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Tyrosine Kinase Inhibitors in Triple Negative Breast Cancer

Corkery, Brendan Martin (2010) Tyrosine Kinase Inhibitors in Triple Negative Breast Cancer. PhD thesis, Dublin City University.

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Abstract

Basal-like breast cancers are generally negative for estrogen and progesterone receptor expression and HER-2 amplification (‘triple negative’ breast cancer, TNBC), and express basal cytokeratins 5/6, and EGFR (epidermal growth factor receptor). No targeted therapy options are currently approved for this subgroup of patients. The main aim of this study was to assess the potential role of selected inhibitors in TNBC, including the small molecule tyrosine kinases inhibitors of EGFR gefitinib and erlotinib, the monoclonal antibody against EGFR cetuximab, and the multi-target tyrosine kinase inhibitor dasatinib. Significantly higher EGFR expression was detected in TNBC compared to HER-2 positive breast cancer cell lines. EGF treatment stimulated phospho-EGFR which was inhibited by gefitinib. Sensitivity to gefitinib was associated with decreases in PMAPK and P-Akt, and G1 cell cycle arrest. Combined treatment with gefitinib and chemotherapy was more effective than either gefitinib or chemotherapy alone. EGFR and P-EGFR expression were examined by immunohistochemistry in 101 breast tumours. Only 6 % were positive for EGFR and 3 % for P-EGFR. Sixteen of the tumours were triple negative, with 31 % and 6 % rates of positivity for EGFR and PEGFR, respectively. It has been reported that dasatinib preferentially inhibits growth in TNBC cell lines compared to other breast cancer subtypes. A dasatinib-resistant variant of the triple negative MDA-MB-231 cell line was established (231-DasB). A dose-dependent decrease in P-Src levels in response to dasatinib was observed in MDA-MB-231 but not in 231-DasB. Proteomic analysis identified 78 significantly altered proteins. Six proteins were uniquely altered in MDA-MB-231 and 9 proteins were uniquely altered in 231-DasB. ANXA1, which has been implicated in breast carcinogenesis previously, was significantly increased in the variant cell line in response to dasatinib. While ANXA1 siRNA knockdown decreased proliferation in MDA-MB-231, it did not significantly alter response to dasatinib.

Item Type:Thesis (PhD)
Date of Award:November 2010
Refereed:No
Supervisor(s):O'Donovan , Norma and Crown, John and Clynes, Martin
Uncontrolled Keywords:tyrosine kinases inhibitors; triple negative breast cancer; gefitinib; erlotinib
Subjects:Biological Sciences > Biology
Medical Sciences > Cancer
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology
Research Initiatives and Centres > National Institute for Cellular Biotechnology (NICB)
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
ID Code:15714
Deposited On:14 Apr 2011 11:25 by Norma O'Donovan. Last Modified 14 Apr 2011 11:25

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