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Title: The role of the apoptotic pathway in hormone resistant breast cancer
Author: Cannings, Elizabeth
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2006
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Activation of the PDK/Akt signal transduction pathway has been linked to endocrine resistance in tamoxifen treated breast cancer patients. Activation of the PBK/Akt pathway causes phosphorylation of Bad leading to modulation of cellular apoptosis. This study was carried out to test the hypothesis that disruption of apoptosis in breast cancer, via Akt activation, is linked with hormone resistance. Immunohistochemistry (IHC) was performed on 402 oestrogen receptor (ER) positive breast cancers using antibodies against PTEN, Bad, pBad (ser 112), Bax, Bcl-2, Bcl- xl, P70S6K, pP70S6K (thr 389) and pP90RSK (thr 359/ser363). In addition FISH was performed on the same cohort for HER2. This was compared with the results for the herceptest performed on the same tumours. I also performed pilot studies looking at the amplification and deletions of PI3K and PTEN respectively in this cohort of patients. Patients whose tumours had high levels of PTEN expression had a favourable outcome compared to those patients with a low PTEN expression. Patients, whose tumours had high levels of Bad expression, had a significantly improved disease-free survival when compared to patients whose tumours had low levels of Bad expression. There were no associations with disease free or overall survival in the remaining antibodies investigated. Pilot studies did not suggest that it would be fruitful to perform FISH on the whole tumour cohort for either PI3K or PTEN. Data presented here shows that reduced Bad expression is associated with relapse in tamoxifen-treated breast cancer patients, supporting our hypothesis that the apoptosis pathway is involved in tamoxifen resistance. My results also show an association between increased expression of PTEN and a reduced overall and disease free survival.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available