The role of oestrogen induced signalling in the suppression of malignant mesothelioma cell growth.
Creators: name: Jennings, Cormac
Publisher: name: Royal College of Surgeons in Ireland
Year: 2019
Subjects: Uncategorized

description: <strong>Malignant Mesothelioma is a rare but highly aggressive tumour that arises from the mesothelial </strong><strong>surfaces of the pleural or peritoneal membranes, the pericardium, or the tunica vaginalis. A </strong><strong>causative link has been established between exposure to asbestos fibres and the subsequent </strong><strong>development of malignant pleural mesothelioma (MPM) in 85% of subjects, while simultaneous </strong><strong>infection with SV40 virus is also believed to contribute to MPM aetiology. MPM is often detected </strong><strong>decades after initial exposure to the carcinogen. Despite recent restrictions on the use of </strong><strong>asbestos, the incidence of MPM is continuing to rise due to the long latency period, 30-40 years </strong><strong>for the development of MPM after asbestos exposure. MPM is invariably terminal and </strong><strong>histological sub-typing is currently the most important prognostic indicator of post diagnosis </strong><strong>survival time.</strong> <strong>Female gender is a positive prognostic indicator for MPM progression, suggesting that disease </strong><strong>incidence and progression may be influenced by circulating hormones or the expression of </strong><strong>steroid receptors, including androgen receptor (AR), progesterone receptor (PR) and oestrogen </strong><strong>receptors (ER). Steroid receptors are hormone activated receptors and transcriptional activation </strong><strong>from these hormone-steroid receptor complexes is facilitated by recruitment of the p160 SRC </strong><strong>family, SRC-1, TIF-2 and AIB-1. Data indicates that over-expression of an ER isoform, ERβ, in </strong><strong>tumours from 15% of patients with MPM, correlates with improved prognosis. Selectively </strong><strong>stimulating ERβ signalling pathways may represent a novel approach to slowing MPM </strong><strong>progression in male as well as female patients.</strong> <strong>The aims of this study were to evaluate expression of the steroid receptors, AR, PR, ER </strong><strong>isoforms and their coactivators, SRC-1, TIF-2 and AIB-1 in MPM cell lines and tumours from a </strong><strong>cohort of patients with confirmed MPM diagnosis using immuno-histochemistry (IHC). </strong><strong>Expression in tumour cells was compared to patient survival. A comparison of prognostic </strong><strong>efficacy of steroid receptors and the SR C isoforms with other indicative parameters of post </strong><strong>diagnosis survival was made, and the role that these proteins may play in MPM tumour </strong><strong>suppression was elucidated.</strong> <strong>IHC carried out on 3 normal and 89 MPM cases indicated that ERpi and ERp2 and the p160 </strong><strong>family of coactivators were expressed at high levels in normal tissue and at various abundances </strong><strong>in MPM tissue tumour sections and cell lines. Positive expression of ERβi and ERβ2 conferred </strong><strong>a survival advantage, as did high expression of TIF-2 across all MPM cases. TIF-2 was also </strong><strong>found to confer a survival advantage in male patients and also in epithelioid only cases, </strong><strong>indicating that it may be an indicator of early transition from epithelioid to sarcomatoid MPM. </strong><strong>Cell viability assays indicated that oestrogen and ERβ inhibit MPM cell growth while luciferase </strong><strong>assays also show a potential role for ERβ in MPM initiation may occur through inhibition of NF</strong><strong>k</strong><strong>B </strong><strong>activity, which has been implicated in the development of MPM</strong>