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Title: Investigating male breast cancer using transcriptomics and immunohistochemistry
Author: Sundara Rajan, Sreekumar
ISNI:       0000 0004 5989 2779
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2016
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Background: The rare nature of male breast cancer (MBC) has led to its management being guided by the extensive research conducted in the field of female breast cancer (FBC). The aim of this study was to evaluate MBC at both protein and molecular level to improve understanding of its pathology. Methodology: Immunohistochemistry analysis was performed in MBC (n=428) TMAs for 18 biomarkers (ERα, ERβ1, ERβ2, ERβ5, Total PR, AR, CK5/6, CK14, CK18, CK19, p53, Bcl-2, Her2, E-cadherin, Ki67, Survivin, Prolactin and FOXA1). The manual scoring of ERα and Ki67 was correlated with a fully automated immunohistochemistry image analysis system (ImmunoRatio™). Finally gene expression profiling (GEP) was undertaken in matched MBC (n=15) and FBC (n=10) samples. Results: There was poor 5 year overall survival (OS) in CK18 and CK19 negative patients (p= 0.05; p= 0.003), as well as poor 10 year OS in CK19 negative patients (p= 0.002). Age (p= 0.001) and nodal status (p= 0.04) was found to be independent predictors of OS at 5 years. There was significant correlations between manual and ImmunoRatio™ ERα (ρ= 0.872; p= 0.000) and Ki67 (r= 0.675; p= 0.000) scores. However due to a low measure of agreement it was not possible to validate Ki67 scoring using ImmunoRatio™. The functional enrichment analysis of GEP data using less stringent criteria (p < 0.05) identified 735 differentially expressed genes. The data analysis showed up-regulation of genes involved in ECM synthesis, degradation and re-modelling in MBC. The end product of one of the up-regulated genes (Fibronectin (FN1)) was validated in the MBC cohort with high fibronectin expression (60%) being positively associated with nodal status and showed a trend towards poor 5 year OS (p= 0.06). Conclusion: In MBC, epithelial cytokeratins, especially CK19 was found to be of prognostic significance. The extracellular matrix remodelling associated genes were found to be up-regulated in MBC. Fibronectin, end product of one of the up-regulated gene was found to have prognostic significance in MBC.
Supervisor: Speirs, V. ; Hanby, A. M. ; Horgan, K. Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available