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Tamoxifen resistance in breast cancer: a proteomic approach

Phillips, Elisabeth (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

Tamoxifen is an effective and well-tolerated treatment for early disease and/or pre-menopausal patients with breast cancer (BC); although many women go on to develop resistance. Currently the five-year survival rate following Tamoxifen resistance (TR) is < 20%; hence the mechanisms need to be better understood. Recent research has focussed on specific pathways, however additional mechanisms are involved and we investigated these using cell line models of BC (MCF7) and TR using a variety of proteomic approaches.
Differential expression and phosphorylation of proteins between the MCF7 and TR cell lines were detected by antibody arrays; which detected changes in Mitogen Activated Protein Kinases and Receptor Tyrosine Kinases family members, and in apoptosis related proteins. There were 21 novel proteins found to be altered in TR.
262 quantifiable proteins were found using SILAC; 29% over expressed in resistance and 25% down regulated. 5 were subsequently picked for validation by Western blot and 2 of these (IQGAP1 and cortactin) were chosen for further investigation with siRNA and functional assays.
IQGAP1 was found to play a role in TR; as decreasing expression of IQGAP1 using SiRNA decreased the proliferation of TR cells and significantly modulated the TR cells ability to invade matrigel.

Type of Work:Ph.D. thesis.
Supervisor(s):Assender, Jean and Martin, Ashley
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Cancer Studies
Subjects:QH301 Biology
QR Microbiology
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
RM Therapeutics. Pharmacology
Institution:University of Birmingham
ID Code:3270
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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