McLoughlin, Louis Francis Vaughan ORCID: 0000-0001-8053-1706 (2022) Interferon-dependant chemoresistance in breast cancer. MSc by research thesis, University of Leeds.
Abstract
Chemoresistance is a major obstacle in the treatment of primary and metastatic breast cancer (BC). Identifying chemoresistance mechanisms utilised by cancer cells is therefore an important step towards sensitising tumours to chemotherapy and improving treatment outcomes. The Hughes group has recently identified an IFN-dependent resistance pathway in claudin-low triple negative breast cancer (TNBC). In this thesis, the relevance of IFN-dependent epirubicin resistance was assessed in multiple BC cell lines representing claudin-low TNBC (MDA-MB-231), HER2-enriched (AU565), luminal A (MCF-7) and luminal B (BT-474) BC through MTT and colony forming assays. The ability of IFN to induce docetaxel resistance was also assessed. The effect of IFN on epirubicin-induced DNA double stranded break formation was investigated in MDA-MB-231 through a γ-H2Ax immunofluorescence assay. In addition, the clinical relevance of IFN signalling was assessed in a cohort of 27 metastatic TNBC patients through immunohistochemical evaluation of IFNβ1 and MX1 expression in cancer and stromal cells. Viability assays showed IFNα1 induced a dose-dependent epirubicin resistance in MDA-MB231 but did not induce resistance in AU565, MCF-7 or BT-474 cells. Moreover, IFN did not induce resistance to docetaxel in any cell lines tested. In MDA-MB-231 cells, the addition of IFNα1 significantly reduced epirubicin-induced expression of γ-H2Ax. Analysis of the cohort of metastatic TNBC patients showed a significant correlation between IFNβ1 expression in lymphocytes and MX1 expression in cancer cells, however this was not associated with survival. In conclusion, this thesis has shown IFN-dependent resistance to be subtype and chemotherapy dependant in BC. Moreover, this thesis has identified paracrine IFN signalling within the TNBC metastatic tumour microenvironment. Further study into the inhibition of this pathway may lead to chemosensitising treatments and improved patient outcomes in claudin-low TNBC. Additionally, investigation of the clinical relevance of this pathway in metastatic BC should be performed using a larger cohort.
Metadata
Supervisors: | Hughes, Thomas and Volpato, Milene |
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Keywords: | Interferon, chemoresistance, breast cancer |
Awarding institution: | University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) |
Depositing User: | Mr Louis Francis Vaughan McLoughlin |
Date Deposited: | 23 Mar 2023 13:27 |
Last Modified: | 23 Mar 2023 13:27 |
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