title: Dietary chemopreventative benzyl isothiocyanate inhibits breast cancer stem cells in vitro and in vivo.
abstract: A small subset of mammary tumor-initiating cells (also known as breast cancer stem cells; bCSC), characterized by expression of different markers [CD44(high)/CD24(low)/epithelial-specific antigen (ESA)+], aldehyde dehydrogenase-1 (ALDH1) activity, and ability to form mammospheres under ultra-low attachment culture conditions, are suspected to evade conventional therapies leading to disease recurrence. Elimination of both therapy-sensitive epithelial tumor cells and therapy-resistant bCSC is therefore necessary for prevention of breast cancer. We have shown previously that a nontoxic small-molecule constituent of edible cruciferous vegetables (benzyl isothiocyanate; BITC) inhibits mammary cancer development in mouse mammary tumor virus-neu (MMTV-neu) transgenic mice by causing epithelial tumor cell apoptosis. The present study shows efficacy of BITC against bCSC in vitro and in vivo. Mammosphere formation frequency and CD44(high)/CD24(low)/ESA+ and/or ALDH1+ populations in cultured MCF-7 (estrogen receptor-positive) and SUM159 (triple-negative) human breast cancer cells were decreased significantly in the presence of plasma achievable concentrations of BITC. BITC administration in the diet (3 μmol BITC/g diet for 29 weeks) resulted in a marked decrease in bCSCs in the MMTV-neu mice tumors in vivo. Overexpression of full-length Ron as well as its truncated form (sfRon), but not urokinase-type plasminogen activator receptor, conferred near complete protection against BITC-mediated inhibition of bCSCs in MCF-7 cells. The BITC treatment downregulated protein levels of Ron and sfRon in cultured breast cancer cells and in tumor xenografts. Ron overexpression resulted in upregulation of bCSC-associated genes Oct-4, SOX-2, and Nanog. In conclusion, the present study indicates that BITC treatment eliminates bCSCs in vitro and in vivo.
authors: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: Su-Hyeong
authors: SH
authors: Kim
authors: Anuradha
authors: A
authors: Sehrawat
authors: Shivendra V
authors: SV
authors: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D004032:Diet; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D017879:Isothiocyanates / Q000494:pharmacology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D017879:Isothiocyanates; D012333:RNA, Messenger; C031403:benzyl isothiocyanate
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