Abstract
2006, 8(Suppl 2):S1 (DOI 10.1186/bcr1544)Background Epidemiological studies have shown that only about 20%of the familial clustering of breast cancer is explained by the knownhighly penetrant mutations in BRCA1 and BCRA2. We have set out tosearch for the genes for the remaining 80%. Twin studies indicate apredominant role of shared genes rather than a shared environment;the patterns of occurrence of breast cancer in families are consistentwith a major polygenic component.Methods We have assembled a population based set of 5,000 breastcancer cases and 5,000 controls from the East Anglian population. Wehave simple clinical and epidemiological information, including familyhistory, and samples of blood and paraffin embedded tumour.We have used association studies based on single nucleotidepolymorphisms, first with candidate genes and then in a genome-widescan of 266,000 single nucleotide polymorphisms, to search for theputative predisposing genes. We have as yet searched only forcommon variants (frequency >5%).Results We have modelled the effects of polygenic predisposition inthe East Anglian population, and have shown that the model predicts awide distribution of individual risk in the population, such that half of allbreast cancers may occur in the 12% of women at greatest risk.Both the candidate gene-based and genome-wide scans have providedprovisional identification of a number of novel susceptibility genes, andthese are currently being confirmed by a world-wide consortium ofindependent laboratories totalling 20,000-plus cases and controls. Nosingle gene so far identified contributes more than 2% of the totalinherited component, consistent with a model in which susceptibility isthe result of a large number of individually small genetic effects.
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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