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

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.


Breast Cancer Campaign funded this work. The authors are grateful to the SEARCH Breast Cancer Study Team for sample collection.

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Scollen, S., Dunning, A., Hesketh, R. et al. Association of gene variants in the transforming growth factor beta signalling pathways with invasive breast cancer risk. Breast Cancer Res 8 (Suppl 2), P28 (2006).

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