The prognostic value of protein and microRNA biomarkers in breast cancer and their role in tumour progression

Identification of biomarkers has proven valuable in prognostication and treatment stratification of individual cases of breast cancer. microRNAs, short non-coding RNA molecules which negatively regulate translation of mRNA, are novel cancer biomarkers. In this work, Dicer expression was assessed in invasive breast cancer (IBC) (n = 446), DCIS (n = 128) and lymph node metastasis (n = 101) by immunohistochemistry. Expression was significantly increased in nodal metastasis compared to primary tumours (P < 0.001). Expression was associated with aggressive tumour characteristics and reduced overall survival (OS) on univariate analysis (P = 0.058) and multivariate analysis (hazard ratio 2.84, 95% CI 1.43-5.62). Further, high Dicer expression was associated with improved disease-free survival (DFS) in the HER2-overexpressing subtype (P = 0.038). Secondly, expression of miR-4726 and miR-4728, microRNAs located in the HER2 amplicon, was evaluated by in situ hybridisation in the same series. Both microRNAs showed reduced expression in malignant compared to benign tissue. An association with IBC HER2 status was not observed. Reduced expression of miR-4726 was associated with improved OS on univariate analysis (P = 0.009). Lastly, variation in Ki67 labelling index between paired biopsy and surgically resected tissue was assessed. Mean Ki67 index was higher in biopsy tissue (12.3% versus 8.2%, P = 0.001, n = 43). When dichotomised using a cut-off of 14%, 23% of pairs showed discordant categorisation ([kappa] = 0.31). There was a trend to lower discordance where more than three biopsy cores were received (P=0.18). The findings suggest Dicer is an important prognostic marker and that its prognostic role may be subtype specific. Lack of association between miR-4728 and HER2 amplification suggests that other mechanisms are involved in regulation of microRNA expression. Discordance observed in the Ki67 labelling index between different types of specimens will need to be evaluated further before Ki67 can be used in clinical practice.

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University of Galway Theses (PhD Theses)