Abstract 3913: Estrogen receptor beta and estrogen receptor beta 5 in triple negative breast cancer cells: IGF-II role in regulation of estrogen receptor beta 5

Abstract

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. They also are more often diagnosed with high-grade breast tumors at an earlier age (pre-menopausal), most of which are negative for the estrogen and progesterone receptors (ER-, PR-). These factors result in a higher mortality rate among AA breast cancer patients. Our lab has demonstrated that AA women have increased levels of IGF-II coupled with lower levels of the IGF-II receptor needed to degrade IGF-II, thus leading to higher IGF-Ii signaling in contrast to CA women. AA women also have a higher expression of the insulin receptor A versus insulin receptor B when compared to CA women, which increases proliferation and decreases metabolic effects (Singh et. al 2011). We have also shown that IGF-II activates the estrogen receptor alpha (ER-α) and estrogen receptor beta (ER-α) in the absence of the estrogen ligand (Richardson et. Al 2011). When co-expressed, ER-α counteracts the proliferative function of ER-α, however the role of ER-α in breast cancer is different in ER-α negative compared to ER-α positive tumors. Furthermore, there are 5 different isoforms of ER-α, of which ER-Δ5 is the most abundantly expressed form in AA women. Since IGF-II activates ER-α and ER-Δ5 is associated with increased mortality and decreased time recurrence, we have designed a study to determine if IGF-II regulates ER-Δ5. We hypothesize that in the absence of ER-α, ER-α may activate the ER-α signaling pathway, and that the elevated expression of ER-Δ5 and its heterodimerization with of ER-α1 contributes to the overall survival disparity. To test this hypothesis we characterized the levels of phophorylated ER-α (pER-α) and compared them to IGF-II levels in triple negative breast cancer cells and normal triple negative epithelial cells. IGF-II levels were analyzed using western blotting for protein, and RT-PCR for mRNA. AA women have a higher expression of IGF-II in both malignant and normal cells, and comparably higher levels of expression of the active form of ER-α when compared to CA breast cancer cell lines. IGF-II stimulation promoted the translocation of ER-Δ5 to different cellular compartments. We propose that ER-Δ5 impairs the inhibitory effects of ER-α and thus may contribute to the survival disparity among AA breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3913. doi:1538-7445.AM2012-3913