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Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.

ABSTRACT: To identify biologically relevant groupings or clusters of nuclear receptors (NR) that are associated with breast neoplasia, with potentially diagnostic, discriminant or prognostic value, we quantitated mRNA expression levels of all 48 members of the human NR superfamily by TaqMan low-density array analysis in 116 curated breast tissue samples, including pre- and postmenopausal normal breast and both ERα(+) and ERα(-) tumor tissue. In addition, we have determined NR levels in independent cohorts of tamoxifen-treated ERα(+) and ERα(-) tissue samples. There were differences in relative NR mRNA expression between neoplastic and normal breast, and between ER(+) and ER(-) tumors. First, there is overexpression of the NUR77 subgroup and EAR2 in neoplastic breast. Second, we identify a signature of five NR (ERα, EAR2, NUR77, TRα, and RARγ) that classifies breast samples with more than 97% cross-validated accuracy into normal or cancer classes. Third, we find a novel negative association between five NR (TRβ, NUR77, RORγ, COUP-TFII, and LRH1) and histological grade. Finally, four NR (COUP-TFII, TRβ, PPARγ, and MR) are significant predictors of metastasis-free survival in tamoxifen-treated breast cancers, independent of ER expression. The present study highlights the discriminant and prognostic value of NR in breast cancer; identifies novel, clinically relevant, NR signatures; and highlights NR signaling pathways with potential roles in breast cancer pathophysiology and as new therapeutic targets.

SUBMITTER: Muscat GE

PROVIDER: S-EPMC5417325 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.

Muscat George E O GE Eriksson Natalie A NA Byth Karen K Loi Sherene S Graham Dinny D Jindal Shalini S Davis Melissa J MJ Clyne Colin C Funder John W JW Simpson Evan R ER Ragan Mark A MA Kuczek Elizabeth E Fuller Peter J PJ Tilley Wayne D WD Leedman Peter J PJ Clarke Christine L CL

Molecular endocrinology (Baltimore, Md.) 20130104 2

To identify biologically relevant groupings or clusters of nuclear receptors (NR) that are associated with breast neoplasia, with potentially diagnostic, discriminant or prognostic value, we quantitated mRNA expression levels of all 48 members of the human NR superfamily by TaqMan low-density array analysis in 116 curated breast tissue samples, including pre- and postmenopausal normal breast and both ERα(+) and ERα(-) tumor tissue. In addition, we have determined NR levels in independent cohorts ...[more]

PMID: 23292282

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Project description:BackgroundThe concept of individualized therapy has advanced the development of prognostic biomarkers to manage patients with breast cancer (BRCA). Immunotherapy has shown great potential in treating BRCA, and the C-X-C motif chemokine receptor (CXCR) has generated interest in regulating tumor progression through the immune microenvironment. Although CXCRs were utilized for prognosis prediction in glioma with favourable capability, the prognostic and therapeutic role of CXCR in BRCA is unclear.MethodsWe used The Cancer Genome Atlas (TCGA) database to analyze 1,095 BRCA patients' transcription, mutation, survival time and survival status. Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE), Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), quanTIseq, and Estimating the Proportion of Immune and Cancer cells (EPIC) algorithms were performed to infer the association of CXCR genes with immune cells. We randomly divided the TCGA dataset into a training set and a validation set according to 1:1, constructed a LASSO Cox regression model based on CXCR family genes using the glmnet R package in the training set, assembled clinical variables to draw a visual Nomogram using the R package rms, and validated the model by receiver operating characteristic (ROC) curves, calibration curves with clinical decision curves in the validation set efficacy.ResultsCompared to normal samples, CXCR3/4/5 messenger RNA (mRNA) expression levels were upregulated in BRCA samples, whereas CXCR1/2 mRNA expression levels were downregulated. High CXCR3/5/6 expression was associated with a good prognosis. Subsequently, we divided the CXCRs into 2 molecular subgroups based on their expression patterns and explored prognosis, immune infiltration, functional enrichment, hallmarks, and immune response differentiation between the two subgroups. After LASSO Cox regression modeling, a CXCR score predicting overall survival (OS) was constructed, and the predictive accuracy was assessed. By pooling clinical variables, a nomogram individual risk assessment method was established to measure the identification of genuinely high-risk patients who should receive interventions.ConclusionsIn summary, CXCR genes were associated with immune infiltration and survival in BRCA patients, and our CXCR-based prognostic model could better predict the prognosis of BRCA patients and provide potential immunotherapy targets for clinical purposes.

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Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.

Publications

Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.

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