Breast Cancer Research and Treatment

, Volume 113, Issue 2, pp 217–230 | Cite as

TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype

  • Monzur Rahman
  • Sean R. Davis
  • Janet G. Pumphrey
  • Jing Bao
  • Marion M. Nau
  • Paul S. Meltzer
  • Stanley Lipkowitz
Preclinical Study

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in some but not all breast cancer cell lines. Breast cancers can be divided into those which express the estrogen (ER) and progesterone (PR) receptors, those with HER-2 amplification, and those without expression of ER, PR, or HER-2 amplification (referred to as basal or triple-negative breast cancer). We tested a panel of 20 breast cancer cell lines representing the different types of breast cancer to evaluate if the molecular phenotype of the breast cancer cells determined their response to TRAIL. The most striking finding was that eight of eleven triple-negative cell lines are sensitive to TRAIL-mediated apoptosis. The eight TRAIL-sensitive triple-negative cell lines have a mesenchymal phenotype while the three TRAIL-resistant triple-negative cell lines have an epithelial phenotype. Two of five cell lines with HER-2 amplification were sensitive to TRAIL and none of the five ER positive cell lines were sensitive. RNAi-mediated knockdown of TRAIL receptor expression demonstrated that TRAIL Receptor 2 (TRAIL-R2) mediates the effects of TRAIL, even when both TRAIL-R1 and TRAIL-R2 are expressed. Finally, inhibition of EGFR, expressed in both TRAIL-sensitive and TRAIL-resistant triple-negative breast cancer cell lines, using a small molecule tyrosine kinase inhibitor (AG1478), enhanced TRAIL-induced apoptosis in TRAIL-sensitive cell lines but did not convert resistant cells into TRAIL-sensitive cells. Together, these findings suggest that a subset of triple-negative breast cancer, those with mesenchymal features, may be the most likely to benefit from TRAIL targeted therapy. These findings could form the basis to select breast cancer patients for clinical trials of TRAIL-R2 ligands.

Keywords

TRAIL Apoptosis Basal breast cancer Triple-negative breast cancer 

Notes

Acknowledgements

We thank Steven Shaw for helpful discussion about moesin and for providing the anti-moesin antibody. We thank Jeffrey Rubin for his careful review of this manuscript and thoughtful comments. Funding This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Supplementary material

10549_2008_9924_MOESM1_ESM.pdf (23 kb)
Table S1 List of genes with a false discovery rate of 2% for the regression analysis of TRAIL sensitivity and gene expression ranked from most to least significant. Column headings are, from left to right, official gene symbol, gene description, Entrez Gene ID, Affymetrix probeset ID, t-statistic, and false discovery rate (adj.P.val). A positive t-statistic is associated with genes that are higher in TRAIL sensitive cell lines. The raw expression data described in Neve et al. [6] was downloaded from http://caArray.nci.nih.gov. (PDF 23 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Monzur Rahman
    • 1
  • Sean R. Davis
    • 2
  • Janet G. Pumphrey
    • 1
  • Jing Bao
    • 1
  • Marion M. Nau
    • 1
  • Paul S. Meltzer
    • 2
  • Stanley Lipkowitz
    • 1
  1. 1.Laboratory of Cellular and Molecular Biology, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaUSA
  2. 2.Genetics Department, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaUSA

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