Abstract 4602: Effect of estrogen receptor antagonistic drugs on expression and regulation of fatty acid synthase (FAS) in ER+ breast cancer cell lines

Abstract

Abstract Expression of estrogen receptor (ER) is detected in more than sixty percent of breast tumors. High levels of Fatty acid synthase (FAS) have been detected in aggressive breast cancers. Due to its high level of expression, FAS has been considered as a tumor marker and a therapeutic target. In normal rat liver, increase in expression of FAS requires glucose and a combination of hormones. Activity of FAS is indirectly regulated by the upstream signaling factor AMPK. AMPK is considered to be the main regulator of cellular metabolism. Upon activation, AMPK down regulates FAS activity and other ATP consuming pathways. In this study, we investigated the possible regulatory role of estrogen receptor (ER) signaling on FAS level and activity. In a panel of ER+ cell lines, very high levels of FAS expression was observed in the majority of the cell lines. The highest levels of FAS were in the ER+/HER2+ cell lines, HCC1419, BT474 and MDA-MB-361, respectively. However, in two other ER+/HER2+ cell lines, UACC732 and UACC812, the expression was similar to or even lower than the HER2 negative cell lines. Three HER2 negative cell lines in the panel also showed very high levels of FAS expression. Upon incubation of the cells in the absence of serum and phenol red condition, a general decrease in the FAS levels was observed that was more evident in HER2 negative cell lines. In the same condition, the effects of ER inhibitory drugs, fulvestrant and tamoxifen, on FAS and p-AMPKα levels were investigated. In ER+ cell lines that contain high levels of p-AKT, ER inhibitors did not affect levels of FAS and p-AMPKα. However, in some cell lines with lower levels of active AKT, tamoxifen and fulvestrant induced changes in FAS and p-AMPKα levels that were variable from cell line to cell line. In MCF-7 cell line, which is highly sensitive to ER inhibitors, both tamoxifen and fulvestrant induced lower FAS and higher p-AMPKα levels. Contrary to this observation, tamoxifen induced higher FAS and lower p-AMPKα levels in T-47D and KPL-1 cell lines. Fulvestrant induced a similar effect in ZR-75-1 cell line. This inducing effect of ER antagonists on FAS perhaps reflects one of the mechanisms that cause the elevation of blood lipids in post menopausal and tamoxifen treated women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4602.