Type

PhD Thesis

Authors

Brendan Martin Corkery

Subjects

Biochemistry

Topics
erlotinib gefitinib triple negative breast cancer tyrosine kinases inhibitors epidermal growth factor receptor egfr biology cell cycle arrest cancer

Tyrosine Kinase Inhibitors in Triple Negative Breast Cancer (2010)

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.
Collections Ireland -> Dublin City University -> Subject = Biological Sciences: Biology
Ireland -> Dublin City University -> Thesis Type = Doctoral Thesis
Ireland -> Dublin City University -> DCU Faculties and Centres = DCU Faculties and Schools: Faculty of Science and Health
Ireland -> Dublin City University -> DCU Faculties and Centres = Research Initiatives and Centres: National Institute for Cellular Biotechnology (NICB)
Ireland -> Dublin City University -> DCU Faculties and Centres = Research Initiatives and Centres
Ireland -> Dublin City University -> Publication Type = Thesis
Ireland -> Dublin City University -> Subject = Medical Sciences: Cancer
Ireland -> Dublin City University -> DCU Faculties and Centres = DCU Faculties and Schools
Ireland -> Dublin City University -> Subject = Biological Sciences
Ireland -> Dublin City University -> Status = Unpublished
Ireland -> Dublin City University -> Subject = Medical Sciences
Ireland -> Dublin City University -> DCU Faculties and Centres = DCU Faculties and Schools: Faculty of Science and Health: School of Biotechnology

Full list of authors on original publication

Brendan Martin Corkery

Experts in our system

1
B Corkery
Dublin City University
Total Publications: 5