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Title: The identification and characterisation of markers clinical outcome in triple negative breast cancers (TNBCs)
Author: Mohamad Hanif, Ezanee Azlina Binti
ISNI:       0000 0004 6498 5646
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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Triple Negative Breast Cancer (TNBC) is an aggressive and is associated with epithelial-mesenchymal transition (EMT)-like features and highly metastatic. TNBCs display negative expression for the estrogen (ER), progesterone (PR) and HER2 receptors with high heterogeneity and have no targeted therapies available (current treatment generic DNA damage chemotherapy cocktail (FEC)). Some TNBCs respond well, or refractory or initially respond but relapse quickly (<18 months). To date, there are no predictive markers that could represent relapse to TNBC. The study aims to identify predictive poor outcome markers to FEC in TNBCs and to identify associated genes/pathways driving this aggressive biology. This study was initiated by microarray analyses on Partek Genomic Suite Software, from an in­house TNBC dataset consisting of poor outcome patients (relapse <5 years post FEC) and good outcome outcome patients (no relapse >5 years post FEC). These profiles were analysed with high (Analysis I; removing non- discriminatory samples and FDR<0.05) and low (Analysis II; inclusive all samples without FDR) stringency settings. Consistent findings were MiR205 downregulation (Analysis I) and TGF02 upregulation (Analysis II) in poor outcome TNBCs. Both markers suggested that they played contrasting roles in the increase of EMT-like processes in TNBC cells which closely resembled TNBC tumours from the poor outcome subgroup (Basal B). We showed that MiR205 is p63-dependent in poor outcome TNBCs due to the action of mutant p53 proteins. Loss of MiR205 consistently results in upregulation of the transcription factor ZEB1, a known inducer of EMT. Conversely, the poor outcome TNBCs overexpress the TGFp2 ligand. Altered regulation of both markers resulted in increasing cell invasion of poor outcome/Basal B cell lines, relative to good outcome/Basal A. Taken together, quantification of these markers could provide valuable insights into how to predict which TNBC patients are likely to relapse following FEC and prediction of additional chemotherapeutic agents alongside FEC to minimize the risk of relapse. This new knowledge could also provide opportunities for the development of novel therapeutic strategies (such as targeting components of the TGFp/SMAD signaling pathway) to improve treatment responses and ultimately improve patient survival in this aggressive subtype of breast cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available