Contribution of Immune Cells to Glucocorticoid Receptor Expression in Breast Cancer

Abstract

<jats:p>Breast cancer (BC) patients experience increased stress with elevated cortisol levels, increasing risk of cancer recurrence. Cortisol binds to a cytoplasmic receptor, glucocorticoid receptor (GR) encoded by GR gene (NR3C1). We hypothesized that not only cancer cells, but even immune cells in the tumor microenvironment (TME) may contribute to GR expression in bulk tumor and influence prognosis. To test this, mRNA expression data was accessed from METABRIC and TCGA. “High” and “low” expression was based on highest and lowest quartiles of NR3C1 gene expression, respectively. Single-cell sequencing data were obtained from GSE75688 and GSE114725 cohorts. Computer algorithms CIBERSORT, Gene Set Enrichment Analysis and TIMER were used. GR-high BC has better median disease-free and disease-specific survival. Single cell sequencing data showed higher GR expression on immune cells compared to cancer and stromal cells. Positive correlation between GR-high BC and CD8+ T-cells was noted. In GR-high tumors, higher cytolytic activity (CYT) with decreased T-regulatory and T-follicular helper cells was observed. High GR expression was associated with lower proliferation index Ki67, enriched in IL-2_STAT5, apoptosis, KRAS, TGF-β signaling, and epithelial-to-mesenchymal transition. Immune cells significantly contribute to GR expression of bulk BC. GR-high BC has a favorable TME with higher CYT with favorable outcomes.</jats:p>

Abundance of Regulatory T Cell (Treg) as a Predictive Biomarker for Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

“…Gene set enrichment analysis were performed with Gene Set Enrichment Analyses (GSEA) software (Java version 4.0) [ 71 , 72 ] with MSigDB Hallmark gene sets [ 73 ]. Statistical significance was set with a false discovery rate (FDR) of 0.25, as recommended by the GSEA software and as we previously reported [ 66 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ].…”

High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

“…Transcriptomic profiling and clinical information of the TCGA pancreatic cancer (TCGA_PAAD) was downloaded from the Genomic Data Commons Data Portal (GDC). To date, we have published a number of reports that elucidated the clinical relevance of microRNA expressions [ 54 , 55 , 56 ] and gene expressions [ 37 , 38 , 39 , 57 , 58 ], and the underlying biology of pathological findings [ 59 , 60 , 61 , 62 , 63 , 64 ]. To maximize the number of pancreatic cancer samples to have the strongest power for statistical analyses, data of 176 patients who had pathological diagnosis of pancreatic cancer were included in the study.…”

“…The average value was used for genes with multiple probes. Gene expression data, which were transformed for log 2 , were used in all analyses as we have previously reported [ 6 , 17 , 36 , 58 , 66 ]. We used published data of Hussain et al (GSE62452; tumor sample; n = 69, adjusted pancreases sample; n = 61) [ 67 ], Chen et al (GSE57495; n = 63) [ 68 ], and Bocklandt et al (GSE28746; tumor sample; n = 45, adjusted pancreases sample; n = 45) [ 69 ] to investigate the association of the G2M pathway scores with patient survival.…”

ITPKC as a Prognostic and Predictive Biomarker of Neoadjuvant Chemotherapy for Triple Negative Breast Cancer

“…In order to identify which cells express ITPKC within a bulk breast cancer tumor, we analyzed ITPKC expression in tumor cells, B cells, stromal cells, myeloid cells and T cells using single-cell sequencing data of primary breast cancer (GSE75688) utilizing the same method we previously reported [ 36 ]. As shown in Figure 1 , ITPKC was significantly expressed higher in breast cancer cells compared with stroma or immune cells.…”

“…These cohorts were chosen because they have clinical response data after neoadjuvant chemotherapy that TCGA lacks. Gene expression levels in the TCGA, such as ITPKC , were directly obtained from the cBio Portal, and the average of the gene expression levels was used when there were multiple probes for a single gene in the gene expression microarray, which was transformed to log2 for analyses as we previously described [ 36 , 51 ]. In terms of survival data, overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) were available in the TCGA, and DFS was available in the GSE25066 cohort.…”