Abstract
Inflammatory Breast Cancer (IBC) is a highly aggressive form of cancer characterized by high rates of proliferation, lymphangiogenesis and metastasis, and an overall poor survival. As regular green tea consumption has been associated with improved prognosis of breast cancer patients, including decreased risk of recurrence, here the effects of the green tea polyphenol epigallocatechin-3-gallate (EGCG) were tested on two IBC lines: SUM-149 and SUM-190. EGCG decreased expression of genes that promote proliferation, migration, invasion, and survival. Consistently, growth, invasive properties, and survival of IBC cells were reduced by EGCG treatment. EGCG also reduced lymphangiogenesis-promoting genes, in particular VEGF-D. Conditioned media from EGCG-treated IBC cells displayed decreased VEGF-D secretion and reduced ability to promote lymphangiogenesis in vitro as measured by hTERT-HDLEC lymphatic endothelial cell migration and tube formation. Tumorsphere formation by SUM-149 cells was robustly inhibited by EGCG, suggesting effects on self-renewal ability. Stem-like SUM-149 cells with high aldehyde dehydrogenase (ALDH) activity, previously implicated in poor patient prognosis, were isolated. EGCG treatment reduced growth and induced apoptosis of the stem-like SUM-149 cells in culture. In an orthotopic mouse model, EGCG decreased growth of pre-existing tumors derived from ALDH-positive stem-like SUM-149 cells and their expression of VEGF-D, which correlated with a significant decrease in peritumoral lymphatic vessel density. Thus, EGCG inhibits the overall aggressive IBC phenotype. Reduction of the stem-like cell compartment by EGCG may explain the decreased risk of breast cancer recurrence among green tea drinkers. Recent clinical trials demonstrate the efficacy of green tea polyphenol extracts in treatment of prostate cancer and lymphocytic leukemia with low toxicity. Given the poor prognosis of IBC patients, our findings suggest further exploration of EGCG or green tea in combinatorial treatments against active IBC disease or in maintenance regimens to avoid recurrence is warranted.
Highlights
Inflammatory breast cancer (IBC) accounts for 1–5% of newly diagnosed breast cancer cases each year in the United States [1]
As an initial test of the effects of EGCG on IBC cells, a preliminary dose-response curve was performed on SUM-149 and SUM-190 cells and a concentration of 40 mg/ml EGCG selected, which inhibited growth of both lines by,50%
EGCG inhibits the expression of genes that promote IBC cell growth, transformed phenotype and survival, and these properties are explored below
Summary
Inflammatory breast cancer (IBC) accounts for 1–5% of newly diagnosed breast cancer cases each year in the United States [1]. It is highly aggressive and frequently locally advanced or metastasized at the time of diagnosis [2]. E-cadherin has been detected by immunostaining in all inflammatory breast cancer tumors [8], and implicated in the formation of IBC tumor emboli and lymphovascular invasion [8,9]. The metastatic aggressive behavior of IBC cells has been attributed to a stem-like cancer cell compartment with high ALDH activity (ALDH-positive cells) [16]
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