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Estrogen Receptor [beta] Exerts Tumor Repressive Functions in Human Malignant Pleural Mesothelioma via EGFR Inactivation and Affects Response to Gefitinib
The role of estrogen and estrogen receptors in oncogenesis has been investigated in various malignancies. Recently our group identified estrogen receptor beta (ER[beta]) expression as an independent prognostic factor in the progression of human Malignant Pleural Mesothelioma (MMe), but the underlyin...
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Published in: | PloS one 2010-11, Vol.5 (11), p.e14110 |
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Main Authors: | , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | The role of estrogen and estrogen receptors in oncogenesis has been investigated in various malignancies. Recently our group identified estrogen receptor beta (ER[beta]) expression as an independent prognostic factor in the progression of human Malignant Pleural Mesothelioma (MMe), but the underlying mechanism by which ER[beta] expression in tumors determines clinical outcome remains largely unknown. This study is aimed at investigating the molecular mechanisms of ER[beta] action in MMe cells and disclosing the potential translational implications of these results. We modulated ER[beta] expression in REN and MSTO-211H MMe cell lines and evaluated cell proliferation and EGF receptor (EGFR) activation. Our data indicate that ER[beta] 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 ER[beta] 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 ER[beta], EGFR and caveolin 1 that results in an altered internalization and in a selective reduced activation of EGFR-coupled signaling, when ER[beta] is over-expressed. We also demonstrate that differential expression of ER[beta] influences MMe tumor cell responsiveness to the therapeutic agent: Gefitinib. This study describes a role for ER[beta] 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. |
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ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0014110 |