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Characterising Response and Resistance Mechanisms to Faslodex in Breast Cancer

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Characterising Response and Resistance Mechanisms to Faslodex in Breast Cancer Characterising response and resistance mechanisms to Faslodex in breast cancer Hayley Elizabeth Francies A thesis presented for the degree of Doctor of Philosophy at Cardiff University September 2013 Breast Cancer Molecular and Pharmacology Group School of Pharmacy and Pharmaceutical Sciences Redwood Building Cardiff University King Edward VII Avenue Cardiff, CF103NB i Abstract In ER+ breast cancer initial responses to antihormones are variable, complete responses are rare and resistance is eventually acquired by many patients. It is important to model these events to discover predictive markers of antihormone outcome and so targeted strategies can be developed to maximise antihormone effectiveness. To date, most studies have employed the MCF-7 cell line which fails to represent the variability of ER+ disease. Focusing on Faslodex, the thesis objective was to use 4 cell lines in vitro encompassing ER+/HER2- (MCF-7/T47D) and ER+/HER2+ (BT474/MDA-MB-361) disease to (i) characterise the magnitude of initial antihormone response, (ii) monitor the onset of resistance by prolonged treatment and (iii) detail gene expression changes during Faslodex treatment. All models were initially growth-inhibited by Faslodex, with superior responses in HER2- lines. Microarray analysis revealed gene cohorts affected by Faslodex treatment differed between HER2+ and HER2- models. While MCF-7, BT474 and MDA-MB-361 cells acquired Faslodex resistance, this failed to develop in the T47D line, providing a model of complete-response. A filtering process identified genes involved in the varying Faslodex responses and clinical relevance was determined using the NEWEST Faslodex clinical trial dataset. Of interest was the Faslodex-induction of CXCR4, as a potential mediator of acquired resistance, while suppression of the RET signalling pathway related to improved initial response in the ER+/HER2- setting. Importantly up-regulation of DCN by Faslodex was associated with improved Faslodex response in T47D cells and also with proliferation (Ki67) fall in the NEWEST clinical trial. shRNA knockdown of DCN reduced the sensitivity of T47D cells to Faslodex and enabled development of resistance. This thesis has successfully identified novel elements of Faslodex response and resistance and further work is now required to clarify the importance of these mediators and to determine if DCN could prove a useful clinical biomarker of Faslodex response. ii Acknowledgements I would like to thank my supervisors, Dr Julia MW Gee and Professor Robert I Nicholson for their guidance and encouragement as well as providing the opportunity to undertake this PhD. Also, every staff member and all PhD students of the Breast Cancer Molecular Pharmacology Group who have provided advice and support on a daily basis in particular Richard McClelland and Lynne Farrow. A huge thank you to Dr Elizabeth Anderson (formerly AstraZeneca) and Dr Naomi Laing who provided access to the NEWEST and Trial 223 clinical data and the bioinformatics team at Alderley Edge, AstraZeneca, who without I would still be staring at the clinical data attempting to make head or tails out of it. Professor Simak Ali and Dr Laki Buluwela provided a great knowledge of shRNA and without access to their facilities at Imperial College London the shRNA studies would have been profoundly more time consuming and difficult. A super thank you to my parents for their constant support, putting a roof over my head, doing all my washing, cleaning, ironing and cooking, generally putting up with me and who without, this whole process would have been substantially more difficult. Jim Sipthorp and Sarah Lammert, two of the best people in my world, for their unwavering support, their keen interest in my work (when often not understanding), and for successfully dealing with my maddening moods throughout this PhD and yet, surprisingly, still love me. Finally, I wish to acknowledge the BBSRC and AstraZeneca who provided the funds to carry out this project. iii iv Table of Contents Abbreviations .......................................................................................................................... 7 Chapter 1 ............................................................................................................................... 12 Introduction ........................................................................................................................... 12 1.1 Incidence and Mortality ............................................................................................... 12 1.2 Oestrogen and breast cancer risk ................................................................................ 12 1.3 Molecular basis for oestrogen action .......................................................................... 13 1.3.1 Classical and Non-classical Genomic Functions of ER ........................................... 14 1.3.2 Ligand-independent genomic ER functions .......................................................... 16 1.3.3 Non-Genomic ER Functions .................................................................................. 16 1.3.4 Convergence of non-genomic and genomic ER actions ........................................ 17 1.4 Therapeutic options for ER+ breast cancer: Targeting ER signalling ........................... 19 1.4.1 The Selective ER Modulator (SERM) Tamoxifen ................................................... 20 1.4.2 Aromatase Inhibitors (AI) ...................................................................................... 21 1.4.3 The Selective ER down-regulator (SERD) Faslodex (Fulvestrant) .......................... 23 1.5 Response and Resistance to endocrine therapies ....................................................... 26 1.5.1 Mechanisms of antihormone resistance .............................................................. 28 1.5.2 Antihormone resistance mechanisms that can be independent of growth factor signalling ........................................................................................................................ 28 1.5.3 Growth factor signalling and endocrine resistance .............................................. 29 1.6 Gene expression profiling and breast cancer .............................................................. 33 1.7 Aims and Objectives ..................................................................................................... 35 1.7.1 Objectives .............................................................................................................. 36 Chapter 2 ............................................................................................................................... 38 Materials and Methods ......................................................................................................... 38 2.1 Cell Culture ................................................................................................................... 38 2.1.1 Routine maintenance ............................................................................................ 38 2.1.2 Short-term cell growth studies ............................................................................. 39 2.1.3 Treatments ............................................................................................................ 40 2.1.4 Statistical analysis of short-term cell growth ........................................................ 41 2.1.5 Long term growth experiments. ........................................................................... 41 2.2 Immunocytochemistry (ICC) ........................................................................................ 42 2.2.1 Ki67 (proliferation marker) ................................................................................... 42 1 2.2.2 HER2 ...................................................................................................................... 43 2.2.3 Oestrogen-receptor ICC Assay .............................................................................. 44 2.2.4 Decorin .................................................................................................................. 45 2.3 Microarray Gene Expression Profiling ......................................................................... 46 2.3.1 Cell Lysis ................................................................................................................ 47 2.3.2 Total RNA Isolation for Tri-Reagent-Lysed Samples ............................................. 47 2.3.3 DNase Treatment of isolated RNA ........................................................................ 48 2.3.4 Affymetrix microarraying procedure .................................................................... 49 2.3.5 Hierarchical Clustering Analysis (HCA) of microarray data ................................... 50 2.3.6 Genesifter analysis of microarray data ................................................................. 50 2.4 Ontological investigation of genes of interest from microarray data ......................... 52 2.5 Verification of genes of interest from microarray data using RT-PCR ......................... 53 2.5.1 Reverse Transcription (RT) .................................................................................... 53 2.5.2 Polymerase Chain Reaction (PCR) ......................................................................... 54 2.5.3 Oligonucleotide Design ......................................................................................... 54 2.5.4 PCR
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