title: Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells.
abstract: OBJECTIVE
  The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. In this study, we evaluated sulforaphane, a natural compound derived from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs and its potential mechanism.
  
  
  METHODS
  Aldefluor assay and mammosphere formation assay were used to evaluate the effect of sulforaphane on breast CSCs in vitro. A nonobese diabetic/severe combined immunodeficient xenograft model was used to determine whether sulforaphane could target breast CSCs in vivo, as assessed by Aldefluor assay, and tumor growth upon cell reimplantation in secondary mice. The potential mechanism was investigated using Western blotting analysis and beta-catenin reporter assay.
  
  
  RESULTS
  Sulforaphane (1-5 micromol/L) decreased aldehyde dehydrogenase-positive cell population by 65% to 80% in human breast cancer cells (P < 0.01) and reduced the size and number of primary mammospheres by 8- to 125-fold and 45% to 75% (P < 0.01), respectively. Daily injection with 50 mg/kg sulforaphane for 2 weeks reduced aldehyde dehydrogenase-positive cells by >50% in nonobese diabetic/severe combined immunodeficient xenograft tumors (P = 0.003). Sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor growth after the reimplantation of primary tumor cells into the secondary mice (P < 0.01). Western blotting analysis and beta-catenin reporter assay showed that sulforaphane downregulated the Wnt/beta-catenin self-renewal pathway.
  
  
  CONCLUSIONS
  Sulforaphane inhibits breast CSCs and downregulates the Wnt/beta-catenin self-renewal pathway. These findings support the use of sulforaphane for the chemoprevention of breast cancer stem cells and warrant further clinical evaluation.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Hasan
authors.initials: H
authors.lastname: Korkaya
authors.forename: Suling
authors.initials: S
authors.lastname: Liu
authors.forename: Hsiu-Fang
authors.initials: HF
authors.lastname: Lee
authors.forename: Bryan
authors.initials: B
authors.lastname: Newman
authors.forename: Yanke
authors.initials: Y
authors.lastname: Yu
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Clouthier
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schwartz
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001937:Brassica / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D017879:Isothiocyanates; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050697:Retinal Dehydrogenase; D036226:Seedlings / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013454:Sulfoxides; D013861:Thiocyanates / Q000008:administration & dosage / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D051153:Wnt Proteins; D051176:beta Catenin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; C016766:sulforaphane
references.citation: Cancer Cell. 2006 Dec;10(6):454-6
references.pmid: 17157785
references.citation: Breast Cancer Res. 2005;7(3):86-95
references.pmid: 15987436
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8455-9
references.pmid: 8710892
references.citation: J Biol Chem. 1998 Aug 7;273(32):19929-32
references.pmid: 9685326
references.citation: Cancer. 2006 Jun 1;106(11):2503-13
references.pmid: 16628653
references.citation: Ann Acad Med Singap. 2007 May;36(5):352-7
references.pmid: 17549283
references.citation: Nature. 2003 May 22;423(6938):409-14
references.pmid: 12717450
references.citation: Cancer Metastasis Rev. 1999;18(2):215-30
references.pmid: 10728985
references.citation: Nature. 2001 Nov 1;414(6859):105-11
references.pmid: 11689955
references.citation: Nat Rev Mol Cell Biol. 2001 Oct;2(10):769-76
references.pmid: 11584304
references.citation: J Nutr. 2004 May;134(5):1134-8
references.pmid: 15113959
references.citation: Cell. 2006 Nov 3;127(3):469-80
references.pmid: 17081971
references.citation: Neoplasia. 2007 Nov;9(11):882-92
references.pmid: 18030356
references.citation: Mutat Res. 2006 Oct 10;601(1-2):92-101
references.pmid: 16843502
references.citation: PLoS Biol. 2009 Jun 2;7(6):e1000121
references.pmid: 19492080
references.citation: Pathobiology. 2008;75(2):75-84
references.pmid: 18544962
references.citation: Dev Biol. 1997 May 1;185(1):82-91
references.pmid: 9169052
references.citation: Nutr Cancer. 2006;55(1):53-62
references.pmid: 16965241
references.citation: Cancer Res. 2009 Jan 15;69(2):466-74
references.pmid: 19147559
references.citation: Carcinogenesis. 2007 Jul;28(7):1485-90
references.pmid: 17347138
references.citation: Acta Pharmacol Sin. 2007 Sep;28(9):1343-54
references.pmid: 17723168
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references.pmid: 12629218
references.citation: Oncol Rep. 2007 Jul;18(1):181-7
references.pmid: 17549366
references.citation: Carcinogenesis. 2008 Dec;29(12):2360-8
references.pmid: 18952594
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3547-9
references.pmid: 12657737
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10367-72
references.pmid: 9294217
references.citation: Biochem Pharmacol. 2004 Sep 15;68(6):1133-8
references.pmid: 15313410
references.citation: Cell Stem Cell. 2007 Nov;1(5):555-67
references.pmid: 18371393
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Nov;14(11 Pt 1):2605-13
references.pmid: 16284385
references.citation: Cell. 2002 Mar 22;108(6):837-47
references.pmid: 11955436
references.citation: J Agric Food Chem. 2006 Sep 20;54(19):7075-82
references.pmid: 16968065
references.citation: J Clin Oncol. 2008 Jun 10;26(17):2813-20
references.pmid: 18539959
references.citation: Drug Metab Dispos. 2003 Jun;31(6):805-13
references.pmid: 12756216
references.citation: Cancer Res. 2008 May 1;68(9):3243-50
references.pmid: 18451150
references.citation: N Engl J Med. 1987 Jun 4;316(23):1435-40
references.pmid: 2437455
references.citation: Cancer Res. 2006 Jun 15;66(12):6063-71
references.pmid: 16778178
references.citation: Breast Cancer Res. 2004;6(6):R605-15
references.pmid: 15535842
references.citation: Carcinogenesis. 2004 Jan;25(1):83-90
references.pmid: 14514658
references.citation: Oncogene. 2002 Dec 5;21(55):8414-27
references.pmid: 12466962
references.citation: Clin Chim Acta. 2002 Feb;316(1-2):43-53
references.pmid: 11750273
references.citation: Mol Cancer Ther. 2007 Mar;6(3):1013-21
references.pmid: 17339367
references.citation: Cancer Res. 2005 Jul 1;65(13):5506-11
references.pmid: 15994920
references.citation: Cancer Lett. 2008 Oct 8;269(2):291-304
references.pmid: 18504070
references.citation: Cancer Lett. 2006 Feb 28;233(2):208-18
references.pmid: 16520150
references.citation: Cancer Res. 2004 Aug 15;64(16):5767-74
references.pmid: 15313918
references.citation: Mol Cancer Ther. 2004 Oct;3(10):1239-48
references.pmid: 15486191
references.citation: Genes Dev. 2003 May 15;17(10):1253-70
references.pmid: 12756227
references.citation: N Engl J Med. 2000 Apr 13;342(15):1119-20
references.pmid: 10760313
references.citation: Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2399-403
references.pmid: 1549603
references.citation: Gut. 2009 Jul;58(7):949-63
references.pmid: 18829980