Forkhead Box Q1 Is a Novel Target of Breast Cancer Stem Cell Inhibition by Diallyl Trisulfide

J Biol Chem. 2016 Jun 24;291(26):13495-508. doi: 10.1074/jbc.M116.715219. Epub 2016 Apr 29.

Abstract

Diallyl trisulfide (DATS), a metabolic byproduct of garlic, is known to inhibit the growth of breast cancer cells in vitro and in vivo This study demonstrates that DATS targets breast cancer stem cells (bCSC). Exposure of MCF-7 and SUM159 human breast cancer cells to pharmacological concentrations of DATS (2.5 and 5 μm) resulted in dose-dependent inhibition of bCSC, as evidenced by a mammosphere assay and flow cytometric analysis of aldehyde dehydrogenase 1 (ALDH1) activity and the CD44(high)/CD24(low)/epithelial specific antigen-positive fraction. DATS-mediated inhibition of bCSC was associated with a decrease in the protein level of FoxQ1. Overexpression of FoxQ1 in MCF-7 and SUM159 cells increased ALDH1 activity and the CD49f(+)/CD24(-) fraction. Inhibition of ALDH1 activity and/or mammosphere formation upon DATS treatment was significantly attenuated by overexpression of FoxQ1. In agreement with these results, stable knockdown of FoxQ1 using small hairpin RNA augmented bCSC inhibition by DATS. Expression profiling for cancer stem cell-related genes suggested that FoxQ1 may negatively regulate the expression of Dachshund homolog 1 (DACH1), whose expression is lost in invasive breast cancer. Chromatin immunoprecipitation confirmed recruitment of FoxQ1 at the DACH1 promoter. Moreover, inducible expression of DACH1 augmented DATS-mediated inhibition of bCSC. Expression of FoxQ1 protein was significantly higher in triple-negative breast cancer cases compared with normal mammary tissues. Moreover, an inverse association was observed between FoxQ1 and DACH1 gene expression in breast cancer cell lines and tumors. DATS administration inhibited ALDH1 activity in vivo in SUM159 xenografts. These results indicate that FoxQ1 is a novel target of bCSC inhibition by DATS.

Keywords: FOXO; breast cancer; cancer stem cells; chemoprevention; natural product.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1
  • Allyl Compounds / pharmacology*
  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Eye Proteins / genetics
  • Eye Proteins / metabolism
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Retinal Dehydrogenase / antagonists & inhibitors*
  • Retinal Dehydrogenase / genetics
  • Retinal Dehydrogenase / metabolism
  • Sulfides / pharmacology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Aldehyde Dehydrogenase 1
  • Allyl Compounds
  • DACH1 protein, human
  • Eye Proteins
  • FOXQ1 protein, human
  • Forkhead Transcription Factors
  • Isoenzymes
  • Neoplasm Proteins
  • Sulfides
  • Transcription Factors
  • diallyl trisulfide
  • ALDH1A1 protein, human
  • Aldh1 protein, mouse
  • Retinal Dehydrogenase