Response: Re: Insulin, Insulin-like Growth Factor-I, and Risk of Breast Cancer in Postmenopausal Women

Extract

We thank Vigneri et al. for their helpful comments regarding our findings suggesting a positive association between insulin level and incident postmenopausal breast cancer ( 1 ). We agree with most of what is stated in their letter, including much of what they proposed could underlie this relationship biologically. However, there are two points we would like to address. First, although we agree that insulin may operate as a cancer promoter through its mitotic and anti-apoptotic activities, we also note that cell proliferation is itself error prone ( 2 ), and consequently, insulin could also have a role in cancer initiation by increasing the probability that genetically altered cells will arise. Second, we agree with the point raised by Vigneri et al. that insulin receptor expression levels, including the exact insulin receptor isoform distribution, are very likely to play an important role in the insulin–breast cancer relationship. However, because our data were serologic, they directly point to an important role of circulating insulin levels in breast carcinogenesis and suggest that lowering these levels could potentially be protective. Insulin levels can be reduced by weight loss, exercise, or potentially through pharmacological means ( 3 , 4 ). The further possibility raised by Vigneri et al., that targeting the insulin receptor (and perhaps certain hybrid receptors in particular) to block the activity of circulating insulin in breast oncogenesis, is a reasonable extension of those findings. In fact, to prevent cancer in high-risk patients or as part of a treatment strategy, it might be appropriate to consider testing both approaches simultaneously. We also wish to point out that although we did not detect an association between postmenopausal breast cancer and circulating insulin-like growth factor-I (IGF-I) levels, it may be difficult to detect such a relationship because there is evidence for apocrine and paracrine production as well as endocrine production of IGF-I ( 5 ). Thus, future studies should assess circulating as well as local tissue levels of IGF-I and IGF-I receptor expression levels for the same reasons raised by Vigneri et al. in relation to insulin and insulin receptors.