Characterising response and resistance mechanisms to\ud Faslodex in breast cancer
Francies, Hayley E.
mesheuropmc: skin and connective tissue diseases
In ER+ breast cancer initial responses to antihormones are variable, complete\ud responses are rare and resistance is eventually acquired by many patients. It is\ud important to model these events to discover predictive markers of antihormone\ud outcome and so targeted strategies can be developed to maximise antihormone\ud effectiveness. To date, most studies have employed the MCF-7 cell line which fails\ud to represent the variability of ER+ disease. Focusing on Faslodex, the thesis\ud objective was to use 4 cell lines in vitro encompassing ER+/HER2- (MCF-7/T47D)\ud and ER+/HER2+ (BT474/MDA-MB-361) disease to (i) characterise the magnitude of\ud initial antihormone response, (ii) monitor the onset of resistance by prolonged\ud treatment and (iii) detail gene expression changes during Faslodex treatment.\ud All models were initially growth-inhibited by Faslodex, with superior responses in\ud HER2- lines. Microarray analysis revealed gene cohorts affected by Faslodex\ud treatment differed between HER2+ and HER2- models. While MCF-7, BT474 and\ud MDA-MB-361 cells acquired Faslodex resistance, this failed to develop in the T47D\ud line, providing a model of complete-response. A filtering process identified genes\ud involved in the varying Faslodex responses and clinical relevance was determined\ud using the NEWEST Faslodex clinical trial dataset.\ud Of interest was the Faslodex-induction of CXCR4, as a potential mediator of\ud acquired resistance, while suppression of the RET signalling pathway related to\ud improved initial response in the ER+/HER2- setting. Importantly up-regulation of\ud DCN by Faslodex was associated with improved Faslodex response in T47D cells and\ud also with proliferation (Ki67) fall in the NEWEST clinical trial. shRNA knockdown of\ud DCN reduced the sensitivity of T47D cells to Faslodex and enabled development of\ud resistance.\ud This thesis has successfully identified novel elements of Faslodex response and\ud resistance and further work is now required to clarify the importance of these\ud mediators and to determine if DCN could prove a useful clinical biomarker of\ud Faslodex response.