Contribution of Immune Cells to Glucocorticoid Receptor Expression in Breast Cancer

• Main Authors: Shipra Gandhi, Ahmed Elkhanany, Masanori Oshi, Tao Dai, Mateusz Opyrchal, Hemn Mohammadpour, Elizabeth A. Repasky, Kazuaki Takabe
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: International Journal of Molecular Sciences
• Subjects: glucocorticoid receptor; breast cancer; NR3C1; immune cells; TCGA; METABRIC
• Online Access: https://www.mdpi.com/1422-0067/21/13/4635
• ISSN: 1661-6596; 1422-0067

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 (<i>NR3C1)</i>. 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.<i> </i>To test this,<i> </i>mRNA expression data was accessed from METABRIC and TCGA. “High” and “low” expression was based on highest and lowest quartiles of <i>NR3C1</i> 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.