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Title: The role of fibroblasts in chemoresistance in triple negative breast cancer
Author: Broad, Robyn Victoria
ISNI:       0000 0004 7655 1327
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2018
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Triple negative breast cancer (TNBC) accounts for 10-15% of breast cancers and is associated with relatively poor prognosis. TNBC is characterised by lack of ER, PR and Her2 expression, and consequently does not respond to the targeted treatments routinely used to treat other breast cancers. Therefore, cytotoxic chemotherapy is the only systemic treatment for primary TNBC in routine use. Resistance to chemotherapy in TNBC is a major clinical issue and is reflected in the relatively high rate of early recurrences. Cancer associated fibroblasts (CAFs) are the most abundant cell type in the tumour stroma and have been shown to influence behaviour of the tumour cells. My aims were to determine whether CAFs modify responses of TNBC cells to chemotherapy, to identify molecular pathways responsible for this cross-talk, and to develop these pathways as potential therapeutic targets to enhance chemotherapy responses. I have shown that breast CAFs, but not normal fibroblasts, dose-dependently protect the claudin-low TNBC cell lines MDA-MB-231 and MDA-MB-157 from the chemotherapeutic epirubicin. By contrast, the basal claudin-high TNBC line MDA-MB-468 was not protected, demonstrating that the CAFs' influence is specific to certain TNBC characteristics. Transcriptome profiling demonstrated that CAF-induced protection of MDA-MB-231 cells was associated with deregulation of specific genes and pathways, including activation of the interferon-signaling pathway. Recombinant interferons were sufficient to protect MDA-MB-231 and MDA-MB-157 cells, implicating IFN as the key mediator of CAF-induced protection. Inhibition of the activation of interferon signaling using blocking antibodies, JAK/STAT inhibitors or under-/over-expression of specific signaling intermediates (miR-155) reduced CAF-dependent protection of MDAMB-231 and MDA-MB-157 cells, suggesting that CAF-induced up-regulation of interferon signaling is necessary for CAF-induced protection. I concluded that CAF-induced activation of interferon signaling in certain TNBCs is a potential mechanism of chemoresistance, and therefore that addition of inhibitors of interferon signaling to chemotherapy regimens in patients with stromal-rich TNBCs may improve chemotherapy responses.
Supervisor: Hughes, Thomas A. ; Thorne, James L. ; Hanby, Andrew M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available