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Estrogen Receptor-β Affects the Prognosis of Human Malignant Mesothelioma

¹ Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and Drug and Food Biotechnology Center, University of Piemonte Orientale A. Avogadro, Novara, Italy; ² Department of Anatomic Pathology, Mestre Hospital, Venezia, Italy; ³ Medical Oncology Unit, Galliera Hospital, and Biostatistics Unit, Department of Health Sciences, University of Genoa, Genova, Italy; ⁴ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom; and ⁵ Italian Mesothelioma Group and ⁶ S. Pietro e Paolo Hospital, Borgosesia, Italy

Requests for reprints: Laura Moro, Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università degli Studi del Piemonte Orientale "A. Avogadro," Via Bovio 6, 28100 Novara, Italy. Phone: 39-321-375820; Fax: 39-321-375821; E-mail: moro{at}pharm.unipmn.it.

Key Words: estrogen receptor-β • malignant pleural mesothelioma • survival

Malignant pleural mesothelioma is an asbestos-related neoplasm with poor prognosis, refractory to current therapies, the incidence of which is expected to increase in the next decades. Female gender was identified as a positive prognostic factor among other clinical and biological prognostic markers for malignant mesothelioma, yet a role of estrogen receptors (ERs) has not been studied. Our goal was to investigate ERs expression in malignant mesothelioma and to assess whether their expression correlates with prognosis. Immunohistochemical analysis revealed intense nuclear ERβ staining in normal pleura that was reduced in tumor tissues. Conversely, neither tumors nor normal pleura stained positive for ER. Multivariate analysis of 78 malignant mesothelioma patients with pathologic stage, histologic type, therapy, sex, and age at diagnosis indicated that ERβ expression is an independent prognostic factor of better survival. Moreover, studies in vitro confirmed that treatment with 17β-estradiol led to an ERβ-mediated inhibition of malignant mesothelioma cell proliferation as well as p21^CIP1 and p27^KIP1 up-regulation. Consistently cell growth was suppressed by ERβ overexpression, causing a G₂-M-phase cell cycle arrest, paralleled by cyclin B1 and survivin down-regulation. Our data support the notion that ERβ acting as a tumor suppressor is of high potential relevance to prediction of disease progression and to therapeutic response of malignant mesothelioma patients. [Cancer Res 2009;69(11):4598–604]