Abstract
As one of the most prevalent malignancies among women, breast cancer (BC) is tightly linked to metabolic dysfunction. However, the correlation between mitochondrial metabolism-related genes (MMRGs) and BC remains unclear. The training and validation datasets for BC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases, respectively. MMRG-related data were obtained from the Molecular Signatures Database. A risk score prognostic model incorporating MMRGs was established based on univariate, LASSO, and multivariate Cox regression analyses. Independent factors affecting BC prognosis were identified through regression analysis and presented in a nomogram. Single-sample gene set enrichment analysis was employed to assess the immune levels of high-risk (HR) and low-risk (LR) groups. The sensitivity of BC patients in the two groups to common anti-tumor drugs was evaluated by utilizing the Genomics of Drug Sensitivity in Cancer database. 12 MMRGs significantly associated with survival were selected from 1234 MMRGs. A 12-gene risk score prognostic model was built. In the multivariate regression analysis incorporating classical clinical factors, the MMRG-related risk score remained an independent prognostic factor. As revealed by tumor immune microenvironment analysis, the LR group with higher survival rates had elevated immune levels. The drug sensitivity results unmasked that the LR group demonstrated higher sensitivity to Irinotecan, Nilotinib, and Oxaliplatin, while the HR group demonstrated higher sensitivity to Lapatinib. The development of MMRG characteristics provides a comprehensive understanding of mitochondrial metabolism in BC, aiding in the prediction of prognosis and tumor microenvironment, and offering promising therapeutic choices for BC patients with different MMRG risk scores.
Graphical abstract
Similar content being viewed by others
Data Availability
The data and materials in the current study are available from the corresponding author on reasonable request.
References
Agarwal S et al (2020) PAICS, a De Novo purine biosynthetic enzyme, is overexpressed in pancreatic cancer and is involved in its progression. Transl Oncol 13(7):100776
Ahmed MB et al (2022) cAMP signaling in cancer: a PKA-CREB and EPAC-centric approach. Cells 11(13):2020
Bai Q et al (2022) Metastatic tumor cell-specific FABP7 promotes NSCLC metastasis via inhibiting beta-catenin degradation. Cells 11(5):805
Barzaman K et al (2020) Breast cancer: Biology, biomarkers, and treatments. Int Immunopharmacol 84:106535
Benatzy Y, Palmer MA, Brune B (2022) Arachidonate 15-lipoxygenase type B: regulation, function, and its role in pathophysiology. Front Pharmacol 13:1042420
Chang NW et al (2013) High levels of arachidonic acid and peroxisome proliferator-activated receptor-alpha in breast cancer tissues are associated with promoting cancer cell proliferation. J Nutr Biochem 24(1):274–281
Chang J et al (2023) Constructing a novel mitochondrial-related gene signature for evaluating the tumor immune microenvironment and predicting survival in stomach adenocarcinoma. J Transl Med 21(1):191
Charoentong P et al (2017) Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep 18(1):248–262
Dalva M et al (2017) Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer. Pancreatology 17(1):83–88
Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378
Desai P, Aggarwal A (2021) Breast cancer in women over 65 years- a review of screening and treatment options. Clin Geriatr Med 37(4):611–623
Dong H et al (2015) Inhibition of breast cancer cell migration by activation of cAMP signaling. Breast Cancer Res Treat 152(1):17–28
Du B et al (2021) PAICS is related to glioma grade and can promote glioma growth and migration. J Cell Mol Med 25(16):7720–7733
