Abstract
BRCA1 was identified in 1994 as one of the genes predisposing to early-onset breast and ovarian cancer. It is currently estimated that 5 to 10% of all breast and ovarian cancer cases are inherited and the breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified as being responsible for up to 21 to 40% of these cases. Although the exact function of BRCA1 remains to be defined, roles in DNA damage repair, cell cycle checkpoint control, transcriptional regulation and, more recently, ubiquitination have been inferred. p63 was identified as a positively regulated BRCA1 target gene through microarray analysis, and the functional significance of the BRCA1/p63 signalling axis was investigated. Knockdown of BRCA1 and p63 leads to enhanced proliferation of breast cancer cell lines and increased stem cell numbers as assayed for by mammosphere culture and Aldefluor assay. Expression of BRCA1 or p63 in a background of low BRCA1 and p63 results in decreased cell proliferation. We therefore examined co-regulated targets of BRCA1 and p63 mediating growth control. S100A2, a tumour suppressor, is a known p63 target. Knockdown of BRCA1 and p63 leads to the loss of S100A2 expression. BRCA1 and p63 were found to be localised to the S100A2 promoter by chromatin immunoprecipitation assay. Loss of p63 resulted in recruitment of BRCA1 to the S100A2 promoter. In a p63 and BRCA1 null background, expression of S100A2 results in a reduction of cell proliferation. Conversely, loss of S100A2 in a BRCA1 and p63 expressing background leads to increased proliferation. We have explored the regulation of signalling pathways by p63 and BRCA1 that are involved in growth control, differentiation and stem cell regulation. We will identify potential regulators of these pathways using microarray analysis to elucidate p63 and BRCA1 co-regulated targets.
Highlights
The response rarely sustains long among the responders for Herceptin monotherapy treatment
We have provided a novel mechanism of acquired resistance to Herceptin in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and have resolved the inconsistencies in the literature regarding the effect of Herceptin on HER2 phosphorylation
Using a range of biochemical and cell-biology techniques, we have shown that BRCA1 is modified by SUMO in response to genotoxic stress, and co-localises at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO conjugating enzyme Ubc9
Summary
The response rarely sustains long among the responders for Herceptin (trastuzumab) monotherapy treatment. 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. The vitreous humour is one of the few tissues in the body that is avascular and virtually acellular, and previous studies have indicated that opticin contributes to the maintenance of this state by inhibition of angiogenesis The aim of this present study is to investigate the effect and mode of action of opticin in suppressing tumour cell proliferation and migration in vitro in a panel of breast cancer cell lines and to establish its therapeutic efficacy in human breast tumour xenografts in vivo. Using receptorselective ligands (patent filed by MRC Technology) specific for the TRAIL death receptors, TRAIL-R1/TRAIL-R2, we have previously shown that primary leukaemic cells isolated from patients with chronic lymphocytic leukaemia can be selectively sensitized to apoptosis by combining an a histone deacetylase inhibitor (HDACi) with a TRAIL-R1-specific form of TRAIL/TRAIL-R1 mAb
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