Abstract
We have previously demonstrated that a functional orthologue of the breast cancer tumour suppressor gene BRCA1 exists in C. elegans (brc-1). Deletion mutants in C. elegans brc-1 or its heterodimeric partner, brd-1, share many of the phenotypic hallmarks of BRCA1-deficient human cells, yet are homozygous viable thus permitting extensive reverse genetic analysis. Using a rapid and inexpensive genome-wide screen in C. elegans we set out to identify genes that could be targeted in human patients to selectively kill tumours defective in the BRCA pathway. To this end we have utilized the complete C. elegans RNA-mediated interference library to systematically inactivate all 19,500 C. elegans genes and have identified those genes whose depletion confers synthetic lethality in combination with brc-1 and brd-1 mutations. In total, this screen identified 20 genes including pme-1 and pme-2, the C. elegans counterparts of PARP, a gene whose inhibition selectively kills BRCA defective tumour cells. We are currently using siRNA to knockdown all human homologues to identify those genes whose inactivation specifically kills mammalian cells harbouring mutations in BRCA1. These results and our current progress will be presented.
Highlights
Ten to twenty per cent of breast tumours exhibit a basallike genetic profile and these tumours carry a poor prognosis
We have modelled the effects of polygenic predisposition in the East Anglian population, and have shown that the model predicts a wide distribution of individual risk in the population, such that half of all breast cancers may occur in the 12% of women at greatest risk
No single gene so far identified contributes more than 2% of the total inherited component, consistent with a model in which susceptibility is the result of a large number of individually small genetic effects
Summary
Ten to twenty per cent of breast tumours exhibit a basallike genetic profile and these tumours carry a poor prognosis. BRCA1 is a tumour suppressor gene which is mutated in up to 5–10% of breast cancer cases and is involved in multiple cellular processes including DNA damage control, cell cycle checkpoint control, apoptosis, ubiquitination and transcriptional regulation. Results We have previously carried out microarray-based expression profiling to examine differences in gene expression when BRCA1 is reconstituted in BRCA1 mutated HCC1937 breast cancer cells. We aim (i) to investigate the expression of the whole family of IAPs across a wide range breast cancer cell lines and tumour samples at both the RNA and protein level, and (ii) to determine whether targeting IAPs alters susceptibility to apoptosis. This study tested the hypothesis that Brk is involved in regulating the tumour cell environment during progression and investigated the effects of suppressing Brk in breast carcinoma cells to determine in which contexts Brk may be a valid therapeutic target. Molecular and clinical evidence points to a role for TGFβ signalling in cancer progression and metastasis; it is unclear at which points of the metastatic process TGFβ signalling occurs and whether it is necessary and/or sufficient to elicit cancer cell motility
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