title: Epigallocatechin-3-gallate inhibits stem-like inflammatory breast cancer cells.
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.
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Nora D
authors.initials: ND
authors.lastname: Mineva
authors.forename: K Eric
authors.initials: KE
authors.lastname: Paulson
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Naber
authors.forename: Amy S
authors.initials: AS
authors.lastname: Yee
authors.forename: Gail E
authors.initials: GE
authors.lastname: Sonenshein
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D042583:Lymphangiogenesis / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D042643:Vascular Endothelial Growth Factor D; D002392:Catechin; C045651:epigallocatechin gallate
references.citation: Breast Cancer Res. 2005;7(2):52-8
references.pmid: 15743511
references.citation: Cancer Lett. 2001 Jun 26;167(2):175-82
references.pmid: 11369139
references.citation: Bioorg Med Chem. 2012 May 1;20(9):3031-7
references.pmid: 22459208
references.citation: Clin Exp Metastasis. 2008;25(7):717-25
references.pmid: 18512120
references.citation: Cancer Sci. 2009 Jun;100(6):1062-8
references.pmid: 19385968
references.citation: Eur J Cancer Prev. 2003 Oct;12(5):383-90
references.pmid: 14512803
references.citation: J Natl Cancer Inst. 1968 Jan;40(1):43-68
references.pmid: 5635018
references.citation: Carcinogenesis. 2012 Apr;33(4):876-85
references.pmid: 22307971
references.citation: Nutr Cancer. 2010;62(7):931-7
references.pmid: 20924968
references.citation: Nat Cell Biol. 2007 Apr;9(4):470-8
references.pmid: 17369819
references.citation: Mol Oncol. 2007 Jun;1(1):84-96
references.pmid: 18516279
references.citation: Oncogene. 2002 May 9;21(20):3172-80
references.pmid: 12082632
references.citation: Cancer. 2007 Oct 1;110(7):1436-44
references.pmid: 17694554
references.citation: Breast Dis. 2005-2006;22:9-23
references.pmid: 16735783
references.citation: Cancer Res. 2000 Oct 15;60(20):5832-8
references.pmid: 11059780
references.citation: Cancer Res. 2006 Jan 15;66(2):1234-40
references.pmid: 16424063
references.citation: Cancer Res. 2001 Jul 1;61(13):5231-41
references.pmid: 11431364
references.citation: J Natl Cancer Inst. 1993 Nov 17;85(22):1819-27
references.pmid: 8230262
references.citation: Clin Cancer Res. 2004 Dec 1;10(23):7965-71
references.pmid: 15585631
references.citation: Hum Pathol. 2013 Mar;44(3):402-11
references.pmid: 23036368
references.citation: Nat Med. 2001 Feb;7(2):192-8
references.pmid: 11175850
references.citation: Nat Med. 2001 Feb;7(2):186-91
references.pmid: 11175849
references.citation: Cancer Res. 2007 Dec 15;67(24):11742-50
references.pmid: 18089804
references.citation: J Biol Chem. 2009 Jan 16;284(3):1385-93
references.pmid: 19029090
references.citation: Clin Cancer Res. 2005 Nov 1;11(21):7637-42
references.pmid: 16278382
references.citation: Clin Cancer Res. 1999 Sep;5(9):2511-9
references.pmid: 10499627
references.citation: J Immunol. 1997 Mar 1;158(5):2165-73
references.pmid: 9036962
references.citation: Eur Urol. 2008 Aug;54(2):472-3
references.pmid: 18406041
references.citation: Jpn J Cancer Res. 1998 Mar;89(3):254-61
references.pmid: 9600118
references.citation: Stem Cell Rev Rep. 2011 Jun;7(2):292-306
references.pmid: 21103958
references.citation: Br J Cancer. 1999 Dec;81(8):1328-34
references.pmid: 10604729
references.citation: Cancer. 2010 Jun 1;116(11 Suppl):2748-54
references.pmid: 20503405
references.citation: Cell Stem Cell. 2007 Nov;1(5):555-67
references.pmid: 18371393
references.citation: Clin Cancer Res. 2009 Jun 15;15(12):4234-41
references.pmid: 19509181
references.citation: J Pathol. 2009 Nov;219(3):356-64
references.pmid: 19718705
references.citation: Cancer Res. 2009 Feb 15;69(4):1302-13
references.pmid: 19190339
references.citation: Cancer Prev Res (Phila). 2009 Jul;2(7):673-82
references.pmid: 19542190
references.citation: Blood. 2009 May 21;113(21):5340-51
references.pmid: 19324906
references.citation: Am J Pathol. 2004 Jul;165(1):11-24
references.pmid: 15215158
references.citation: Oncologist. 2011;16(12):1675-83
references.pmid: 22147002
references.citation: Mol Cancer Res. 2007 Apr;5(4):321-9
references.pmid: 17426247
references.citation: Curr Opin Cell Biol. 2009 Apr;21(2):154-65
references.pmid: 19230644
references.citation: Breast Cancer Res. 2000;2(6):423-9
references.pmid: 11250736
references.citation: Mod Pathol. 2001 May;14(5):458-64
references.pmid: 11353057
references.citation: J Cell Physiol. 2009 Sep;220(3):593-9
references.pmid: 19373868
references.citation: Clin Cancer Res. 2010 Jan 1;16(1):45-55
references.pmid: 20028757
references.citation: Clin Cancer Res. 2003 Feb;9(2):716-21
references.pmid: 12576440
references.citation: J Clin Oncol. 2009 Aug 10;27(23):3808-14
references.pmid: 19470922
references.citation: Surg Oncol. 2005 Nov;14(3):133-43
references.pmid: 16154355