Identification of anti-hormone induced genes as potential therapeutic targets in breast cancer

Shaw, Victoria E. 2007. Identification of anti-hormone induced genes as potential therapeutic targets in breast cancer. PhD Thesis, Cardiff University.

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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.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
ISBN:	9781303181986
Date of First Compliant Deposit:	30 March 2016
Last Modified:	19 Mar 2016 23:33
URI:	https://orca.cardiff.ac.uk/id/eprint/55672

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