Insulin-like growth factor-I (
IGF-I) has mitogenic and anti-apoptotic effects on
breast cancer cells. Epidemiologic studies have shown that high plasma levels of
IGF-I and low levels of
IGF binding protein (BP)-3 are associated with increased risk of
breast cancer in premenopausal women. The actions of
IGF-I are mediated through the
IGF-I receptor (IGF-IR) and are regulated by IGFBPs. In circulation, most of the
IGF-I binds to
IGFBP-3, and binding of
IGF-I to
IGFBP-3 inhibits the actions of
IGF-I. Since free
IGF-I, which does not bind to IGFBPs, can readily cross the endothelial barrier to interact with IGF-IR, circulating free
IGF-I is thought to be more relevant to the biologic activity of
IGF-I. To examine the association of free
IGF-I with
breast cancer, we compared free
IGF-I levels between 40 newly diagnosed
breast cancer patients and 40 age- and race-matched healthy controls. Plasma levels of free
IGF-I, total
IGF-I and
IGF-II, as well as total, intact and fragment
IGFBP-3, were measured using commercial immunoassay kits. The association between
IGF-I and
breast cancer was examined using the conditional logistic regression analysis. Analysis of correlation (Spearman) showed that free
IGF-I was correlated with total
IGF-I and
IGFBP-3 but not with
IGF-II. The odds ratios for
breast cancer patients having high plasma
IGF-I (> or = median) after adjusting for menopausal status and
IGFBP-3 were 2.00 (p < o r = 0.376) for total
IGF-I and 6.31 (p < or = 0.047) for free
IGF-I. A high ratio of
IGF-I to
IGFBP-3 was also associated with
breast cancer (p < 0.05). No association was found for
IGF-II, nor for total, intact and fragment
IGFBP-3. The findings of this study suggest that measuring free
IGF-I in circulation is more useful than measuring total
IGF-I with respect to evaluation of an association between
IGF-I and
breast cancer risk.