A Novel Peroxisome-Related Gene Signature Predicts Breast Cancer Prognosis and Correlates with T Cell Suppression

Overview

Journal Breast Cancer (Dove Med Press)

Publisher Dove Medical Press

Date 2024 Dec 16

PMID 39678026

Authors

Yunxiang Wang

Sheng Xu

Junfeng Liu

Pan Qi

Affiliations

Soon will be listed here.

Abstract

Background: Peroxisomes are increasingly linked to cancer development, yet the prognostic role of peroxisome-related genes (PRGs) in breast cancer remains unclear.

Objective: This study aimed to construct a prognostic model based on PRG expression in breast cancer to clarify their prognostic value and clinical implications.

Methods: Transcriptomic data from TCGA and GEO were used for training and validation cohorts. TME characteristics were analyzed with ESTIMATE, MCP-counter, and CIBERSORT algorithms. qPCR validated mRNA expression levels of risk genes, and data analysis was conducted in R.

Results: Univariate and multivariate Cox regression identified a 7-gene PRG risk signature (ACBD5, ACSL5, DAO, NOS2, PEX3, PEX10, and SLC27A2) predicting breast cancer prognosis in training (n=1069), internal validation (n=327), and external validation (merged from four GEO datasets, n=640) datasets. While basal and Her2 subtypes had higher risk scores than luminal subtypes, a significant prognostic impact of the PRG risk signature was seen only in luminal subtypes. The high-risk subgroup exhibited a higher frequency of focal synonymous copy number alterations (SCNAs), arm-level amplifications and deletions, and single nucleotide variations. These increased genomic aberrations were associated with greater immune suppression and reduced CD8+ T cell infiltration. Bulk RNA sequencing and single-cell analyses revealed distinct expression patterns of peroxisome-related genes (PRGs) in the breast cancer TME: PEX3 was primarily expressed in malignant and stromal cells, while ACSL5 showed high expression in T cells. Additionally, the PRG risk signature demonstrated efficacy comparable to that of well-known biomarkers for predicting immunotherapy responses. Drug sensitivity analysis revealed that the PRG high-risk subgroup was sensitive to inhibitors of BCL-2 family proteins (BCL-2, BCL-XL, and MCL1) and other kinases (PLK1, PLK1, BTK, CHDK1, and EGFR).

Conclusion: The PRG risk signature serves as a promising biomarker for evaluating peroxisomal activity, prognosis, and responsiveness to immunotherapy in breast cancer.

References

Ma W, Li T, Wu S, Li J, Wang X, Li H . LOX and ACSL5 as potential relapse markers for pancreatic cancer patients. Cancer Biol Ther. 2019; 20(6):787-798. PMC: 6605990. DOI: 10.1080/15384047.2018.1564565. View

Liu C, Hu F, Xie G, Miao Y, Li X, Zeng Y . GSCA: an integrated platform for gene set cancer analysis at genomic, pharmacogenomic and immunogenomic levels. Brief Bioinform. 2022; 24(1). DOI: 10.1093/bib/bbac558. View

Mermel C, Schumacher S, Hill B, Meyerson M, Beroukhim R, Getz G . GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011; 12(4):R41. PMC: 3218867. DOI: 10.1186/gb-2011-12-4-r41. View

Porporato P, Filigheddu N, Bravo-San Pedro J, Kroemer G, Galluzzi L . Mitochondrial metabolism and cancer. Cell Res. 2017; 28(3):265-280. PMC: 5835768. DOI: 10.1038/cr.2017.155. View

Pearce E, Walsh M, Cejas P, Harms G, Shen H, Wang L . Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009; 460(7251):103-7. PMC: 2803086. DOI: 10.1038/nature08097. View

Benjamin D, Cozzo A, Ji X, Roberts L, Louie S, Mulvihill M . Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity. Proc Natl Acad Sci U S A. 2013; 110(37):14912-7. PMC: 3773741. DOI: 10.1073/pnas.1310894110. View

Zhang J, Tripathi D, Jing J, Alexander A, Kim J, Powell R . ATM functions at the peroxisome to induce pexophagy in response to ROS. Nat Cell Biol. 2015; 17(10):1259-1269. PMC: 4589490. DOI: 10.1038/ncb3230. View

Zhang Q, Zhou W, Yu S, Ju Y, To S, Wong A . Metabolic reprogramming of ovarian cancer involves ACSL1-mediated metastasis stimulation through upregulated protein myristoylation. Oncogene. 2020; 40(1):97-111. DOI: 10.1038/s41388-020-01516-4. View

Jansen R, Santana-Molina C, van den Noort M, Devos D, van der Klei I . Comparative Genomics of Peroxisome Biogenesis Proteins: Making Sense of the PEX Proteins. Front Cell Dev Biol. 2021; 9:654163. PMC: 8172628. DOI: 10.3389/fcell.2021.654163. View

10.

Zhu Y, Zhu L, Lu L, Zhang L, Zhang G, Wang Q . Role and mechanism of the alkylglycerone phosphate synthase in suppressing the invasion potential of human glioma and hepatic carcinoma cells in vitro. Oncol Rep. 2014; 32(1):431-6. DOI: 10.3892/or.2014.3189. View

11.

Ploumaki I, Triantafyllou E, Koumprentziotis I, Karampinos K, Drougkas K, Karavolias I . Bcl-2 pathway inhibition in solid tumors: a review of clinical trials. Clin Transl Oncol. 2023; 25(6):1554-1578. PMC: 10203027. DOI: 10.1007/s12094-022-03070-9. View

12.

Pollegioni L, Piubelli L, Sacchi S, Pilone M, Molla G . Physiological functions of D-amino acid oxidases: from yeast to humans. Cell Mol Life Sci. 2007; 64(11):1373-94. PMC: 11136250. DOI: 10.1007/s00018-007-6558-4. View

13.

Wanders R, Waterham H . Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem. 2006; 75:295-332. DOI: 10.1146/annurev.biochem.74.082803.133329. View

14.

Waterham H, Ferdinandusse S, Wanders R . Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta. 2015; 1863(5):922-33. DOI: 10.1016/j.bbamcr.2015.11.015. View

15.

Wang C, Sun D, Huang X, Wan C, Li Z, Han Y . Integrative analyses of single-cell transcriptome and regulome using MAESTRO. Genome Biol. 2020; 21(1):198. PMC: 7412809. DOI: 10.1186/s13059-020-02116-x. View

16.

Fransen M, Nordgren M, Wang B, Apanasets O . Role of peroxisomes in ROS/RNS-metabolism: implications for human disease. Biochim Biophys Acta. 2011; 1822(9):1363-73. DOI: 10.1016/j.bbadis.2011.12.001. View

17.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

18.

Jo D, Park S, Kim A, Park N, Kim J, Bae J . Loss of HSPA9 induces peroxisomal degradation by increasing pexophagy. Autophagy. 2020; 16(11):1989-2003. PMC: 7595578. DOI: 10.1080/15548627.2020.1712812. View

19.

Tan Z, Deng Y, Cai Z, He H, Tang Z, Feng Y . ACOX2 Serves as a Favorable Indicator Related to Lipid Metabolism and Oxidative Stress for Biochemical Recurrence in Prostate Cancer. J Cancer. 2024; 15(10):3010-3023. PMC: 11064250. DOI: 10.7150/jca.93832. View

20.

Luengo A, Gui D, Vander Heiden M . Targeting Metabolism for Cancer Therapy. Cell Chem Biol. 2017; 24(9):1161-1180. PMC: 5744685. DOI: 10.1016/j.chembiol.2017.08.028. View