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Title: Determining the genes responsible for drug resistance in ovarian and breast cancer stem cells
Author: Eyre, Rachel
ISNI:       0000 0004 2745 2111
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2012
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The majority of deaths in ovarian and breast cancer are caused by recurrent metastatic disease which is usually multidrug resistant. This progression has been hypothesised to be due in part to the presence of cancer stem cells, a subset of cells which are capable of self renewal and are able to survive chemotherapy and migrate to distant sites. Side population (SP) cells, identified by the efflux of the DNA binding dye Hoechst 33342 through ABC transporters, are a known adult stem cell group and have been suggested as a cancer stem cell in various cancers. The aims of this study were (i) to determine the presence and prevalence of SP cells in ovarian and breast cancer cell lines and clinical samples, and (ii) to ascertain their role both as cancer stem cells and in cancer drug resistance through ABC transporter identification and specific transporter knockdown. SP cells were identified in both ovarian and breast cancer cell lines and clinical samples. These SP cells expressed known stem cell genes and exhibited stem cell characteristics. SP cells in both ovarian and breast cancer cell lines were more drug resistant than non- SP (NSP, bulk tumour cells), and furthermore this drug resistance was shown to be due to expression of different ABC transporters in different tissue specific cancers. ABCG2 was found to be the predominate transporter expressed in breast cancer cell line derived SP populations, however silencing ABCG2 in MCF-7 breast cancer cell SP did not either completely inhibit SP presence or increase cell sensitivity to chemotherapy. In contrast ABCB1 was the predominant transporter expressed in ovarian cancer cell line (IGROV1 and HeyA8MDR) derived SP cells and silencing this transporter both fully inhibited SP cells and significantly increased SP cell death following treatment with paclitaxel. In clinical samples, the presence of SP cells in fine needle aspirates from breast cancer patients correlated to oestrogen receptor negative disease and the triple negative phenotype (ER-,PR-,HER2-), a marker of poor patient prognosis. This study has provided evidence of a role for SP cells in both breast and ovarian cancer. SP cells have a possible prognostic role in breast cancer, and ABCB1 should be considered as a therapeutic target in ovarian cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available