TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype
TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype
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DOI：
10.1007/s10549-008-9924-5
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发表时间：
2009-01-01
影响因子：
3.8
通讯作者：
Lipkowitz, Stanley
中科院分区：
文献类型：
--
作者：
Rahman, Monzur;Davis, Sean R.;Lipkowitz, Stanley
肿瘤坏死因子相关细胞凋亡诱导配体（TRAIL）在部分但非所有乳腺癌细胞系中诱导细胞凋亡。乳腺癌可分为表达雌激素（ER）和孕激素（PR）受体的乳腺癌、具有HER-2扩增的乳腺癌和不表达ER、PR或HER-2扩增的乳腺癌（称为基底或三阴性乳腺癌）。我们测试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了它们对TRAIL的反应。最引人注目的发现是，11个三阴性细胞系中有8个对TRAIL介导的凋亡敏感。八种TRAIL敏感的三阴性细胞系具有间充质表型，而三种TRAIL抗性的三阴性细胞系具有上皮表型。HER-2扩增的5个细胞系中有2个对TRAIL敏感，5个ER阳性细胞系均不敏感。RNAi介导的TRAIL受体表达的敲低表明，TRAIL受体2（TRAIL-R2）介导TRAIL的作用，即使当TRAIL-R1和TRAIL-R2都表达时。最后，使用小分子酪氨酸激酶抑制剂（AG 1478）抑制EGFR（其在TRAIL敏感性和TRAIL抗性三阴性乳腺癌细胞系中表达）增强了TRAIL敏感性细胞系中的TRAIL诱导的凋亡，但没有将抗性细胞转化为TRAIL敏感性细胞。总之，这些发现表明，一个三阴性乳腺癌的子集，那些具有间充质特征的，可能是最有可能受益于TRAIL靶向治疗。这些发现可以为选择乳腺癌患者进行TRAIL-R2配体的临床试验奠定基础。
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.