The focus of this application is the exploration of a novel risk factor for breast cancer, namely insulin resistance and hyperinsulinemia. The hypothesis is that hyperinsulinemia promotes the development of breast cancer, and that hyperinsulinemic insulin resistance is an integral feature of women with breast cancer. In support of this hypothesis, a recent study conducted by the Netherlands Cancer Institute, in which 223 women with Stage I and II breast cancer and 441 control women were assessed, reports that women with breast cancer manifest significant insulin resistance and elevated circulating insulin levels. This is important because insulin could promote carcinogenesis via a variety of mechanisms. These include, but are not limited to, 1) stimulation of cellular proliferation, 2) enhanced delivery of estrogens to breast tissue by insulin-induced suppression of circulating sex hormone-binding globulin (SHBG) levels, 3) stimulation of ovarian androgen production (these androgens then serving as substrate for aromatization to estrogens), and 4) increased estrogen production both peripherally and locally in breast cancer tissue itself via stimulation of aromatase activity. If insulin resistance and hyperinsulinemia indeed prove to be identifiable risk factors for breast cancer, innovative preventative and therapeutic strategies could be developed based on this information. However, the study reported by the Netherlands Cancer Institute did not directly assess insulin sensitivity. Results obtained by the method employed by this group for measuring insulin sensitivity (a random serum C-peptide level) are subject to justified criticism and healthy skepticism. Therefore, we propose to confirm or refute the preliminary report of The Netherlands Cancer Institute by rigorously assessing insulin sensitivity in women with breast cancer at the time of diagnosis, and in a matched control group of women without breast cancer. Furthermore, analyses will include comparisons of basal insulin sensitivity and sex steroids, as well as an exploration of possible correlations between hyperinsulinemic insulin resistance and serum sex steroid levels. Finally, we also propose to directly and provocatively test the hypothesis that hyperinsulinemia deleteriously alters the steroidal milieu of women with breast cancer by suppressing serum insulin levels in women with breast cancer while concurrently monitoring circulating sex steroids.