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Atp-Binding Cassette Subfamily C (Abcc) Transporter 1 (Abcc1) and 4 (Abcc4) Independent of Their Drug Efflux Ability Affects Breast Cancer Biology

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Atp-Binding Cassette Subfamily C (Abcc) Transporter 1 (Abcc1) and 4 (Abcc4) Independent of Their Drug Efflux Ability Affects Breast Cancer Biology Some pages of this thesis may have been removed for copyright restrictions. If you have discovered material in Aston Research Explorer which is unlawful e.g. breaches copyright, (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please read our Takedown policy and contact the service immediately ([email protected]) ATP-BINDING CASSETTE SUBFAMILY C (ABCC) TRANSPORTER 1 (ABCC1) AND 4 (ABCC4) INDEPENDENT OF THEIR DRUG EFFLUX ABILITY AFFECTS BREAST CANCER BIOLOGY FLOREN GUY LOW Doctor of Philosophy ASTON UNIVERSITY December 2018 © Floren Guy Low, 2018 Floren Guy Low asserts his moral right to be identified as the author of this thesis. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright belongs to its author and that no quotation from the thesis and no information derived from it may be published without appropriate permission or acknowledgement. 1 Aston University ATP-binding cassette subfamily C (ABCC) transporter 1 (ABCC1) and 4 (ABCC4) independent of their drug efflux ability affects breast cancer biology Floren Guy Low Doctor of Philosophy 2018 Thesis Summary Breast cancer treatment has been a challenge to date, due in part to cancer cells acquiring drug resistance. One of the mechanisms by which resistance can occur is the overexpression of drug efflux pumps such as ATP-binding cassette, subfamily C (ABCC) transporter 1 (ABCC1) and 4 (ABCC4), which are members of ABC transporters. Recently research has shown that these proteins may be implicated in cancer biology independent of cytotoxic drug efflux, but so far little is known about this in regards to breast cancer. ABCC1 and ABCC4 protein levels in MDA-MB231 and MCF-7, human breast cancer derived cell lines were measured by Western blot. The role of ABCC1 and ABCC4 in cell proliferation and migration were evaluated by colony formation, MTT and scratch assays in the presence of various ABCC inhibitors – MK571, Indomethacin, Reversan, Ceefourin 1 and Ceefourin 2, inhibitors of ABCC4. Similarly the effect on proliferation, migration and invasion was monitored following knock down of ABCC1 and ABCC4 with ABCC1- and ABCC4- specific siRNAs, or overexpression using transfection with pcDNA3.1 plasmids containing the ABCC1 and ABCC4 genes. The potential correlation between ABCC1 and/or ABCC4 and the expression of G- protein-coupled receptor 55 (GPR55), or extracellular signal-regulated kinase (ERK), or the extracellular efflux of cyclic adenosine monophosphate (cAMP), prostaglandin E2 (PGE2), sphingosine-1-phosphate (S1P) and cyteinyl leukotrienes (LTC4, LTD4 and LTE4) were investigated by Western blot and enzyme-linked immunosorbent assays. This thesis demonstrates that the expression levels of ABC transporters varies between breast cancer cell lines. Our results suggest that ABCC1 may be more involved in mediating breast cancer cell proliferation than ABCC4 and in contrary ABCC4 may be involved in mediating breast cancer cell invasion more than ABCC1. There is also an indication that both ABCC1 and ABCC4 are implicated in breast cancer migration. In addition, potential correlation between ABCC1 and/or ABCC4 with cAMP or S1P efflux looks promising but further investigation is required. Taken together this thesis shows that ABCC1 and ABCC4 may be implicated in breast cancer development and progression. Further investigations are needed to validate our current results, but ABCC1 and ABCC4 could be potential therapeutic targets for breast cancer. Keywords: MDA-MB231, MCF-7, ABCC inhibitor, siRNA, transfection. 2 Acknowledgements I would like to give a special thank you to my supervisor, Dr Alice Rothnie for all of her help, advice and support throughout the entire length of this PhD and for giving me this opportunity to do a PhD in her lab. Also I would like to thank her current and past group members including David Hardy, Jaimin Patel and Aiman Gulamhussein for their help. I also would like to thank my associate supervisor Professor Roslyn Bill for her moral support. I would like to thank Dr James Brown for allowing me to use the PikoReal 96 Real-Time PCR system for quantitative PCR work in his lab and also Kiran Shabir for her help in reverse transcription polymerase chain reaction (RT-PCR) and in enzyme-linked immunosorbent assay (ELISA). I would like to thank Charlotte Bland for her help in using the Cell IQ time lapse imaging system. To everyone in lab MB331 and office MB440, thanks for your encouragement, support and friendship, which has made me feel welcome and appreciated. To Aston University for granting me a Life & Health Sciences overseas PhD bursary. Thank you to all of my friends who have supported me in one way or another. Finally, to my family, my Dad, Mum, brother and sister for their continuous support, encouragement and for believing in me. 3 Table of Contents Thesis Summary................................................................................................................................. 2 Acknowledgements ........................................................................................................................... 3 List of Abbreviations ....................................................................................................................... 11 List of Tables ..................................................................................................................................... 15 List of Figures ................................................................................................................................... 17 Chapter 1 – Introduction ................................................................................................................ 23 1.1 Nature of Cancer ............................................................................................................... 23 1.1.2 Types of tumours ....................................................................................................... 24 1.1.3 Localisation of cancers ............................................................................................ 25 1.1.4 Progressive development of cancers .................................................................. 27 1.1.5 Monoclonal and polyclonal growth....................................................................... 27 1.1.6 Known or suspected causes of cancers ............................................................. 29 1.2 Oncogenes and tumour suppressor genes ............................................................... 29 1.2.1 Oncogenes .................................................................................................................. 29 1.2.1.1 Proto-oncogene to oncogene ......................................................................... 30 1.2.2 Tumour suppressor genes ...................................................................................... 34 1.2.3 MicroRNA genes ........................................................................................................ 37 1.3 Cancer metastasis ............................................................................................................ 37 1.3.1 Invasion metastasis cascade ................................................................................. 38 1.3.1.1 Local invasion ..................................................................................................... 39 1.3.1.2 Intravasation ........................................................................................................ 40 1.3.1.3 Survival in the circulatory system ................................................................. 41 1.3.1.4 Arrest at distant organ site and extravasation ........................................... 42 1.3.1.5 Micrometastasis formation .............................................................................. 43 1.3.1.6 Metastatic colonisation ..................................................................................... 43 1.4 Breast cancer metastasis ............................................................................................... 44 1.4.1 Detection of breast cancer metastasis ................................................................ 44 1.4.2 Treatment of breast cancer metastasis ............................................................... 45 1.5 Drug resistance in cancer cells ..................................................................................... 46 1.5.1 Drug inactivation........................................................................................................ 47 1.5.2 Drug target alteration................................................................................................ 48 1.5.3 DNA damage repair ................................................................................................... 50 1.5.4 Cell death inhibition .................................................................................................. 50 1.5.5 Epithelial-Mesenchymal Transition (EMT) .......................................................... 51 4 1.5.6 Drug efflux ................................................................................................................... 52 1.5.8 Strategies implemented to overcome drug resistance.................................... 54 1.6 ATP-binding cassette (ABC) transporters .................................................................
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