NR2F1, a Tumor Dormancy Marker, Is Expressed Predominantly in Cancer-Associated Fibroblasts and Is Associated with Suppressed Breast Cancer Cell Proliferation

Abstract

Background: Tumor dormancy is a crucial mechanism responsible for the late recurrence of breast cancer. Thus, we investigated the clinical relevance of the expression of NR2F1, a known dormancy biomarker. Methods: A total of 6758 transcriptomes of bulk tumors from multiple breast cancer patient cohorts and two single-cell sequence cohorts were analyzed. Results: Breast cancer (BC) with high NR2F1 expression enriched TGFβ signaling, multiple metastases, and stem cell-related pathways. Cell proliferation-related gene sets were suppressed, and MKi67 expression was lower in high NR2F1 BC. In tumors with high Nottingham grade, NR2F1 expression was found to be lower. There was no consistent relationship between NR2F1 expression and metastasis or survival. Cancer mutation rates, immune responses, and immune cell infiltrations were lower in high NR2F1 tumors, whereas the infiltration of stromal cells including cancer-associated fibroblasts (CAFs) was higher. NR2F1 was predominantly expressed in CAFs, particularly inflammatory CAFs, rather than in cancer cells, consistently in the two single-cell sequence cohorts. Conclusions: NR2F1 expression in breast cancer is associated with tumor dormancy traits, and it is predominantly expressed in CAFs in the tumor microenvironment.

Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution

“…Despite significant advances made in the molecular mechanisms of quiescence, a specific marker that can be used routinely to identify the existence of QCCs is still missing. NR2F1 has been proposed as a marker to identify dormant DTCs in the bone marrow of breast cancer patients [51], but it was recently shown to be expressed also in cancer-associated fibroblasts in primary tumors [52]. In colorectal cancer, we have consistently observed QCCs with a ZEB2 + /Ki67 − phenotype in untreated and chemotherapy-treated xenografts.…”

Intestinal fibrosis in aganglionic segment of Hirschsprung's disease revealed by single‐cell RNA sequencing

“… 52 In addition, NR2F1 protein is a known tumour dormancy marker in cancer‐associated fibroblasts. 53 …”

“…It is worth noting that transcription factor NR2F1 protein is involved in regulating ECM expression and tissue fibrosis in silicosis 52 . In addition, NR2F1 protein is a known tumour dormancy marker in cancer‐associated fibroblasts 53 …”

“…Transcription factor NR2F1 protein was involved in regulating ECM expression and tissue fibrosis in silicosis—a form of pulmonary fibrosis. 52 Besides, NR2F1 protein is a known tumour dormancy marker that promotes quiescence of various cancer cells, predominantly expressed in cancer‐associated fibroblasts, 53 suggesting that it may intervene in the ENCC migration.…”

“…52 In addition, NR2F1 protein is a known tumour dormancy marker in cancer-associated fibroblasts. 53 The abnormal expression of fibrosis-related regulatory factors and transcription factors in ECM-related stromal cells indicate that there is a fibrotic phenotype in the HSCR segments, especially in the aganglionic segments. These factors may be involved in the regulation of intestinal fibrosis.…”