DC-SCRIPT：原发性乳腺癌中的核受体调节及其预后意义。

DC-SCRIPT: nuclear receptor modulation and prognostic significance in primary breast cancer.

机构信息

Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

出版信息

J Natl Cancer Inst. 2010 Jan 6;102(1):54-68. doi: 10.1093/jnci/djp441. Epub 2009 Dec 14.

DOI:10.1093/jnci/djp441

PMID:20008677

Abstract

BACKGROUND

Nuclear receptors, including estrogen receptor (ER), progesterone receptor (PR)-B, peroxisome proliferator-activated receptor gamma, and retinoic acid receptor alpha, have been implicated in breast cancer etiology and progression. We investigated the role of dendritic cell-specific transcript (DC-SCRIPT) as coregulator of these nuclear receptors and as a prognostic factor in breast cancer.

METHODS

The effect of DC-SCRIPT on the transcriptional activity of nuclear receptors was assessed by luciferase reporter assays. DC-SCRIPT expression in normal and tumor tissue from breast cancer patients was analyzed by polymerase chain reaction and immunohistochemistry. The prognostic value of tumor DC-SCRIPT mRNA expression was assessed in three independent cohorts of breast cancer patients: a discovery group (n = 47) and a validation group (n = 97) (neither of which had received systemic adjuvant therapy) and in a tamoxifen-treated validation group (n = 68) by using a DC-SCRIPT to porphobilinogen deaminase transcript ratio cutoff of 0.15 determined in the discovery group. Univariate and multivariable Cox proportional hazards model analyses were performed. All statistical tests were two-sided.

RESULTS

DC-SCRIPT suppressed ER- and PR-mediated transcription in a ligand-dependent fashion, whereas it enhanced the retinoic acid receptor alpha- and peroxisome proliferator-activated receptor gamma-mediated transcription. In breast tissue samples from nine patients, DC-SCRIPT mRNA was expressed at lower levels in the tumor than in the corresponding normal tissue (P = .010). Patients in the discovery group with high tumor DC-SCRIPT mRNA levels (66%) had a longer disease-free interval than those with a low DC-SCRIPT mRNA level (34%) (hazard ratio [HR] of recurrence for high vs low DC-SCRIPT level = 0.23, 95% confidence interval [CI] = 0.06 to 0.93, P = .039), which was confirmed in the validation group (HR of recurrence = 0.50, 95% CI = 0.26 to 0.95, P = .034). This prognostic value was confined to patients with ER- and/or PR-positive tumors (discovery group: HR of recurrence = 0.16, 95% CI = 0.03 to 0.89, P = .030; validation group: HR of recurrence = 0.42, 95% CI = 0.19 to 0.91, P = .028) and was also observed in the second validation group (HR = 0.46, 95% CI = 0.22 to 0.97, P = .040). DC-SCRIPT was an independent prognostic factor after correction for tumor size, lymph node status, and adjuvant therapy (n = 145; HR = 0.50, 95% CI = 0.29 to 0.85, P = .010).

CONCLUSION

DC-SCRIPT is a key regulator of nuclear receptor activity that has prognostic value in breast cancer.

摘要

背景

核受体，包括雌激素受体（ER）、孕激素受体（PR）-B、过氧化物酶体增殖物激活受体γ和视黄酸受体α，与乳腺癌的病因和进展有关。我们研究了树突状细胞特异性转录物（DC-SCRIPT）作为这些核受体的共调节剂以及作为乳腺癌预后因素的作用。

方法

通过荧光素酶报告基因检测评估 DC-SCRIPT 对核受体转录活性的影响。通过聚合酶链反应和免疫组织化学分析乳腺癌患者正常和肿瘤组织中的 DC-SCRIPT 表达。使用在发现组中确定的 DC-SCRIPT 与原卟啉原脱氨酶转录物比的 0.15 截止值，在三个独立的乳腺癌患者队列中评估肿瘤 DC-SCRIPT mRNA 表达的预后价值：发现组（n=47）和验证组（n=97）（均未接受系统辅助治疗）和接受他莫昔芬治疗的验证组（n=68）。进行单变量和多变量 Cox 比例风险模型分析。所有统计检验均为双侧。

结果

DC-SCRIPT 以配体依赖性方式抑制 ER 和 PR 介导的转录，而增强视黄酸受体α和过氧化物酶体增殖物激活受体γ介导的转录。在 9 名患者的乳腺组织样本中，肿瘤中 DC-SCRIPT mRNA 的表达水平低于相应的正常组织（P=0.010）。发现组中 DC-SCRIPT mRNA 水平较高的患者（66%）无病间隔时间长于 DC-SCRIPT mRNA 水平较低的患者（34%）（高 DC-SCRIPT 水平与低 DC-SCRIPT 水平相比复发的 HR=0.23，95%CI=0.06 至 0.93，P=0.039），这在验证组中得到了证实（复发的 HR=0.50，95%CI=0.26 至 0.95，P=0.034）。该预后价值仅限于 ER 和/或 PR 阳性肿瘤患者（发现组：复发的 HR=0.16，95%CI=0.03 至 0.89，P=0.030；验证组：复发的 HR=0.42，95%CI=0.19 至 0.91，P=0.028），并且在第二个验证组中也观察到（HR=0.46，95%CI=0.22 至 0.97，P=0.040）。在纠正肿瘤大小、淋巴结状态和辅助治疗后（n=145），DC-SCRIPT 是独立的预后因素（HR=0.50，95%CI=0.29 至 0.85，P=0.010）。