Background: Obesity is associated with a modest increase in the risk of postmenopausal breast cancer (RR = 1.5 – 2.0); but, because nearly a third of the U.S. population is obese, the population attributable risk is estimated at 15%. Obesity can cause insulin resistance culminating in Type II diabetes. Notably, breast cancer incidence is significantly increased in the years preceding a diagnosis of type II diabetes. Because IGFBP-1 expression is tightly regulated by insulin, it is an excellent marker of insulin resistance in healthy individuals. Methods: These data are based on well-annotated prospectively acquired baseline blood and breast tissue samples from 72 high risk women between the ages of 37 and 86 years who participated in a chemoprevention trial. None of the women had been diagnosed with Type II diabetes. Women with plasma IGFBP1 levels in the lowest tertile (mean 2.1 ng/ml) were classified as insulin-resistant. Results: Plasma IGFBP1 was strongly inversely correlated with BMI (R2 = 0.247, P < 0.0001). Insulin-resistant women had marginally higher mean plasma free estradiol levels than women not classified as insulin-resistant (2.13 x 10-12M versus 1.53 x 10-12M, P = 0.072). There was no difference in plasma IGF1, IGF2, or IGFBP3 levels. Illumina whole genome expression microarray data was available for breast tissue from 55 women. Women classified as insulin-resistant showed evidence of an adaptive response to oxidative stress based on significant upregulation of NQO1, GSTK1, CYP4ZP2, and SRXN1 (P < 0.001). Conclusions: Marginally increased circulating estradiol may contribute to the increased breast cancer risk observed in insulin-resistant women. However, insulin resistance increases oxidative stress in breast tissue and may promote carcinogenesis through induction of oxidative DNA damage.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6025.
Thirty-first San Antonio Breast Cancer Symposium Dec 10-14, 2008; San Antonio, TX