TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype
- 809 Downloads
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.
KeywordsTRAIL Apoptosis Basal breast cancer Triple-negative breast cancer
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.
- 5.Cuello M, Ettenberg SA, Clark AS, Keane MM, Posner RH, Nau MM, Dennis PA, Lipkowitz S (2001) Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res 61(12):4892–4900PubMedGoogle Scholar
- 8.Smyth GK (2005) Limma: linear models for microarray data. In: Gentleman RC et al (eds) Bioinformatics and computational biology solutions using R and Bioconductor. Springer, New York, pp 397–420Google Scholar
- 9.Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a pratical and powerful approach to multiple testing. J R Stat Soc 57:289–300Google Scholar
- 13.Weinberg RA (2007) The biology of cancer. Garland Science, New YorkGoogle Scholar
- 15.Finn RS, Dering J, Ginther C, Wilson CA, Glaspy P, Tchekmedyian N, Slamon DJ (2007) Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/”triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res Treat 105(3):319–326PubMedCrossRefGoogle Scholar
- 26.Umemura S, Takekoshi S, Suzuki Y, Saitoh Y, Tokuda Y, Osamura RY (2005) Estrogen receptor-negative and human epidermal growth factor receptor 2-negative breast cancer tissue have the highest Ki-67 labeling index and EGFR expression: gene amplification does not contribute to EGFR expression. Oncol Rep 14(2):337–343PubMedGoogle Scholar
- 27.Willipinski-Stapelfeldt B, Riethdorf S, Assmann V, Woelfle U, Rau T, Sauter G, Heukeshoven J, Pantel K (2005) Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin Cancer Res 11(22):8006–8014PubMedCrossRefGoogle Scholar
- 34.Kelley RF, Totpal K, Lindstrom SH, Mathieu M, Billeci K, Deforge L, Pai R, Hymowitz SG, Ashkenazi A (2005) Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling. J Biol Chem 280(3):2205–2212PubMedCrossRefGoogle Scholar