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Polymorphisms and Circulating Levels in the Insulin-Like Growth Factor System and Risk of Breast Cancer: A Systematic Review

¹ Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine; ² The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom; and ³ University Division of Surgery, Bristol Royal Infirmary, Bristol, United Kingdom

Request for reprints: Isabel dos Santos Silva, Non-Communicable Disease Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom. Phone: 44-20-7927-2113; Fax: 44-20-7580-6897. E-mail: isabel.silva{at}lshtm.ac.uk

We reviewed all English-language articles on associations among circulating levels of the insulin-like growth factors (IGF) and their binding proteins (IGFBP), polymorphisms in their genes, and breast cancer risk. In premenopausal women, five of eight IGF-I studies and four of six IGFBP-3 studies of circulating levels found that women in the highest quantile had more than twice the risk of developing breast cancer of those in the lowest, although in some this effect was only apparent at young ages. In postmenopausal women, however, there was no consistent effect. A simple sequence length polymorphism 1 kb 5' to IGF-I was examined in relation to circulating levels of IGF-I (12 studies) or breast cancer risk (4 studies), but there was no convincing evidence of any effect. For an A/C polymorphism 5' to IGFBP-3, all three studies were consistent with a modest effect on circulating levels, but no evidence of a direct effect on breast cancer risk was seen in the only relevant study. Variation within the reference range of IGF-I and IGFBP-3 may confer only modest increases in breast cancer risk, and any single polymorphism may only account for a small proportion of that variation. Nevertheless, population attributable fractions for high circulating levels of IGF-I and IGFBP-3 and for common genetic variants could be substantial. Further large studies, or combined analysis of data from existing studies, are needed to quantify these effects more precisely.

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