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Title: Investigating c-FLIP suppression and TRAIL treatment in breast cancer
Author: Silva, Andreia M.
ISNI:       0000 0004 7229 4597
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2017
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Breast cancer mortality is invariably due to metastasis, the dissemination of cancer cells from the primary tumour to distant organs. This process is proposed to arise from the breast cancer stem cells (bCSCs), the minority of cells within a tumour that are capable of propagating new tumour growth. bCSCs are also associated with potentiating endocrine therapy resistance and therefore relapse after tamoxifen or anastrozole treatments. Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is an anti-cancer agent that induces apoptosis in bCSCs and has almost no toxicity to normal cells. However, there is an inherent resistance to TRAIL in vitro in a large proportion of breast cancer cell types due to the expression of the survival factor cellular FLICE-Like Inhibitory Protein (c-FLIP). It has been shown that siRNA-mediated suppression of the gene for c-FLIP combined with TRAIL is effective in vitro at sensitising bCSCs to apoptosis in breast cancer cell lines. To test whether these findings have direct clinical relevance for breast cancer patients, diagnostic biopsies, surgical breast resections and pleural effusions were collected from the clinic. Testing TRAIL alone in breast samples resulted in a decrease in the number of tumourspheres in 82% of tumours that have acquired endocrine resistance to tamoxifen and anastrozole. Importantly, TRAIL was efficient in vivo at decreasing primary tumour size in tumours that have acquired resistance to tamoxifen in vivo and number of metastases of an anastrozole-resistant sample. Additionally, TRAIL was also effective at decreasing bCSCs in triple negative metastatic tumours, corroborating studies supporting a relationship between a mesenchymal phenotype and TRAIL sensitivity. However, there was no correlation between TRAIL response and either ER or HER2 status in primary breast samples. Furthermore, c-FLIP was suppressed, either genetically (siRNA) or pharmacologically (OH14) and combined with TRAIL treatment sensitised bulk and bCSCs to TRAIL in breast tumours from patients with metastatic disease irrespective of their estrogen receptor (ER)/HER2 status. As the tumour microenvironment can modulate drug responses, TRAIL treatment was investigated on breast cancer epithelial cells in the presence of cancer associated fibroblasts (CAFs) and CAFs-conditioned medium (CM). Short exposure to CAFs and CM sensitised MCF-7 and primary metastatic cells to TRAIL whereas a longer exposure to CM conferred resistance to TRAIL potentially due to an induction of epithelial-mesenchymal transition. With these results in primary cells, TRAIL could be a valuable treatment to the clinic for patients that have acquired resistance to endocrine treatments. Additionally, c-FLIP suppression and TRAIL treatment could be a promising therapeutic treatment at eliminating bCSCs in patients with metastatic disease. We hypothesise that a partial EMT confers resistance to TRAIL but a full EMT state is associated with resistance to TRAIL.
Supervisor: Not available Sponsor: European Cancer Stem Cell Research Institute
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General) ; RC Internal medicine ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)