Blueberry Phytochemicals Inhibit Growth and Metastatic Potential of MDA-MB-231 Breast Cancer Cells through Modulation of the Phosphatidylinositol 3-Kinase Pathway
Lynn S. Adams1,
Sheryl Phung1,
Natalie Yee1,
Navindra P. Seeram2,
Liya Li2, and
Shiuan Chen
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.