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Title: Mechanism of resistance to oestrogen deprivation in breast cancer
Author: Staka, Cindy M.
ISNI:       0000 0004 2748 4957
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2006
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Oestrogen deprivation strategies, notably aromatase inhibitors, are of increasing value in hormone sensitive breast cancer. Unfortunately, however, oestrogen deprivation, like all other antihormones, is subject to acquisition of resistance. Further understanding of resistance is required to design approaches to effectively treat this state. This project aimed to delineate and target the underlying autocrine signalling mechanisms promoting this resistant phenotype, using a unique severely oestrogen and growth factor deprived in vitro breast cancer model, MCF-7X. The MCF-7X model revealed breast cancer cells are readily able to survive oestrogen deprivation, but are not oestrogen hypersensitive and lack input from classical growth factor receptors under conditions of parallel exogenous growth factor deprivation, contrasting previous models derived in the presence of stripped serum. However, there was a retained importance of oestrogen receptor (ERa) signalling, supporting use of the pure anti-oestrogen faslodex, which reduces ERa level, AF-1 phosphorylation at serine 118 (via an unknown kinase) and ERa-regulated transcriptional activity in MCF-7X cells. Furthermore, intracellular kinase signalling, primarily PI3K/AKT, contributed in MCF-7X cells, again driving transcriptional and growth-promoting activity of ERa, in this instance via ERa serine 167 phosphorylation. Critically, individual/dual targeting with faslodex and/or PI3K inhibition, while initially partially inhibitory of ERa phosphorylation and growth, ultimately supported emergence of resistance. This was invariably associated with gain of the growth factor receptors EGFR/HER2 and IGF1R and kinase-promoted re-activation of ERa phosphorylation/function. However, triple treatment using faslodex, PI3K and MAPK blockade to completely eliminate ERa phosphorylation substantially improved anti-tumour response and prevented resistance. Clearly, intelligent design of combination treatments of faslodex with targeted therapies to totally deplete ERa activity is needed to maximally inhibit oestrogen deprivation resistance. In contrast, the project showed sequential use of such agents may translate into poorer prognosis, since faslodex resistant cells were more aggressive (potentially driven by HER2).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available