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

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.MethodsThe 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.ResultsDC-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).ConclusionDC-SCRIPT is a key regulator of nuclear receptor activity that has prognostic value in breast cancer.