Rahman Monzur, Davis Sean R, Pumphrey Janet G, Bao Jing, Nau Marion M, Meltzer Paul S, Lipkowitz Stanley
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Blg 37, Room 2066, 37 Convent Drive, Bethesda, MD 20892-4256, USA.
Breast Cancer Res Treat. 2009 Jan;113(2):217-30. doi: 10.1007/s10549-008-9924-5. Epub 2008 Feb 12.
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.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可诱导部分而非全部乳腺癌细胞系发生凋亡。乳腺癌可分为表达雌激素（ER）和孕激素（PR）受体的类型、HER-2基因扩增的类型以及不表达ER、PR或HER-2基因扩增的类型（称为基底样或三阴性乳腺癌）。我们检测了一组代表不同类型乳腺癌的20种乳腺癌细胞系，以评估乳腺癌细胞的分子表型是否决定其对TRAIL的反应。最显著的发现是，11种三阴性细胞系中有8种对TRAIL介导的凋亡敏感。8种对TRAIL敏感的三阴性细胞系具有间充质表型，而3种对TRAIL耐药的三阴性细胞系具有上皮表型。5种HER-2基因扩增的细胞系中有2种对TRAIL敏感，而5种ER阳性细胞系均不敏感。RNA干扰介导降低TRAIL受体表达表明，即使TRAIL-R1和TRAIL-R2均表达，TRAIL受体2（TRAIL-R2）也介导TRAIL的作用。最后，使用小分子酪氨酸激酶抑制剂（AG1478）抑制TRAIL敏感和TRAIL耐药的三阴性乳腺癌细胞系中均表达的表皮生长因子受体（EGFR），可增强TRAIL敏感细胞系中TRAIL诱导的凋亡，但不能将耐药细胞转化为对TRAIL敏感的细胞。总之，这些发现表明，具有间充质特征的三阴性乳腺癌亚群可能最有可能从TRAIL靶向治疗中获益。这些发现可为选择乳腺癌患者进行TRAIL-R2配体的临床试验奠定基础。
