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Combination of post-transcriptional and post-translational down-regulation of the oestrogen receptor in breast cancer

Longman, Michael Roy 2011. Combination of post-transcriptional and post-translational down-regulation of the oestrogen receptor in breast cancer. PhD Thesis, Cardiff University.

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Greater concentrations of fulvestrant are being employed within the clinic due to increased oestrogen receptor (ER) down-regulation and greater clinical benefit in ER+ breast cancer. However, complete ER down-regulation has not been achieved. The importance of residual ER is unknown and could allow cells to survive initial anti-hormone impact and progression to hormone insensitivity. This project aims to go further than current clinical therapy, using the MCF-7 cell model to target and assess the importance of residual ER. Cells were treated with fulvestrant aiming to achieve maximal ER down-regulation. The effect of any residual ER on signalling and growth was subsequently assessed. An alternative model for ER loss, ER siRNA, was employed to see whether this had a greater anti-ER effect. Finally, fulvestrant and ER siRNA were employed in combination to assess whether these agents work synergistically to give greater ER down-regulation and increased anti- tumour effect. With fulvestrant at 10"7M, ER levels were markedly reduced, although residual ER was observed that remained with increasing drug concentrations. There was significant reduction of ER signalling, proliferation and growth, but the inhibition was incomplete. When ER siRNA was assessed, similar results were obtained, with comparable and incomplete ER loss, residual signalling and growth. Following combination treatment of fulvestrant and ER siRNA, residual ER was almost undetectable, though this did not correspond to greater loss of ER signalling or growth when compared to either agent alone. While this work showed greater ER loss than previously recorded by targeting both protein and mRNA together, no greater anti-tumour activity was observed. Thus, while the mechanism underlying residual growth warrants future investigation (along with longer exposure), targeting ER alone, no matter how successfully, may not be the best treatment regimen and a combination of targets may be required as the optimum strategy to treat ER+ breast cancer.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
ISBN: 9781303196058
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:29

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