Abstract 3885: FXR is implicated in matrix metalloproteinases regulation, tumor invasion and metastasis in breast cancer.

Abstract

Abstract Metastatic breast cancer is a principle cause of female mortality. In general, metastatic cancers show poor response to current treatments and therefore the development of new therapies is essential. Metastasis is a multi-step process where cancer cells migrate from the primary tumour to other distant organs. For this to occur, degradation of the extracellular matrix is required, allowing cancer cells to invade the vasculature and migrate to distant sites. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that breakdown the extracellular matrix, with increased expression of MMP-2 and -9 associated with metastatic breast cancer. MMP activity is tightly regulated by the tissue inhibitors of metalloproteinases (TIMPs): TIMP-1 inhibits MMP-9 activity while TIMP-2 inhibits MMP-2 activity. Studies have shown that the nuclear receptor Farnesoid X-receptor (FXR) is involved in regulation of MMP and TIMP activity in hepatic and vascular tissues. As FXR is highly expressed in metastatic breast cancer, the aim of the current study was to investigate whether FXR is a novel regulator of MMP-2 and -9 in breast cancer cells. The viability of the breast cancer cell lines MCF7 (Estrogen receptor positive) and MDA-MB-468 (Estrogen receptor negative) was measured after exposure to the FXR agonists chenodeoxycholic acid (CDCA) and 3-[2-[2-Chloro-4-[[3-(2, 6-dichlorophenyl)-5-(1-methylethyl)-4 isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064). In both cases, these FXR ligands caused cell death in both cell lines, with reduction of cell viability being significantly higher in the triple negative MDA-MB-468 cells. mRNA and protein levels of MMP-2 and -9 within both cell lines did not change after FXR activation, as measured by real time PCR and Western blotting. However, GW4064 did increase secreted MMP activity, as measured by a fluorescent substrate, in a concentration dependent manner, whereas CDCA had no effect. Such data suggests that while FXR ligands may be cytotoxic to breast cancer cells, they may also increase the risk of invasion and metastasis. Citation Format: Noura Alasmael, Lisiane B. Meira, Karen Swales, Nick Plant. FXR is implicated in matrix metalloproteinases regulation, tumor invasion and metastasis in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3885. doi:10.1158/1538-7445.AM2013-3885