Estrogen Receptor-β Up-Regulates IGF1R Expression and Activity to Inhibit Apoptosis and Increase Growth of Medulloblastoma

Abstract

Medulloblastoma (Med) is the most common malignant brain tumor in children. The role of ESR2 [estrogen receptor (ER)-β] in promoting Med growth was comprehensively examined in three in vivo models and human cell lines. In a novel Med ERβ-null knockout model developed by crossing Esr2(-/-) mice with cerebellar granule cell precursor specific Ptch1 conditional knockout mice, the tumor growth rate was significantly decreased in males and females. The absence of Esr2 resulted in increased apoptosis, decreased B-cell lymphoma 2 (BCL2), and IGF-1 receptor (IGF1R) expression, and decreased levels of active MAPKs (ERK1/2) and protein kinase B (AKT). Treatment of Med in Ptch1(+/-) Trp53(-/-) mice with the antiestrogen chemotherapeutic drug Faslodex significantly increased symptom-free survival, which was associated with increased apoptosis and decreased BCL2 and IGF1R expression and signaling. Similar effects were also observed in nude mice bearing D283Med xenografts. In vitro studies in human D283Med cells metabolically stressed by glutamine withdrawal found that 17β-estradiol and the ERβ selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile dose dependently protected Med cells from caspase-3-dependent cell death. Those effects were associated with increased phosphorylation of IGF1R, long-term increases in ERK1/2 and AKT signaling, and increased expression of IGF-1, IGF1R, and BCL2. Results of pharmacological experiments revealed that the cytoprotective actions of estradiol were dependent on ERβ and IGF1R receptor tyrosine kinase activity and independent of ERα and G protein-coupled estrogen receptor 1 (G protein coupled receptor 30). The presented results demonstrate that estrogen promotes Med growth through ERβ-mediated increases in IGF1R expression and activity, which induce cytoprotective mechanisms that decrease apoptosis.

Heterozygous mutation of Sonic Hedgehog receptor (Ptch) drives cerebellar overgrowth and sex-specifically alters hippocampal and cortical layer structure, activity, and social behavior in female mice

“…Considering the progressive nature of MB development in Ptch1 +/- , the apparent increased sensitivity of females to dysregulated SHH signaling could be related to the increased levels of circulating estrogens in mature females. These activities of estrogen are mediated through modulation of rapid estrogen signaling, estrogen receptor-regulated gene expression, and resulting modulation of growth factor-related signal transduction pathways (Cookman and Belcher, 2015; Garcia-Segura et al, 2006). Increased activation of ERβ signaling increases GCP mitogenesis and migration, and upregulates neuroprotective mechanisms in mature granule cells, which also act in the etiology and progression of MB to drive tumor progression (Belcher, 2008; Cookman and Belcher, 2015; Guillette et al, 2018).…”

“…These activities of estrogen are mediated through modulation of rapid estrogen signaling, estrogen receptor-regulated gene expression, and resulting modulation of growth factor-related signal transduction pathways (Cookman and Belcher, 2015; Garcia-Segura et al, 2006). Increased activation of ERβ signaling increases GCP mitogenesis and migration, and upregulates neuroprotective mechanisms in mature granule cells, which also act in the etiology and progression of MB to drive tumor progression (Belcher, 2008; Cookman and Belcher, 2015; Guillette et al, 2018). It is possible that the more sever phenotypes detected in Ptch1 +/- female mice are related to a relative increase in estrogen signaling in ERβ positive Ptch1 +/- granule cell-like precursors.…”

“…Estrogen receptor β (ERβ) is expressed in maturing GCPs and MB tumor cells and can modify MB growth and progression (Belcher, 2008; Jakab et al, 2001). Increased estrogen receptor signaling during cerebellar development and MB progression results in upregulation of cytoprotective ERβ-dependent insulin-like growth factor signaling that impacts GCP maturation and migration, and can increase MB tumor growth rate (Belcher, 2008; Cookman and Belcher, 2015).…”

Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition

“…Estrogen receptors play an important role in the regulation of numerous metabolic and proliferative processes, including tumorigenesis, preferentially through interaction with specifi c response element in the target genes (Mueller et al 2000;Cookman and Belcher 2015;Lau and To 2016;Ur Rahman and Cao 2016;Wesolowska et al 2016;Zhu et al 2016). Estrogen receptors are responsible for the regulation of cell growth and apoptosis as well as are involved, at least partly, in the development, proliferation, and progression of some cancers.…”

“…At the same time, Li et al (2013) have shown that in U87 cells estrogen receptors inhibit the cell proliferation and reduced cells in the S+G2/M phase and that hypoxia induced estrogen receptor-β5 expression in glioma as a self-protective mechanism against tumor proliferation. Recently, Cookman and Belcher (2015) have demonstrated that estrogen promotes medulloblastoma growth through estrogen receptor-β-mediated increases in IGF1R expression and activity, which induce cytoprotective mechanisms that decrease apoptosis.…”