Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.584161
Title: Identification of anti-hormone induced genes as potential therapeutic targets in breast cancer
Author: Shaw, Victoria
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2007
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Abstract:
Tamoxifen, a competitive inhibitor of oestradiol binding to the oestrogen receptor ER, remains a key anti-hormonal treatment for ER ve breast cancer although its effectiveness is limited by development of resistance. It is hypothesised that in addition to blockade of pro-proliferative/anti-apoptotic genes, anti-oestrogens exert an early protective effect, inducing cell survival and pro-invasive genes that enable a subset of cells to escape the anti-tumour effects of the anti-oestrogens and facilitate disease progression. It was hoped that identification of such early compensatory events in this thesis and their subsequent therapeutic targeting in combination with anti-oestrogens would be able to improve anti-tumour response. Proof of this principle exists since co-targeting of anti-oestrogen-induced epidermal growth factor receptor EGFR alongside tamoxifen has been reported to improve growth inhibition in ER ve MCF-7 human breast cancer cells and delay acquisition of resistance. After filtering, hierarchical clustering and ontological investigation, 8 possible compensatory genes were identified as anti-oestrogen tamoxifen and faslodex-induced /oestrogen-suppressed at an early time point in MCF-7 cells in vitro using cDNA microarrays bearing 1200 cancer-related genes, comparing anti-oestrogen with oestrogen E2 treatment and control oestrogen deprived conditions. RT-PCR and protein investigation gave further insight into expression levels of these genes based on ER occupancy. Genes induced by both an anti-oestrogen-occupied ER and an unoccupied ER versus E2 treatment were the Rnd family member RhoE and nucleoside diphosphate kinase NME3 implicated in migration and cell survival respectively, and the anti-apoptotic transcription factor NFkBl. The adhesive junction protein 5-catenin, cell survival elements 14-3-3 and chaperone Bag-1 and nuclear serine/threonine kinase NDR implicated in progression were all induced by an anti-oestrogen occupied ER but not by an unoccupied ER versus E2 treatment. Co-treating with the NFkB inhibitor parthenolide and faslodex suppressed NFkBl DNA binding, transcriptional activity and improved growth inhibition of MCF-7 cells. These data demonstrate that several genes of adverse potential are induced during the anti-oestrogen-responsive phase, and that their co-targeting has promise to improve anti-tumour response.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.584161  DOI: Not available
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