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Title: The interaction between the type 1 receptor tyrosine kinases and the oestrogen receptor in human breast cancer : the role of the Ras/Raf-1/MAPK pathway
Author: McGlynn, Liane Marie
ISNI:       0000 0001 3624 3336
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2006
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Tamoxifen and chemotherapy are key treatments for breast cancer patients. Tamoxifen, an oestrogen antagonist, is a non-steroidal that acts as a selective oestrogen receptor modulator (SERM). It competitively inhibits the interaction of oestrogen with the oestrogen receptor, blocking the effects of E2 and inhibiting receptor activity. Chemotherapy uses cytotoxic drugs to kill cancer cells, by preventing them from multiplying, invading and metastasing. Despite the extensive use of both treatments, failure to respond to them is a major clinical problem and this is the cause of significant morbidity and mortality. To overcome this and to improve patients' treatment options, we need to understand the mechanisms regulating the development of resistance. The Ras/Raf-l/MAPK pathway regulates multiple cellular processes such as proliferation, apoptosis, differentiation, senescence and migration. MAPK activation results in phosphorylation of more than 50 substrates within the cytosol and nucleus. One key substrate of MAPK is the oestrogen receptor (ERalpha). Activated MAPK directly and indirectly phosphorylates serine 118 and 167, respectively, in the AF-2 domain of the receptor. Stimulation of the Ras pathway results in the ligand-independent activation of the ERalpha. Consequently, this pathway has been identified as a key player in the development and progression of tumourigenesis. Research suggests that activation of this pathway mediates response to tamoxifen, by activating ERalpha in a ligand-independent manner, and to chemotherapy, by increasing cell proliferation. This current study investigated the hypothesis that expression and activation of Ras/Raf-l/MAPK influences patient outcome and treatment response, using breast tumours from three different patient cohorts and an immunohistochemical approach. It also examined the relationship between MAPK and oestrogen receptor, both can localise to the cytoplasm and/or nuclei of cells but it is unclear how and where they interact. Therefore, in vitro studies, including immunofluorescence, were performed to investigate the relationship between MAPK and ERalpha, and their role in driving tamoxifen resistance. The pilot study, comprised of ER positive and negative patients who received a range of treatments, revealed that increased expression of N-Ras in breast tumours was related to reduced disease-free and overall survival time. It also highlighted the unexpected finding that Ras localised to the nuclei of breast tumour cells. The presence of nuclear Ras was confirmed by in vitro studies. The expression of Ras, Raf-1 and MAPK proteins was investigated further, in tumours from ER positive patients, who were treated with tamoxifen (STB study), and in tumours from ER positive and negative patients who received chemotherapy treatment (NEAT/BR9601 study). These two studies highlighted that the Ras pathway mediated outcome in patients treated with Tamoxifen but not chemotherapy. This research highlights the impact of the Ras pathway on breast cancer patients' response to treatment. It also reveals some interesting findings regarding the interaction between MAPK and ER, and offers a possible mechanism for the development of Tamoxifen resistance.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral