Abstract
Triple negative breast cancer refers to a spectrum of breast tumours which are characterised by the lack of overexpressing hormone or HER2 receptors. These tumours present as high grade and tend to have reduced progression free survival rates because of their aggressive and metastatic behaviour. The lack of targeted therapies for triple negative breast cancer also contributes to the observed poor outcomes.During a genetic profiling screen of aggressive breast tumours, mRNA levels of IQGAP3 were specifically found to be upregulated in triple negative tumours compared to other types of the disease and normal tissue samples. IQGAP3 is the most recently discovered member of the IQGAP family of scaffold proteins. Even though IQGAP1 is a well described effector for the Rho GTPases and has also been heavily associated with tumourigenesis and cancer cell motility, far less is known about IQGAP3. The aim of this project was to investigate the role of IQGAP3 in triple negative breast cancer cell behaviour. At first, IQGAP3 was found to be expressed across a panel of triple negative cell lines. Modulating expression levels of IQGAP3 conferred morphological changes, disrupted cell migration and inhibited the ability of cells to form specialised invasive adhesion structures, termed invadopodia. Reduced expression of IQGAP3 disrupted RhoA activity and actomyosin contractility. IQGAP3 was also found to interact with PAK6 and Filamin-A; proteins already associated with the regulation of cell morphology. Indeed, PAK6 overexpression rescued the IQGAP3 depletion phenotype. IQGAP domains have previously been suggested to have potential therapeutic value thus IQGAP3 could be a promising candidate to target in order to inhibit metastasis in triple negative breast cancer.
| Date of Award | 2017 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Andrew Tutt (Supervisor) & Claire Wells (Supervisor) |