Pathology - Theses
Permanent URI for this collection
Search Results
1 - 1 of 1
-
ItemMolecular markers in sporadic and BRCA1-associated basal breast cancers( 2011)Basal breast cancers are a subgroup of breast cancers with a distinctive gene expression profile, basal cytokeratin expression, and a “triple negative” phenotype (i.e. negativity for hormone receptors and HER2 amplification). There are currently limited options for targeted therapy in these cancers. The aim of this thesis is to characterise some of the critical pathways that are responsible for the pathogenesis of these breast cancers and to identify molecular markers that may predict prognosis and response to treatment. MicroRNAs (miRNAs) are small non-coding RNAs that suppress translation through imperfect base pairing with target mRNAs. There are limited data regarding miRNA expression in basal cancers and its impact on protein synthesis. I hypothesised that i) basal breast cancers have a distinctive miRNA profile, and ii) differences in miRNA profiles exist between sporadic and BRCA1 basal cancers. Analysis of miRNA array data generated from 44 grade 3 cancers (including 11 BRCA1 basal, 16 sporadic basal and 17 luminal cancers) revealed a distinctive “basal” miRNA signature. Via a combination of target prediction algorithms and immunohistochemistry, it was shown that in basal cancers, miRNAs may be involved in the regulation of important regulatory pathways such as the MAPK/ERK pathway. It was also shown that BRCA1 and sporadic basal cancers differ in their miRNA profiles. This was reflected by differences in the expression of genes such as cyclin D1, NRP1 and FOXP1. These findings may have important diagnostic implications, as immunohistochemical assessment of basal cancers, in addition to a detailed family history, may potentially identify patients who may benefit from BRCA1 mutational analysis. I also hypothesised that prognosis and response to treatment in basal cancers may be affected by factors in the tumour microenvironment, such as hypoxia and the anti-tumour immune response, and by intrinsic cellular mechanisms such as cohesin/Rad21 mediated DNA repair and ERβ expression. Investigation of molecular marker expression in cohorts of sporadic and familial breast cancers revealed the behaviour of basal cancers is partly due to an enhanced hypoxic response. In BRCA1 basal cancers, enhanced hypoxic drive may be a consequence of suppressed PHD activity and aberrantly located FIH expression. This hypoxic response may also drive regulatory T cell (Treg) recruitment by inducing CXCR4 up-regulation in Treg, resulting in the suppression of the anti-tumour immune response. Lastly, hypoxia, cohesin/Rad21 mediated DNA repair via homologous recombination (HR) and cytoplasmic ERβ2 expression may impair the response of basal cancers to chemotherapeutic agents. For cohesin/Rad21, this was supported by in vitro experiments where Rad21 knockdown in a basal cell line was associated with enhanced chemosensitivity to DNA damaging agents. In summary, the findings in this thesis highlight the potential diagnostic, prognostic and predictive roles of a number of molecular markers in basal breast cancers. In the era of molecular medicine, these findings support the potential use of miRNAs as a diagnostic marker of BRCA1 status, and the development of therapy directed against specific pathways (i.e. hypoxia, regulatory T cells and HR repair) in these aggressive cancers, for which there is currently no targeted treatment available.