Estrogen receptor β exerts tumor repressive functions in human malignant pleural mesothelioma via EGFR inactivation and affects response to gefitinib

Our plain-English summary of Estrogen receptor β exerts tumor repressive functions in human malignant pleural mesothelioma via EGFR inactivation and affects response to gefitinib, by G. Pinton, W. Thomas, P. Bellini, et al (PloS One, 2010).

The study

• Authors: G. Pinton, W. Thomas, P. Bellini, A.G. Manente, R.E. Favoni, B.J. Harvey, L. Mutti, L. Moro
• Journal: PloS One
• Published: 2010;5(11):e14110
• Cited by: 55 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The 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.

Methods: We modulated ERβ expression in REN and MSTO-211H MMe cell lines and evaluated cell proliferation and EGF receptor (EGFR) activation.

Results: Our 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.

Conclusions: This 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.

In plain English

This laboratory study used two human malignant pleural mesothelioma cell lines, REN and MSTO-211H. No patients were studied and asbestos was not examined. The authors tested how a protein called estrogen receptor beta (ERβ) affects tumor cell growth. Adding ERβ to MSTO-211H cells, which normally lack it, slowed their growth, cut colony formation in soft agar by about 50%, and reduced growth signaling through the EGF receptor (EGFR). Switching ERβ off in REN cells made them grow faster, form 3 to 4 times as many colonies, and show more EGFR-linked signaling. ERβ was found physically associated with EGFR and a protein called caveolin 1. REN cells were only weakly sensitive to gefitinib, a drug that blocks EGFR. Extra ERβ did not significantly change this, while switching ERβ off made the cells more sensitive. The authors concluded that their cell data give a possible explanation for why EGFR inhibitors were ineffective in phase II trials for patients with ERβ-positive epithelioid mesothelioma. They suggested such drugs might work better in ERβ-negative tumors, alone or with Akt inhibitors.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory experiment on human mesothelioma cell lines grown in culture (in vitro)
• Who was studied: Two human malignant pleural mesothelioma cell lines: REN, an epithelioid line and the main model, and MSTO-211H, a line established from the pleural effusion of a patient with biphasic mesothelioma; no patients were studied
• Exposure: Asbestos exposure was not studied. The experiments raised ERβ levels (plasmid) or silenced ERβ (shRNA) in the cells, and treated the cells with EGF and with the EGFR inhibitor gefitinib
• Main results:
  • In MSTO-211H cells, expressing ERβ significantly suppressed proliferation (p less than 0.05)
  • In MSTO-211H cells, ERβ expression reduced soft-agar colonies by about 50%
  • In REN cells, silencing ERβ increased EGFR, Akt and ERK1/2 phosphorylation (activation)
  • In REN cells, silencing ERβ gave a 3 to 4-fold increase in soft-agar colonies
  • In REN cells over-expressing ERβ, EGF-induced Akt activation was completely abolished
  • In REN cells, over-expressing ERβ increased its association with EGFR and caveolin 1, independent of EGF
  • REN cells were weakly sensitive to gefitinib, and over-expressing ERβ did not significantly change sensitivity
  • In REN cells, silencing ERβ made the cells more sensitive to EGFR blockade
• The authors' conclusion: The authors concluded their data give a possible explanation for why EGFR inhibitors were ineffective in phase II trials for ERβ-positive epithelioid mesothelioma. They suggested these drugs might be used more successfully in more aggressive, ERβ-negative tumors, alone or combined with Akt inhibitors.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, EGFR, Carcinogenesis, Epithelioid.

Related studies

• Gefitinib targets EGFR dimerization and ERK1/2 phosphorylation to inhibit pleural mesothelioma cell proliferation — R.E. Favoni, A. Pattarozzi, et al. (2010)
• Estrogen receptor-beta affects the prognosis of human malignant mesothelioma — G. Pinton, E. Brunelli, et al. (2009)
• Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells — A.G. Manente, G. Pinton, et al. (2015)
• KDM6B histone demethylase is an epigenetic regulator of estrogen receptor β expression in human pleural mesothelioma — A.G. Manente, G. Pinton, et al. (2016)
• Agonist activation of estrogen receptor beta (ERβ) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity — G. Pinton, A.G. Manente, et al. (2014)
• Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy — M. Brevet, S. Shimizu, et al. (2011)

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