Abstract
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.
Highlights
Often ignored and under-appreciated, breast cancer patients suffer from potentially debilitating stress, anxiety, depression, and impaired cognitive function [1,2]
Our study showed that CD8+ T cells have higher glucocorticoid receptor (GR) expression, we did not see any difference in their distribution between GR-high and GR-low breast cancer
Our study shows that GR-high tumors have favorable outcomes, mostly in estrogen receptor (ER) positive breast cancer subtype, which is consistent with previous results
Summary
Often ignored and under-appreciated, breast cancer patients suffer from potentially debilitating stress, anxiety, depression, and impaired cognitive function [1,2]. Stress has been demonstrated to result in an increased incidence of cancer recurrence [3]. Breast cancer patients with no stressful or traumatic life events have significantly longer disease-free intervals compared to patients who have experienced these events [3]. Stress activates the hypothalamic–pituitary–adrenal axis with corticotropin-releasing factor produced in the hypothalamus, which stimulates the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. ACTH signals the adrenal cortex to produce glucocorticoids—the stress hormone ‘cortisol’ secreted by the zona fasciculata of the adrenal glands. Cortisol generates physical response to stress by binding to its cytoplasmic receptor, glucocorticoid receptor (GR), which is the transcription factor encoded by the NR3C1 gene [5], promoting “stress response” [6,7]
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