DC-SCRIPT: Nuclear Receptor Modulation and Prognostic Significance in Primary Breast Cancer

• Published in: JNCI : Journal of the National Cancer Institute Vol. 102; no. 1; pp. 54 - 68
• Main Authors: Ansems, M., Hontelez, S., Looman, M. W. G., Karthaus, N., Bult, P., Bonenkamp, J. J., Jansen, J. H., Sweep, F. C. G. J., Span, P. N., Adema, Gosse J.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 06.01.2010; Oxford Publishing Limited (England)
• Subjects: Analysis of Variance; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; Clinical trials; Disease-Free Survival; DNA, Complementary - metabolism; Female; Humans; Immunohistochemistry; Immunoprecipitation; Medical prognosis; Polymerase Chain Reaction; PPAR gamma - metabolism; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Receptors, Retinoic Acid - metabolism; Retinoic Acid Receptor alpha; Retinoid X Receptor alpha - metabolism; RNA, Messenger - metabolism; Studies; Transcription, Genetic
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djp441

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.