TSC22D1 and PSAP predict clinical outcome of tamoxifen treatment in patients with recurrent breast cancer
TSC22D1 and PSAP predict clinical outcome of tamoxifen treatment in patients with recurrent breast cancer
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DOI：
10.1007/s10549-008-9934-3
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发表时间：
2009-01-01
影响因子：
3.8
通讯作者：
Berns, Els M. J. J.
中科院分区：
文献类型：
--
作者：
Meijer, Danielle;Jansen, Maurice P. H. M.;Berns, Els M. J. J.
目的在体外功能筛选中鉴定TSC22结构域家族成员1(TSC22D1)和丙皂苷(PSAP)两个基因，以寻找与他莫昔芬耐药相关的基因。这些基因也出现在我们之前建立的对三苯氧胺一线治疗耐药的81个基因签名中。本研究的目的是探讨这些基因对复发乳腺癌患者他莫昔芬治疗失败的预测价值。实验设计采用实时定量聚合酶链式反应(qRT-PCR)检测223例雌激素受体阳性的复发性乳腺肿瘤患者中TSC22D1和PSAP的mRNA水平。这项研究的主要目标是无进展生存期(PFS)。结果TSC22D1mRNA和PSAPmRNA的高表达与PFS显著相关(HR=1.3，95%CI=1.04~1.64P=0.023；HR=1.40，95%CI=1.03~1.88，P=0.029)。多因素分析显示，两种基因表达水平高的患者无临床益处(OR=0.19，95%CI=0.06~0.62，P=0.006)，PFS最短(HR=2.05，95%CI=1.29~3.25，P=0.002)。结论这些结果证实了我们先前的体外和与肿瘤相关的发现，并表明他莫昔芬治疗乳腺癌患者失败。TSC22D1和PSAP均与临床结局相关，并可能在治疗耐药中发挥作用。
Purpose Two genes, TSC22 domain family, member 1 (TSC22D1) and prosaposin (PSAP) were identified in an in vitro functional screen for genes having a causative role in tamoxifen resistance. These genes were also present in our previously established 81-gene signature for resistance to first-line tamoxifen therapy. The aim of this study was to investigate the predictive value of these genes for tamoxifen therapy failure in patients with recurrent breast cancer. Experimental Design The mRNA levels of TSC22D1 and PSAP were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in 223 estrogen receptor-positive primary breast tumors of patients with recurrent disease treated with first-line tamoxifen therapy. The main objective of this study was the length of progression-free survival (PFS). Results High mRNA levels of TSC22D1 and PSAP were significantly associated with shorter PFS and both were independent of the traditional predictive factors (HR = 1.30, 95% CI = 1.04-1.64 P = 0.023; and HR = 1.40, 95% CI = 1.03-1.88, P = 0.029, respectively). In multivariate analysis, patients with high mRNA levels of both genes associated significantly with no clinical benefit (OR = 0.19, 95% CI = 0.06-0.62, P = 0.006) and had the shortest PFS (HR = 2.05, 95% CI = 1.29-3.25, P = 0.002). Conclusion These results confirm our previous in vitro and tumor-related findings and are indicative for the failure of tamoxifen treatment in breast-cancer patients. Both TSC22D1 and PSAP are associated with clinical outcome and may have a functional role in therapy resistance.