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: Su-Hyeong Kim, Anuradha Sehrawat, Shivendra V Singh
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 6 Issue 8 Pg. 782-90 (Aug 2013) ISSN: 1940-6215 [Electronic] United States
• PMID: 23661606 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Isothiocyanates
• RNA, Messenger
• benzyl isothiocyanate

Topics

• Animals
• Apoptosis
• Blotting, Western
• Breast Neoplasms (metabolism, pathology, prevention & control)
• Cell Proliferation
• Diet
• Epithelial-Mesenchymal Transition
• Female
• Flow Cytometry
• Humans
• In Vitro Techniques
• Isothiocyanates (pharmacology)
• Mammary Tumor Virus, Mouse (genetics)
• Mice
• Mice, Transgenic
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured