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Title: The role of suppressors of cytokine signalling 1-7 in breast cancer
Author: Sasi , Walid
ISNI:       0000 0004 5921 8039
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2015
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Suppressors of cytokine signalling (SOCS) are important negative regulators of several signalling pathways and their role in cancer development has been recently investigated. In this thesis; I first examined SOCS 1-7 genes expression in normal and breast cancer tissue using real-time PCR, and correlated this with several clinico-pathological prognostic factors including TNM stage, tumour grade and clinical outcome over lO-year follow-up. SOCS1, SOCS4-7 expression decreased with higher TNM stage, SOCS2-3 expression decreased with higher Nottingham Prognostic Index (NPI), and SOCS7 expression decreased with higher tumour grade. Higher SOCS 1-2, SOCS7 expression levels were found among patients who remained disease-free compared to those who developed local recurrence, and higher SOCS2, SOCS4, and SOCS7 as well as SOCSl-2 levels were found in patients who remained disease-free versus those who developed distant recurrence or died from breast cancer respectively. In survival analysis, higher levels of SOCSl, SOCS3 and SOCS7 were significant predictors of better disease-free survival (DFS) and overall survival (as), while SOCS4 was a significant predictor of better as. Secondly; I studied SOCS7 role. MCF7 and MDA-MB-23l breast cancer cells were transfected with anti-SOCS7 ribozymal transgene, creating sublines with SOCS7 knockdown that was verified by RT-PCR. Data suggest a SOCS7 tumour suppressor role in breast cancer, both in vitro and in vivo, as SOCS7 knockdown has enhanced cellular in vitro growth and migration, and in vivo MCF7- tumour growth in the athymic nude mice. As previous evidence suggested an anti-phospholipase Cy-l (PLCy-l) role for SOCS7, the in vitro cellular functions were evaluated with and without Insulin-like Growth Factor-I (IGF- I), Hepatocyte Growth Factor (HGF), and the PLCy-l inhibitor (U73122) treatment. SOCS7 loss resulted in increased in vitro cellular growth and migration leading to a synergistic effect on their response to IGF-I and HGF. This role could be attributed to SOCS7 downstream interaction with PLCy-l. These data support a tumour suppressing role for several SOCS family members in breast cancer. The study of SOCS7 showed a precise anti PLCy-l signalling role. Further research is required to explore SOCSs diagnostic and therapeutic applications in breast cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available