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Title: Significance of microRNAs and microRNA maturation regulators in breast cancer
Author: Khoshnaw, Sarkawt Majeed Omar
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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Background: MicroRNAs (miRNAs) modulate gene expression by targeting mRNAs for cleavage or translational suppression. miRNAs have deregulated expression in human breast cancer (BC), and there is evidence suggesting that they function primarily as tumour suppressors. Dicer and Drosha are two proteins which play key roles in miRNA biogenesis to produce mature miRNAs from their precursor molecules, and are known to be deranged in human Be. The contribution of miRNAs and their maturation regulators in the initiation and progression of human Be can be exploited to achieve novel modifications in the existing diagnostic and therapeutic approaches in Be management. Methods: Protein expression levels of miRNA maturation regu lators, Dicer and Drosha, were assessed immunohistochemically in 2 sets of Be: 1) full-face sections of selected Be cases (n = 24) with normal breast parenchymal tissue (NBPT) and lesions representing different stages of Be progression (Ductal carcinoma in situ, DCIS; invasive breast cancer, IBC; and metastatic breast cancer, MBC) to assess their differential expression, 2) tissue microa rrays (TMAs) comprising a large and well-characterised series of primary IBC (n = 1902) to evaluate their biological, clinicopathological, prognostic and predictive significance. Additionally, miRNA expression profiling was explored in the 4 tissue components (NBPT, DCIS, IBC and MBC) of 7 BC cases using an Agilent microa rray-based miRNA profiling study, to investigate the differential expression of miRNAs in NBPT and different stages of BC progression. Results: Dicer and Drosha protein expression was observed to decrease with BC progression, which implies that loss of these two miRNA maturation regulators might have a role in the process of Be progression. In the IBC series, loss of Dicer expression was associated with features of aggressive behaviour including higher histological grade and loss of ER, PR and BRCA1 protein expression . Moreover, Dicer expression was revealed to be an independent predictor of a shorter disease free interval at 5 years, and predictive of better response to chemotherapy and to endocrine therapy. Loss of Drosha cytoplasmic expression was associated with higher tumour stage and loss of expression of BRCA1 and basal phenotype; and loss of Drosha nuclear expression was associated with larger tumour size, higher tumour grade, and loss of ER, PR, BRCA1, E-cadherin and CK14. Loss of Drosha cytoplasmic expression was associated with shorter Be specific survival, BC recurrence, and distant metastases, and th is correlation was maintained in ER-negative and HER2- negative cases. Loss of Drosha cytoplasmic expression was predictive of better response to systemic therapy in ER-negative patients. Furthermore, we present data revealing that some miRNAs are differentially expressed across the 4 tissue components (NBPT, DCIS, IBC and MBC). The comprehensive survey of miRNA expression profiling, confirmed differential expression of one miRNA previously reported to be deranged in BC, and identified 6 miRNAs downregulated du ring BC progression, 5 downregulated and 1 upregulated, which have not previously been linked to Be. Among the novel downregulated miRNA candidates, 2 (hsa-miR-1181 and hsa-miR-4322) were revealed to gradually reduce in amount across the 4 tissue components. These observatinos support the hypothesis that miRNAs play a role in tumourigenesis and in advancing BC tissues towards acquiring metastatic potential. Conclusions: The intimate involvement of miRNAs and their maturation regulators in malignant transformation, cellular invasion and metastases in BC makes them potentially relevant as future diagnostic, predictive and therapeutic targets. Although the current study is preliminary, we believe the results add to the present knowledge of Significance of miRNAs and their regulators in Be. Therefore, the results would serve as a robust initial set of potential biomarkers for validation in a larger cohort of patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available