Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells.
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.
Li
Yanyan
Y
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Zhang
Tao
T
Korkaya
Hasan
H
Liu
Suling
S
Lee
Hsiu-Fang
HF
Newman
Bryan
B
Yu
Yanke
Y
Clouthier
Shawn G
SG
Schwartz
Steven J
SJ
Wicha
Max S
MS
Sun
Duxin
D
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
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
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