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Title: Role of insulin-like growth factor-type 1 receptor (IGF-IR) signalling in tamoxifen-resistant breast cancer
Author: Knowlden, Janice M.
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2008
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The aim of the first part of this thesis was to determine the role played by IGF-IR in mediating the growth of EGFR-positive tamoxifen-resistant variants of MCF-7 Tam-R and T47D T47D-R breast cancer cell lines. The results identify a general tamoxifen-resistant mechanism whereby the autocrine release and action of IGF-II, mediated through the IGF-IR, plays a significant and crucial supporting role in regulating basal EGFR/MAPK signalling and cell proliferation and this occurs via a c-SRC-dependent mechanism in both Tam-R and T47D-R cells. The latter aim of this thesis was to determine further mechanisms of cross-talk between EGFR and IGF-IR in a range of EGFR-positive cancer cell lines. These studies identified a novel physical interaction between the EGFR and IRS-1 in each of these cell lines. In Tam-R breast and LNCaP prostate cancer cells, recruitment of IRS-1 by EGFR limited the availability of IRS-1 to associate with IGF-IR, thus inhibiting IGF-IR signalling capacity. Blockade of EGFR activity with gefitinib allowed re-association of IRS-1 with IGF-IR and re-establishment of IGF-IR signalling, the dominant growth regulatory mechanism of gefitinib resistance in Tam-R cells. Thus, gefitinib played an active role in limiting its own efficacy in these cells by promoting activation of a resistance pathway. Importantly, induction of this pathway by gefitinib could be abrogated by co-treatment with an IGF-IR inhibitor. Such findings identify the IGF-IR as a potential therapeutic target for the treatment of both tamoxifen-resistant and gefitinib-resistant breast and prostate cancers.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available