Date of Award

2013

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Warren Thomas

Second Supervisor

Professor Brian Harvey

Third Supervisor

Professor Elaine Kay

Funder/Sponsor

Health Research Board of Ireland

Keywords

Lung Neoplasms, Asbestos, Receptors, Steroid.

Abstract

Malignant Mesothelioma is a rare but highly aggressive tumour that arises from the mesothelial surfaces of the pleural or peritoneal membranes, the pericardium, or the tunica vaginalis. A causative link has been established between exposure to asbestos fibres and the subsequent development of malignant pleural mesothelioma (MPM) in 85% of subjects, while simultaneous infection with SV40 virus is also believed to contribute to MPM aetiology. MPM is often detected decades after initial exposure to the carcinogen. Despite recent restrictions on the use of asbestos, the incidence of MPM is continuing to rise due to the long latency period, 30-40 years for the development of MPM after asbestos exposure. MPM is invariably terminal and histological sub-typing is currently the most important prognostic indicator of post diagnosis survival time.

Female gender is a positive prognostic indicator for MPM progression, suggesting that disease incidence and progression may be influenced by circulating hormones or the expression of steroid receptors, including androgen receptor (AR), progesterone receptor (PR) and oestrogen receptors (ER). Steroid receptors are hormone activated receptors and transcriptional activation from these hormone-steroid receptor complexes is facilitated by recruitment of the p160 SRC family, SRC-1, TIF-2 and AIB-1. Data indicates that over-expression of an ER isoform, ERβ, in tumours from 15% of patients with MPM, correlates with improved prognosis. Selectively stimulating ERβ signalling pathways may represent a novel approach to slowing MPM progression in male as well as female patients.

The aims of this study were to evaluate expression of the steroid receptors, AR, PR, ER isoforms and their coactivators, SRC-1, TIF-2 and AIB-1 in MPM cell lines and tumours from a cohort of patients with confirmed MPM diagnosis using immuno-histochemistry (IHC). Expression in tumour cells was compared to patient survival. A comparison of prognostic efficacy of steroid receptors and the SR C isoforms with other indicative parameters of post diagnosis survival was made, and the role that these proteins may play in MPM tumour suppression was elucidated.

IHC carried out on 3 normal and 89 MPM cases indicated that ERpi and ERp2 and the p160 family of coactivators were expressed at high levels in normal tissue and at various abundances in MPM tissue tumour sections and cell lines. Positive expression of ERβi and ERβ2 conferred a survival advantage, as did high expression of TIF-2 across all MPM cases. TIF-2 was also found to confer a survival advantage in male patients and also in epithelioid only cases, indicating that it may be an indicator of early transition from epithelioid to sarcomatoid MPM. Cell viability assays indicated that oestrogen and ERβ inhibit MPM cell growth while luciferase assays also show a potential role for ERβ in MPM initiation may occur through inhibition of NFkB activity, which has been implicated in the development of MPM

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Creative Commons License
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Comments

Submitted for the Award of Doctor of Philosophy (PhD) to the Royal College of Surgeons, 2013.

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