Abstract African American (AA) women with breast cancer are more likely to be diagnosed at a more advanced stage of the disease, have a higher recurrence rate and a poorer prognosis than Caucasian (CA) women. African American women are more often diagnosed with high-grade breast tumors at an earlier age most of which are negative for the estrogen and progesterone receptors. These factors result in a higher mortality rate among AA patients. This survival disparity can be attributed to socieconomic status and other related factors, however there are biological factors that may also be involved. The insulin-like growth factor II (IGF-II) plays a crucial role in fetal and cancer development by signaling through the IGF-I receptor (IGF-IR), the insulin receptor (InsR) and crosstalk with the estrogen receptor alpha (ER-α). Compared to CA women, AA women have an increased level of proIGF-II expression in breast tissues and higher signaling activation through the IGF-1 and InsRs. Since the estrogen receptor beta (ER-β) is also expressed in a majority of breast cancers we propose that IGF-II may also activate the ER-β signaling pathway. ER-β has 5 isoforms of which ER-β5 is the most abundantly expressed among AA women with breast cancer and it is associated with a poor prognosis and decreased survival. Thus, our hypothesis is that IGF-II activation of the ER-β5 contributes to the survival disparity between AA women and CA women. To test this hypothesis we analyzed the expression of ER-β5 in AA and CA breast cancer cell lines by western blot, siRNA analysis and IGF-II stimulation. IGF-II not only modulated the phosphorylation of ER-β5, but it also promoted the translocation of ER-β5 to different organelles. Thus, we conclude that ER-β5 may contribute to the survival disparity among AA breast cancer patients since ER-β5 impairs the inhibitory effect of other ER-β isoforms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1114. doi:10.1158/1538-7445.AM2011-1114