A link to breast cancer survival disparity among African American women:IGF-II regulates mitochondria to prevent apoptosis and promote chemoresistance

B106 The disparity in survival among African American (AA) women affected by breast cancer associates with poorly understood clinical-pathological correlates. A comprehensive molecular approach to understand the biological basis of the increased mortality and poorer prognosis in this ethnic group is critically needed to target the differences in outcomes among AA patients. We are addressing this need by investigating how IGF-II contributes to the survival disparity observed among AA breast cancer patients. IGF-II plays a pivotal role in fetal and cancer development by signaling through the IGF-I and Insulin receptors, thus regulating proliferation, apoptosis and energy production. This potent mitogen is not expressed in normal adult cells but it is re-expressed in breast cancer and “free” circulating IGF-II levels in humans significantly correlate to breast tumor size. Furthermore, transgenic animal models that result in constitutive IGF-II expression also show a significant increase in breast cancer that develops at an early age and is more aggressive. We recently demonstrated that IGF-II regulates the anti-apoptotic proteins survivin, Bcl-2 and Bcl-XL in breast cancer cells. These proteins protect the mitochondria and prevent cell death (apoptosis). Inhibition of IGF-II by Resveratrol (RSV) caused the inhibition of all threeproteins and stimulated mitochondrial depolarization and apoptosis. RSV is a potent anticancer phytoestrogen presently under evaluation in clinical trials. These effects were blocked by addition of IGF-II. RSV treatment had no effect on IGF-II transfected MCF-7 cells. Thus, IGF-II plays a critical role in regulating proteins that are essential to protect the mitochondria and prevent apoptosis. Our present study investigates the role of IGF-II in the survival disparity observed among AA breast cancer patients. How does the expression of IGF-II and survival proteins compare in normal/tumor tissues? Is there a difference in the expression of these proteins between AA and Caucasian women? Paraffin slides and frozen, paired samples were obtained from the Cooperative Human Tissue Network. Breast cancer cells from AA and Caucasian patients were obtained from the American Type Culture Collection. IGF-II, survivin, Bcl2 and Bcl-XL were analyzed by Western blot in paired, breast cancer/normal tissues and in subcellular compartments of breast cancer cells. Analysis of IGF-II and survival proteins revealed significantly higher levels of IGF-II, survivin, Bcl-2 and Bcl-XL in tumor tissues compared to normal tissues. Of great significance was the higher expression of these proteins detected in “normal” tissue from AA women as compared to Caucasian women. A limited pathological analysis (from stained slides) demonstrated that the increased IGF-II expression in “normal” tissues was limited to areas with fibrocystic changes. Since expression of these proteins prevents apoptosis and promotes chemoresistance, we propose that cancer initiated by these cells may promote the development of a more aggressive, malignant tumor contributing to the increased mortality observed among AA breast cancer patients. We conclude that IGF-II effects in the mitochondria and its regulation of survival proteins is a novel mechanism of cancer cell survival and chemoresistance.