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Title: High Throughput Functional Analysis for the Identification of Breast Cancer Targets
Author: Iorns, Elizabeth Jane
ISNI:       0000 0004 2678 9118
Awarding Body: Institute of Cancer Research (University Of London)
Current Institution: Institute of Cancer Research
Date of Award: 2008
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Endocrine therapies, which inhibit estrogen receptor a (ERa) signalling, are the most common and effective treatment for ERa positive breast cancer. However, the utility of these agents is limited by the frequent development of resistance. The precise mechanisms underlying endocrine therapy resistance remain incompletely understood and further work is therefore required to identify potential therapeutic targets to inhibit the development of resistance, as well as to identify alternative novel targets for therapy. In this thesis, an RNA interference (RNAi) screen was used to identify modifiers of sensitivity to the most commonly used endocrine therapy, tamoxifen. CDKlO was identified as an important determinant of resistance and was investigated further. CDKlO silencing was shown to activate the MAPK signalling pathway, circumventing the reliance of breast cancer cells upon estrogen signalling. Patients with ERa positive breast tumours that express low levels ofCDKlO were shown to relapse early on tamoxifen and methylation of the CDKlO promoter was observed in a significant proportion of patients, suggesting a mechanism for loss of CDKl 0 expression in tamoxifen resistant tumours. By suppressing gene expression, RNAi, to a certain extent, models the pharmacological inhibition of a target protein. Parallel small molecule screens were performed alongside the RNAi screen to identify small molecule inhibitors that sensitise to tamoxifen. Both the RNAi and small molecule screens identified the PDKl pathway as a potential target for sensitisation. The mechanisms underlying tamoxifen sensitisation were examined. To determine novel therapeutic targets for cancer, genes that are critical to the survival of tumour cells but which are largely redundant in normal cells must be identified. Parallel RNAi screens in cancer cell lines were used to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes potentially constitute selectively lethal targets for cancer therapy. This approach was combined with gene expression and genomic analysis, allowing the identification of novel functionally important therapeutic targets, including WEEl. WEEl was essential for the viability ofWEEl overexpressing cancer cell lines and a subgroup of breast tumours that overexpress WEEl was identified, suggesting WEEl could be a therapeutic target for breast cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available