Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511160
Title: The interaction between vascular endothelial growth factor and oestrogen signalling in breast cancer
Author: Banerjee, Susana
Awarding Body: Institute of Cancer Research (University Of London)
Current Institution: Institute of Cancer Research (University Of London)
Date of Award: 2009
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Abstract:
Therapies targeting the oestrogenic stimulation of tumour growth have been a major success in reducing mortality from oestrogen receptor (ER)-positive breast cancer. However, resistance remains a major clinical problem. Various cellular signalling pathways, including the pro-angiogenic Vascular Endothelial Growth Factor (VEGF) pathway, have been implicated in the mechanism of therapeutic resistance. The aim of this project was to investigate the relationship between oestrogen- and VEGF-mediated signalling in breast cancer. The clinical relevance of the interaction between the ER and VEGF pathways was evaluated in two clinical studies: (i) Circulating VEGF and sVEGFR-1 levels were measured both before and after administration of endocrine therapy in women with primary breast cancer. The results provided evidence for possible cross-talk between ER- and VEGF-signalling. However, the aromatase inhibitor (AI) anastrozole and the ER-antagonist tamoxifen had differential effects on VEGF and sVEGFR-1. (ii) The expression of VEGF, VEGFR-2 and pVEGFR-2 and assoications with ER, PgR, pp38 and HER2 were investigated in paired samples of breast cancers before and after relapse following tamoxifen treatment. Positive correlations between ER and PgR with VEGF were noted in the relapse specimens which were not present in the primary cancers, providing support for an interaction between the ER- and VEGF-signalling pathways that may be relevant to endocrine therapy resistance. The role of ER in the regulation of VEGF expression was investigated in cell lines modelling resistance to tamoxifen and Als. Oestradiol(bound)-ER increased VEGF promoter activity and VEGF secretion and HER2 knockdown reduced VEGF secretion. This suggested that ER regulates VEGF in resistance and showed that an imperfect oestrogen response element (ERE) dependent mechanism is likely to be involved. The possibility of targeting ER- and VEGF- pathways together was investigated, initially by combining an Al with a VEGFR inhibitor (PTK787). Unexpectedly, this inhibitor was shown to directly inhibit aromatase activity in vitro. PTK787 decreased the number of vessels, cell turnover index, uterine weight, PgR and TFF1 in vivo suggesting that dual targeting of both angiogenic and endocrine signalling in a single agent is possible and may be worth exploring further. This series of studies has provided new insight into the significance of VEGF in ER-positive breast cancer, particularly that which has progressed to endocrine resistance. In addition, the ability of a single small molecule inhibitor to inhibit two distinct biological pathways may allow the rational development of agents designed to inhibit cross class targets.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Phd
EThOS ID: uk.bl.ethos.511160  DOI: Not available
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