Abstract 565: Benzyl isothiocyanate-mediated inhibition of epithelial-mesenchymal transition in human breast cancer cells is associated with downregulation of urokinase-type plasminogen activator and its receptor

Abstract

Abstract Novel approaches for chemoprevention of breast cancer are clinically attractive not only because many risk factors associated with this disease are not easily modifiable (e.g., genetic predisposition) but also due to the fact that the currently available chemopreventive options targeted against breast cancer (e.g., estrogen receptor antagonists) are sub-optimal and plagued with adverse side effects. Needless to emphasize that breast cancer continues to be a leading cause of cancer-related death in American women despite significant advances towards targeted therapies. Benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables (e.g., garden cress), seems promising for chemoprevention of breast cancer based on our own preclinical work. For example, we have shown previously that BITC administration not only inhibits growth of human breast cancer xenografts (MDA-MB-231) in athymic mice but also imparts significant protection against mammary cancer development in a transgenic mouse model (MMTV-neu). More recent studies from our laboratory have revealed that BITC is a potent inhibitor of epithelial-mesenchymal transition (EMT) in human breast cancer cells, but the mechanism underlying this effect is not known. In the present study, we addressed this question using MDA-MB-231, MDA-MB-468, and SUM159 human breast cancer cells as a model. Overexpression of superoxide dismutase, which confers significant protection against proapoptotic and proautophagic cell death responses to BITC, did not have any meaningful impact on BITC-mediated inhibition of EMT. Likewise, ectopic expression of constitutively active STAT3, a transcription factor implicated in EMT regulation, had no effect on EMT inhibition by BITC. Instead, the BITC-mediated inhibition of EMT was associated with suppression of protein and mRNA levels of urokinase-type plasminogen activator (uPA) and its receptor (uPAR). Secretion of uPA in culture media of breast cancer cells was also decreased significantly upon BITC treatment. BITC-mediated inhibition of MDA-MB-231 xenograft growth in vivo was accompanied by downregulation of uPA and uPAR protein expression in the tumor and suppression of uPA secretion in plasma. Ectopic expression of uPAR in MDA-MB-468 and MCF-7 cells conferred partial but significant protection against BITC-mediated inhibition of EMT, cell migration, and/or cell invasion. Collectively, these results indicate that BITC-mediated inhibition of EMT is caused, at least in part, by suppression of the uPA/uPAR system. This investigation was supported by the USPHS grant RO1 CA129347-05, awarded by the National Cancer Institute. 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 565. doi:1538-7445.AM2012-565