Blueberry Phytochemicals Inhibit Growth and Metastatic Potential of MDA-MB-231 Breast Cancer Cells through Modulation of the Phosphatidylinositol 3-Kinase Pathway

Abstract

Dietary phytochemicals are known to exhibit a variety of anticarcinogenic properties. This study investigated the chemopreventive activity of blueberry extract in triple-negative breast cancer cell lines in vitro and in vivo. Blueberry decreased cell proliferation in HCC38, HCC1937, and MDA-MB-231 cells with no effect on the nontumorigenic MCF-10A cell line. Decreased metastatic potential of MDA-MB-231 cells by blueberry was shown through inhibition of cell motility using wound-healing assays and migration through a polyethylene terephthalate membrane. Blueberry treatment decreased the activity of matrix metalloproteinase-9 and the secretion of urokinase-type plasminogen activator while increasing tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 secretion in MDA-MB-231 conditioned medium as shown by Western blotting. Cell signaling pathways that control the expression/activation of these processes were investigated via Western blotting and reporter gene assay. Treatment with blueberry decreased phosphatidylinositol 3-kinase (PI3K)/AKT and NFκB activation in MDA-MB-231 cells, where protein kinase C and extracellular signal-regulated kinase (ERK) were not affected. In vivo, the efficacy of blueberry to inhibit triple-negative breast tumor growth was evaluated using the MDA-MB-231 xenograft model. Tumor weight and proliferation (Ki-67 expression) were decreased in blueberry-treated mice, where apoptosis (caspase-3 expression) was increased compared with controls. Immunohistochemical analysis of tumors from blueberry-fed mice showed decreased activation of AKT and p65 NFκB signaling proteins with no effect on the phosphorylation of ERK. These data illustrate the inhibitory effect of blueberry phytochemicals on the growth and metastatic potential of MDA-MB-231 cells through modulation of the PI3K/AKT/NFκB pathway. Cancer Res; 70(9); 3594-605.

Ellagic Acid Exerts Anti-proliferation Effects via Modulation of Tgf-Β/Smad3 Signaling in MCF-7 Breast Cancer Cells

“…These findings are consistent with earlier studies. Adams et al found that blueberry extracts, which were rich in ellagic acid, could modulate the PI3K/AKT/NF kappa B pathway and inhibit the growth and metastasis of MDA-MB-231 breast cancer cells (Adams et al, 2010). Li et al reported that ellagic acid induced G0/G1 cell cycle arrest and apoptosis in bladder cancer T24 cells .…”

Cytotoxicity, Apoptosis Induction and Anti-Metastatic Potential of Oroxylum indicum in Human Breast Cancer Cells

“…There have been a plethora of reports in the scientific literature documenting the chemopreventive potential of phytochemicals such as Lupulone, Hesperidin and blueberry phytochemicals in various cancer cell lines like those from tumors in the colon and the breast (Park et al, 2008;Lamy et al, 2009;Adams et al, 2010). Further, studies have been done to demonstrate that the common unifying theme involves the activation of caspase-3, despite differences in the relative involvement of the upstream molecular players in the extrinsic and intrinsic pathways of apoptosis with respect to Curcumin treatment (Gao et al, 2005;Takai et al, 2012).…”

A Comparison of Antioxidant Properties in Organic and Conventional Blueberries

“…Phytochemicals in blueberries have been shown to decrease the secretion of urokinase-type plasminogen activator (uPA) and increase the secretion of plasminogen activator inhibitor (PAI), both of which are cell-signaling proteins that inhibit tumor cell proliferation and metastatic potential in breast cancer cells (Adams et al, 2010). Anthocyanin, the flavonoid responsible for the pigmentation in blueberries, has both antioxidant and anti-cancer properties (Seeram, Yanjun, & Muraleedharan, 2003).…”