Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells

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 sulforaphan...

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Published in:	Cancer letters Vol. 394; pp. 52 - 64
Main Authors:	Burnett, Joseph P., Lim, Gi, Li, Yanyan, Shah, Ronak B., Lim, Rebekah, Paholak, Hayley J., McDermott, Sean P., Sun, Lichao, Tsume, Yasuhiro, Bai, Shuhua, Wicha, Max S., Sun, Duxin, Zhang, Tao
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier B.V 28.05.2017 Elsevier Limited
Subjects:	Aldehyde dehydrogenase Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Antitumor activity Breast cancer Cancer stem cell Cancer therapies Cell Death - drug effects Cell Line, Tumor Cell Proliferation - drug effects Chemotherapy Clinical medicine Cytokines Cytotoxicity Docetaxel Dose-Response Relationship, Drug Drug resistance Female Gene Expression Regulation, Neoplastic Hematology, Oncology and Palliative Medicine Humans Inflammation Mediators - metabolism Interleukin 6 Interleukin-6 - metabolism Interleukin-8 - metabolism Isothiocyanates - pharmacology Laboratories Metastasis Mice, Inbred NOD Mice, SCID Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology NF-kappa B p52 Subunit - genetics NF-kappa B p52 Subunit - metabolism Paclitaxel Paclitaxel - pharmacology Pancreatic cancer Phenotype Prostate Signal Transduction - drug effects Stem cell transplantation Stem cells Sulforaphane Sulfoxides Taxanes Taxoids - pharmacology Time Factors Transcription Transcription Factor RelA - genetics Transcription Factor RelA - metabolism Transcription, Genetic Transfection Triple negative breast cancer Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - metabolism Triple Negative Breast Neoplasms - pathology Tubulin Modulators - pharmacology Tumor Burden - drug effects Tumors Xenograft Model Antitumor Assays Xenografts IL ELDA Docetaxel Cancer stem cell ALDH CSC PAC Sulforaphane Paclitaxel DOC SFN TNBC Triple negative breast cancer paclitaxel sulforaphane extreme limiting dilution analysis cancer stem cell docetaxel aldehyde dehydrogenase-positive triple negative breast cancer interleukin
ISSN:	0304-3835, 1872-7980
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Summary:	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. •Standard taxane-based treatment increases inflammatory cytokine secretion.•Paclitaxel and docetaxel enrich the CSC population.•Anti-CSC compound sulforaphane inhibits NF-κB transcriptional activity.•Sulforaphane reverses taxane-induced CSCs enrichment.•Combination greatly reduces primary tumor volume and secondary tumor formation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work.
ISSN:	0304-3835 1872-7980
DOI:	10.1016/j.canlet.2017.02.023