Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer
Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer
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DOI：
10.1007/s00109-009-0510-z
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发表时间：
2009-10-01
影响因子：
4.7
通讯作者：
Walczak, Henning
中科院分区：
文献类型：
--
作者：
Ganten, Tom M.;Sykora, Jaromir;Walczak, Henning
肿瘤坏死因子相关凋亡诱导配体（TRAIL）在与TRAIL受体1和2（TRAIL-R1/DR 4和TRAIL-R2/DR 5）结合后诱导凋亡。TRAIL-R3（DcR 1）和TRAIL-R4（DcR 2）没有或只有截短的胞质死亡结构域。因此，它们不能诱导细胞凋亡，而是已经提出抑制TRAIL诱导的细胞凋亡。目前正在临床试验中测试诱导凋亡的TRAIL-R1和TRAIL-R2的激动剂。为了确定所有表面结合的TRAIL受体的表达模式及其预后临床价值，我们通过免疫组化研究了311例乳腺癌患者的肿瘤样本。TRAIL受体表达谱与临床病理数据、无病生存期和总生存期相关。TRAIL-R1在分化较好的肿瘤中表达更强，与预后较好的替代标志物（激素受体状态，Bcl-2，阴性淋巴结状态）呈正相关，但与Her 2/neu和增殖标志物Ki 67的表达呈负相关。相反，TRAIL-R2和TRAIL-R4表达与较高的肿瘤分级、较高的Ki 67指数、较高的Her 2/neu表达和诊断时的阳性淋巴结状态相关，但与较低的Bcl-2表达相关。因此，TRAIL受体的表达模式是预测淋巴结状态。具有TRAIL-R2但没有TRAIL-R1的1级和2级肿瘤患者在47%的病例中显示出阳性淋巴结状态。反之亦然，只有19%的患者具有高TRAIL-R1但低TRAIL-R2的阳性淋巴结状态。最引人注目的是，TRAIL-R4和TRAIL-R2表达与乳腺癌患者的总生存率呈负相关。尽管TRAIL-R2与更具侵袭性的肿瘤行为相关，但乳腺癌可能对TRAIL-R2诱导的细胞凋亡敏感，这表明TRAIL-R2可能因此用于治疗靶向此类肿瘤。因此，TRAIL受体表达谱的测定可能有助于确定哪些乳腺癌患者具有较高的淋巴结转移风险和较差的总体生存率，另一方面将有助于指导基于TRAIL的肿瘤治疗。
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis upon binding to TRAIL receptors 1 and 2 (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) have no or only a truncated cytoplasmic death domain. Consequently, they cannot induce apoptosis and instead have been proposed to inhibit apoptosis induction by TRAIL. Agonists for the apoptosis-inducing TRAIL-R1 and TRAIL-R2 are currently tested in clinical trials. To determine the expression pattern of all surface-bound TRAIL receptors and their prognostic clinical value, we investigated tumour samples of 311 patients with breast cancer by immunohistochemistry. TRAIL receptor expression profiles were correlated with clinico-pathological data, disease-free survival and overall survival. TRAIL-R1 was more strongly expressed in better differentiated tumours, and correlated positively with surrogate markers of a better prognosis (hormone receptor status, Bcl-2, negative nodal status), but negatively with the expression of Her2/neu and the proliferation marker Ki67. In contrast, TRAIL-R2 and TRAIL-R4 expression correlated with higher tumour grades, higher Ki67 index, higher Her2/neu expression and a positive nodal status at the time of diagnosis, but with lower expression of Bcl-2. Thus, the TRAIL receptor expression pattern was predictive of nodal status. Patients with grade 1 and 2 tumours, who had TRAIL-R2 but no TRAIL-R1, showed a positive lymph node status in 47% of the cases. Vice versa, only 19% had a positive nodal status with high TRAIL-R1 but low TRAIL-R2. Most strikingly, TRAIL-R4 and -R2 expression negatively correlated with overall survival of breast cancer patients. Although TRAIL-R2 correlated with more aggressive tumour behaviour, mammary carcinoma could be sensitised to TRAIL-R2-induced apoptosis, suggesting that TRAIL-R2 might therefore be used to therapeutically target such tumours. Hence, determination of the TRAIL receptor expression profile may aid in defining which breast cancer patients have a higher risk of lymph node metastasis and worse overall survival and on the other hand will help to guide TRAIL-based tumour therapy.