title: Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells.
abstract: Triple negative breast cancer (TNBC) typically exhibits rapid progression, high mortality and faster relapse rates relative to other breast cancer subtypes. In this report we examine the combination of taxanes (paclitaxel or docetaxel) with a breast cancer stem cell (CSC)-targeting agent sulforaphane for use against TNBC. We demonstrate that paclitaxel or docetaxel treatment induces IL-6 secretion and results in expansion of CSCs in TNBC cell lines. Conversely, sulforaphane is capable of preferentially eliminating CSCs, by inhibiting NF-κB p65 subunit translocation, downregulating p52 and consequent downstream transcriptional activity. Sulforaphane also reverses taxane-induced aldehyde dehydrogenase-positive (ALDH+) cell enrichment, and dramatically reduces the size and number of primary and secondary mammospheres formed. In vivo in an advanced treatment orthotopic mouse xenograft model together with extreme limiting dilution analysis (ELDA), the combination of docetaxel and sulforaphane exhibits a greater reduction in primary tumor volume and significantly reduces secondary tumor formation relative to either treatment alone. These results suggest that treatment of TNBCs with cytotoxic chemotherapy would be greatly benefited by the addition of sulforaphane to prevent expansion of and eliminate breast CSCs.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Burnett
authors.affiliation: School of Science and Humanities, Husson University, Bangor, ME 04401, USA.
authors.forename: Gi
authors.initials: G
authors.lastname: Lim
authors.affiliation: School of Science and Humanities, Husson University, Bangor, ME 04401, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ronak B
authors.initials: RB
authors.lastname: Shah
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Husson University, Bangor, ME 04401, USA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Lim
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hayley J
authors.initials: HJ
authors.lastname: Paholak
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: McDermott
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lichao
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsume
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Husson University, Bangor, ME 04401, USA.
authors.forename: Shuhua
authors.initials: S
authors.lastname: Bai
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: duxins@med.umich.edu.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Husson University, Bangor, ME 04401, USA. Electronic address: zhangt@husson.edu.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D013454:Sulfoxides; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050257:Tubulin Modulators / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C508606:CXCL8 protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D017879:Isothiocyanates; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; C498143:RELA protein, human; D013454:Sulfoxides; D043823:Taxoids; D051996:Transcription Factor RelA; D050257:Tubulin Modulators; D000077143:Docetaxel; C016766:sulforaphane; D017239:Paclitaxel
keywords: Cancer stem cell; Docetaxel; Paclitaxel; Sulforaphane; Triple negative breast cancer