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The BRCA1 tumour suppressor gene is mutated in a significant proportion of hereditary breast cancer cases. Downregulation of BRCA1 mRNA and protein expression has also been reported in approximately 30% of sporadic breast cancer cases. BRCA1 is strongly implicated in the maintenance of genomic stability by its involvement in multiple cellular pathways including DNA damage signalling, DNA repair, cell cycle regulation, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis. Both pathological and gene expression profiling studies provide evidence that breast cancers with germline mutations in BRCA1 are different from non-BRCA1-related breast cancers.
Extensive gene expression profiling and data analysis has been performed on a cohort of 70 formalin-fixed, paraffin-embedded-derived BRCA1 mutated breast tumours and matched sporadic controls using the Almac Breast Cancer DSA™ research tool. Validation of gene targets has been performed by quantitative RT-PCR and western blotting.
A list of differentially expressed transcripts has been derived from the comparison of these BRCA1 mutant breast tumours to matched sporadic controls. Functional analysis of this gene list was performed to identify the main pathways and processes that are deregulated by these transcripts. BRCA1 deficiency was associated with deregulation of pathways involved in: immune response, metastasis and invasion, cytoskeletal remodelling, spindle assembly and chromosome separation, and apoptosis and survival. We have now validated several panels of genes that characterise this BRCA1-deficient breast cancer profile. A high-throughput siRNA-based screening strategy will now be performed to identify functionally relevant BRCA1-associated gene targets involved in cell growth, differentiation and chemotherapy response.
This approach has identified a set of transcripts that could be used to identify both hereditary and sporadic breast cancer patients with BRCA1 deficiency.