Abstract
BackgroundThe role of estrogen and estrogen receptors in oncogenesis has been investigated in various malignancies. Recently our group identified estrogen receptor beta (ERβ) expression as an independent prognostic factor in the progression of human Malignant Pleural Mesothelioma (MMe), but the underlying mechanism by which ERβ expression in tumors determines clinical outcome remains largely unknown. This study is aimed at investigating the molecular mechanisms of ERβ action in MMe cells and disclosing the potential translational implications of these results.MethodsWe modulated ERβ expression in REN and MSTO-211H MMe cell lines and evaluated cell proliferation and EGF receptor (EGFR) activation.ResultsOur data indicate that ERβ knockdown in ER positive cells confers a more invasive phenotype, increases anchorage independent proliferation and elevates the constitutive activation of EGFR-coupled signal transduction pathways. Conversely, re-expression of ERβ in ER negative cells confers a more epithelioid phenotype, decreases their capacity for anchorage independent growth and down-modulates proliferative signal transduction pathways. We identify a physical interaction between ERβ, EGFR and caveolin 1 that results in an altered internalization and in a selective reduced activation of EGFR-coupled signaling, when ERβ is over-expressed. We also demonstrate that differential expression of ERβ influences MMe tumor cell responsiveness to the therapeutic agent: Gefitinib.ConclusionsThis study describes a role for ERβ in the modulation of cell proliferation and EGFR activation and provides a rationale to facilitate the targeting of a subgroup of MMe patients who would benefit most from therapy with Gefitinib alone or in combination with Akt inhibitors.
Highlights
Malignant pleural mesothelioma (MMe) is a highly aggressive tumor, most often associated with asbestos exposure, a role for SV40 and genetic susceptibility have been proposed [1]
estrogen receptor beta (ERb) expression conferred a more epithelioid phenotype on the MSTO-211H cells compared to mock transfected cells, characterized by a more cortical actin distribution (Fig. 1B). 48 hours after transfection, total protein extracts were prepared from mock- and ERb -transfected cells
Western blot analysis confirmed the efficacy of ERb expression to down modulate EGF receptor (EGFR), Akt and ERK1/2 phosphorylation without a change in the total abundance of these proteins expression, while it resulted in cyclin D1 protein reduction (Fig. 1A)
Summary
Malignant pleural mesothelioma (MMe) is a highly aggressive tumor, most often associated with asbestos exposure, a role for SV40 and genetic susceptibility have been proposed [1]. We recently published data demonstrating that estrogen receptor beta (ERb) is linked with better prognosis in MMe patients and is likely to act as tumor repressor [5]. Estrogens exert their biological effects through two distinct receptors: ERa and ERb. The ERs are transcribed from two different genes and display specific tissue expression patterns as well as distinct ligand specificities even though both bind the most biologically active estrogen, 17b-estradiol [6]. Our group identified estrogen receptor beta (ERb) expression as an independent prognostic factor in the progression of human Malignant Pleural Mesothelioma (MMe), but the underlying mechanism by which ERb expression in tumors determines clinical outcome remains largely unknown. This study is aimed at investigating the molecular mechanisms of ERb action in MMe cells and disclosing the potential translational implications of these results
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