Abstract 4140: Inhibition of mTOR signaling by psoralidin in breast cancer

Abstract

Abstract Breast carcinoma is the most common malignancy in women and is the second leading cause of cancer-related deaths in the United States. Mammalian target of rapamycin (mTOR) is a major effector of the PI3Kinase/Akt pro-survival signaling pathway and has received significant attention as a therapeutic target for the treatment of various malignancies. Rapamycin and its analogs are specific mTOR antagonists; however their toxicity hampers wide use in the clinical setting for the treatment of breast cancer. This compels development of new strategies for the treatment of advanced, triple and double negative breast cancers. Psoralidin is one of the major active ingredients in Psoralea corylifolia, herbal plant that is extensively used in Asian and African traditional medicines. In our study we tested the effects of psoralidin on the mTOR pathway in estrogen-responsive (MCF-7) and -refractory (MDA 231) breast cancer cells. Our results suggest that psoralidin inhibits phoshporlyation of mTOR resulting in the inhibition of the phosphorylation of mTOR effectors (p70S6K and 4EBP1) in both MCF-7 and MDA 231 cells. Interestingly, there was no significant down regulation of pAkt expression in either cell lines following treatment with psoralidin. While dissecting the effect of psoralidin on epithelial-mesenchymal transition (EMT), we found that psoralidin inhibits expression of β-catenin with a concomitant increase in the expression of E-cadherin in both estrogen-responsive and -refractory breast cancers cells. In addition, treatment with psoralidin effectively inhibits the growth of both estrogen-responsive (MCF-7) and -refractory (MDA 231) breast cancer cells and induces apoptosis without causing significant toxicity to normal breast epithelial cells (MCF-10A). Currently we are pursuing studies using xenograft models to determine the effect of psoralidin in estrogen-responsive and -refractory breast cancers animal models. The outcome of this study may provide a mechanistic validation of psoralidin as a potent compound that may be used for the treatment of breast cancer. 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 4140.