GBM. Although AR-regulated signaling pathways are well established in prostate cancer, the involvement of AR in GBM and the potential AR-dependent or independent regulated signaling pathway in GBM is not known.ĪR signaling inhibitors such as enzalutamide target the AR signaling pathway at three key stages: by blocking binding of androgens to AR, by inhibiting nuclear translocation of activated AR, and by impairing binding of activated AR to DNA. These AR-independent pathways can promote cancer cell survival and growth (reviewed in ) and appear to be a major androgen-independent driver of AR-regulated gene expression in castration-resistant prostate cancer.ĪR splice variants lacking the LBD, such as AR-V7/AR3, which arise primarily through exon skipping and cryptic exon inclusion, are activated by a ligand-independent mechanism such as the ones mentioned above. Such pathways include receptor tyrosine kinases (RTKs), such as the insulin-like growth factor keratinocyte growth factor (KGF), EGFR and Human Epidermal Growth Factor Receptor 2 (HER2). It has been shown in prostate and breast cancers that activation of AR can be achieved also by ligand-independent signaling through crosstalk with other molecular signaling pathways, as a consequence of activation of the downstream PI3K/AKT/mTOR. In the presence of ligand, the ligand-binding domain is released from heat shock protein and AR is translocated into the nucleus, where it binds to the androgen-response-element in the promoter and stimulates transcription of androgen- responsive genes. It functions as a steroid-hormone-activated-transcription-factor and is composed of the N-Terminal-Regulatory-Domain, the DNA-Binding-Domain and the Ligand-Binding-Domain (LBD). The association between sex steroid receptors and brain tumors was first described in 1983, but in contrast to the well-established oncogenic role played by androgen receptor (AR) in prostate cancer (reviewed in ) and the growing evidence of its role in breast cancer (reviewed in ), the expression and significance of AR in GBM is controversial and poorly studied. Activation of EGFR results in a downstream phosphoinositol 3 kinase (PI3 kinase)/Akt cascade, facilitating cell survival, proliferation, and migration, and thus is crucial to tumorigenesis. The most common genetic aberrations associated with malignant glioma are amplification or activating mutations of the epidermal growth factor receptor (EGFR) or both. Glioblastoma (GBM) is the most common and the most aggressive primary brain tumor, with a very poor prognosis. The presence of AR-V7/AR3 in glioblastoma, together with the present data showing that genetic silencing of the full length AR in cell lines and pharmacological inhibition of AR, induce GBM cell death in vivo and in vitro, point to the important role of AR in GBM survival and render a potential therapeutic target for this devastating disease. Enzalutamide given orally to nude mice bearing subcutaneous human glioma xenografts resulted in a 72% reduction in tumor volume (p=0.0027). Silencing of AR expression by siRNA induced cell death in the three tested glioblastoma cell lines. AR antagonists, induced concentration-dependent death in three glioblastoma cell lines, as well as in two glioma initiating cell lines. Following these findings, we examined the effect of pharmacological inhibition of androgen receptor in vitro and in vivo, as well as of genetic silencing of the receptor in glioblastoma cell lines. Thirty percent of the glioblastomas (n=21) also expressed a constitutively active AR-splice-variant (AR-V7/AR3) lacking the Ligand-Binding-Domain. AR-RNA was overexpressed (>2.5 fold) in 93% (n=30), and AR-protein was induced (>two fold) in 56% of the glioblastomas samples (n=16). The AR gene was amplified in 27% of glioblastoma specimens from men (n=22) and of 38.2% from women (n=21). ![]() ![]() We have observed that androgen receptor (AR) is amplified in glioblastomas at the DNA, RNA and protein levels. The median survival time of patients with glioblastoma is still poor (14.6 month), partly due to a lack of effective treatment.
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