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Title: Drug adapted breast cancer cell lines as models of acquired resistance
Author: Bird, Joanna L.
ISNI:       0000 0004 9357 3413
Awarding Body: University of Kent
Current Institution: University of Kent
Date of Award: 2019
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It is estimated that approximately half a million women are alive today thanks to the use of endocrine therapy in ER+ breast cancer, and even more have benefitted from its life-extending affect and palliation. There are two main forms of endocrine therapy: aromatase inhibition (the enzyme responsible for converting androgens to oestrogen) and direct inhibition of the oestrogen receptor with tamoxifen. A large proportion of ER+ breast cancer patients are treated with endocrine therapy as a first-line therapy or an adjuvant therapy. Several mechanisms have been suggested to explain resistance to tamoxifen, but given the complexity of oestrogen signalling itself, there are a number of mechanisms that could potentially be altered to result in increased tolerance to the drug. Most publications investigate mechanisms of resistance in a single cell line setting, here we have systematically generated two panels of 6 ER+ breast cancer cell lines in tandem (resulting in a total of 46 sublines) one as a potential model for resistance to long-term systemic oestrogen deprivation, like that naturally found in postmenopausal women or patients treated with aromatase inhibitors (24 sublines), the other a model for acquired resistance to long-term tamoxifen exposure (22 sublines). These panels have been characterised for response to tamoxifen, clinically relevant metabolites of tamoxifen and other commonly used anti-cancer agents to treat breast cancer. Oestrogen receptor localisation and expression levels were evaluated for the purpose of gaining an idea of changes found in aromatase inhibitor resistance vs tamoxifen resistance. Over the course of this thesis, drug response data has been presented for a large number of drug-adapted breast cancer cell lines. Additionally to this, we have investigated cross resistance to DNA damaging agents in the advent of resistance to platinum (Pt) based anti-cancer drugs in triple negative breast cancer cell lines. We have used a range of DNA-damaging agents as preliminary data to gain insight into potential sensitivity or cross-resistance to other modes of DNA damage in triple negative breast cancer cell lines that have acquired resistance to cisplatin, carboplatin and oxaliplatin. We also looked at potential changes to MEK/ERK and AKT signalling as a result of drug resistance in the Pt-drug resistant sublines compared to parental cell lines, along with sensitivity to MEK, AKT and ChK1 inhibitors.
Supervisor: Michaelis, Martin ; Wass, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR Microbiology