Downregulated Copper Homeostasis-Related Gene FOXO1 as a Novel Indicator for the Prognosis and Immune Response of Breast Cancer

Abstract

Copper (Cu) is one of the essential microelements for all living systems. Studies have illustrated the biological significance of Cu homeostasis in human cancers, including breast cancer (BRCA). Nevertheless, the detailed roles of Cu homeostasis in BRCA need to be further explored. Here, we identified a downregulated Cu homeostasis-related gene FOXO1 and investigated the potential functions of FOXO1 in BRCA through several bioinformation databases. The BRCA patients with high level of FOXO1 displayed favorable prognostic values. Subsequently, enrichment analysis of FOXO1 coexpressed genes revealed that the top three enriched KEGG pathways were spliceosome, oxidative phosphorylation, and ribosome. Immunoinfiltration analysis indicated that aberrantly expressed FOXO1 showed positive correlations with the subcellular infiltration of macrophages and neutrophils in BRCA. Moreover, FOXO1 expression was positively associated with multiple immune checkpoints, such as sialic acid-binding immunoglobulin-like lectin 15 (SIGLEC15), indoleamine 2,3-dioxygenase 1 (IDO1), programmed cell death 1 ligand 1 (PD-L1/CD274), hepatitis A virus cellular receptor 2 (HAVCR2), programmed cell death 1 (PDCD1), cytotoxic T lymphocyte antigen 4 (CTLA4), and programmed cell death 1 ligand 2 (PDCD1LG2). Overall, these findings would deepen our understanding of FOXO1 in BRCA prognosis and immunotherapy response, representing a promising therapeutic strategy for BRCA patients.

A novel defined risk signature of cuproptosis-related long non-coding RNA for predicting prognosis, immune infiltration, and immunotherapy response in lung adenocarcinoma

“…Interestingly, Voli and colleagues stated a strong correlation between PD-L1 expression and intracellular copper levels, noting that copper dysregulators inhibit PD-L1 in vitro and in vivo , resulting in increased tumor-infiltrating lymphocytes ( Voli et al, 2018 ). In a recent study, Zeng demonstrated that FOXO1, a gene significantly associated with PDCD1, downregulated copper homeostasis is a novel indicator of breast cancer prognosis and immune response ( Zeng et al, 2022 ). The TIDE database related analysis confirmed the above points of our view.…”

Hsa_circ_0007823 Overexpression Suppresses the Progression of Triple-Negative Breast Cancer via Regulating miR-182-5p-FOXO1 Axis

“… 44 A study of Zeng et al reported that FOXO1 was associated with immune cell infiltration, immune checkpoint expression, and response to immunotherapy in breast cancer. 45 It has been found that FOXO1 expression was also responsible for stemness and sensitivity of breast cancer cells to chemotherapeutic agents, such as tamoxifen and paclitaxel. 46 , 47 Combined with our results, it can be inferred that hsa_circ_0007823 overexpression may inhibit the progression of TNBC through regulating the miR-182-5p/FOXO1 axis.…”

Cuproptosis: emerging biomarkers and potential therapeutics in cancers

“…Cells relying on glycolysis are around 1000 times more sensitive to copper ion inducers than cells depending on mitochondrial respiration. Conversely, ferredoxin 1 (FDX1) lowers CU2+ to CU+, encouraging lipoylation and aggregation of enzymes responsible for controlling the mitochondrial TCA cycle (63). On the other hand, FDX1 results in the instability of iron-sulfur proteins (Fe-S), which sets off a stress response in the mitochondria and produces cuproptosis (64).…”