Association of gene variants in the transforming growth factor beta signalling pathways with invasive breast cancer risk

S Scollen,Am Dunning,R Hesketh,Jc Metcalfe

doi:10.1186/bcr1583

Abstract

We are performing comprehensive association studies of single nucleotide polymorphisms (SNPs) in genes in the transforming growth factor beta (TGFβ) signalling pathways in a female breast cancer case-control study. TGFβ acts as a suppressor of primary tumour initiation but is implicated as a promoter of the later malignant stages. A hypothesis explaining this dual action proposes that TGFβ acts through the ubiquitous ALK5/SMADs2&3 signalling pathway to inhibit proliferation of primary tumour cells, but acts through the endothelial-specific ALK1/SMADs1&5 pathway to promote angiogenesis, which is required for progression to malignancy. In a previous study we showed that a SNP generating a leucine to proline substitution in the signal peptide of the TGFB1 protein was associated with a 1.24-fold increase in the risk of invasive breast cancer, with increased levels of the protein in human serum and with a 2.8-fold increase in amount of the protein secreted in vitro. It is also plausible that other genes in the TGFβ signalling pathways might be associated with altered risk of breast cancer. We have initiated systematic breast cancer association studies with SNPs in the genes encoding proteins directly implicated in TGFβ signalling pathways, including the LTBP and TGFβ isoforms, ALK1, ALK5 and TGFBR2 receptors, and SMADs 1–7. A comprehensive SNP tagging approach was used to select variants for genotyping in a staged study design using up to 4,600 cases and 4,600 controls, all from the East Anglian region of the United Kingdom (>98% of northwestern European ancestry). To date, nine genes (TGFB1, TGFB2, TGFB3, ALK1, ALK5, TGFBR2, Endoglin, SMAD2 and SMAD4) have been analysed. From 285 common SNPs (minor allele frequency >0.05), identified from the International HapMap project data, 83 tagging SNPs have been defined and genotyped. Statistically significant associations with cancer susceptibility have been identified with at least one variant in five of the genes. The TGFB2, TGFB3, Endoglin and SMAD4 genes are not associated. A further eight genes will be studied.

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

Introduction

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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Conclusion