Garufi C et al (2001) Single-agent oxaliplatin in pretreated advanced breast cancer patients: a phase II study. Ann Oncol 12(2):179–182
Giaquinto AN et al (2022) Breast cancer statistics, 2022. CA Cancer J Clin 72(6):524–541
Gombos A, Awada A (2017) Advances in chemical pharmacotherapy to manage advanced breast cancer. Expert Opin Pharmacother 18(1):95–103
Grasso D et al (2020) Mitochondria in cancer. Cell Stress 4(6):114–146
Harbeck N, Gnant M (2017) Breast cancer. Lancet 389(10074):1134–1150
Huang J et al (2021) MTHFD2 facilitates breast cancer cell proliferation via the AKT signaling pathway. Exp Ther Med 22(1):703
Ihle CL, Wright-Hobart SJ, Owens P (2022) Therapeutics targeting the metastatic breast cancer bone microenvironment. Pharmacol Ther 239:108280
Jeong D et al (2021) ELOVL2: a novel tumor suppressor attenuating tamoxifen resistance in breast cancer. Am J Cancer Res 11(6):2568–2589
Jeschke J et al (2017) DNA methylation-based immune response signature improves patient diagnosis in multiple cancers. J Clin Invest 127(8):3090–3102
Jiang P et al (2018) Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med 24(10):1550–1558
Johansson BB et al (2018) The role of the carboxyl ester lipase (CEL) gene in pancreatic disease. Pancreatology 18(1):12–19
Kagawa Y et al (2019) Role of FABP7 in tumor cell signaling. Adv Biol Regul 71:206–218
Kawiak A (2022) Molecular research and treatment of breast cancer. Int J Mol Sci 23(17):9617
Kciuk M, Marciniak B, Kontek R (2020) Irinotecan-still an important player in cancer chemotherapy: a comprehensive overview. Int J Mol Sci 21(14):4919
Kittler R et al (2013) A comprehensive nuclear receptor network for breast cancer cells. Cell Rep 3(2):538–551
Kopinski PK et al (2021) Mitochondrial DNA variation and cancer. Nat Rev Cancer 21(7):431–445
Kulkarni S et al (2008) COX-2 and PPARgamma expression are potential markers of recurrence risk in mammary duct carcinoma in-situ. BMC Cancer 8:36
Lapatinib, in LiverTox: clinical and research information on drug-induced liver injury (2012) Bethesda (MD)
Le L et al (2023) 5-Azacytidine promotes HCC cell metastasis by up-regulating RDH16 expression. Eur J Pharmacol 950:175736
Lin CH et al (2021) High prevalence of APOA1/C3/A4/A5 alterations in luminal breast cancers among young women in East Asia. NPJ Breast Cancer 7(1):88
Liu ZH et al (2020) ZIC2 is downregulated and represses tumor growth via the regulation of STAT3 in breast cancer. Int J Cancer 147(2):505–518
Liu X et al (2021a) PRRC2A promotes hepatocellular carcinoma progression and associates with immune infiltration. J Hepatocell Carcinoma 8:1495–1511
Liu H et al (2021b) Metabolic molecule PLA2G2D is a potential prognostic biomarker correlating with immune cell infiltration and the expression of immune checkpoint genes in cervical squamous cell carcinoma. Front Oncol 11:755668
Lu J, Tan M, Cai Q (2015) The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett 356(2 Pt A):156–64
Mao YS et al (2020) Epidemiological characteristic and current status of surgical treatment for esophageal cancer by analysis of national registry database. Zhonghua Zhong Liu Za Zhi 42(3):228–233
Meng M et al (2018) Knockdown of PAICS inhibits malignant proliferation of human breast cancer cell lines. Biol Res 51(1):24
Meng C, Sun Y, Liu G (2023) Establishment of a prognostic model for ovarian cancer based on mitochondrial metabolism-related genes. Front Oncol 13:1144430
Merino Bonilla JA, Torres Tabanera M, Ros Mendoza LH (2017) Breast cancer in the 21st century: from early detection to new therapies. Radiologia 59(5):368–379
Niu M et al (2021) DCTPP1, an oncogene regulated by miR-378a-3p, promotes proliferation of breast cancer via DNA repair signaling pathway. Front Oncol 11:641931
Oh DY, Bang YJ (2020) HER2-targeted therapies—a role beyond breast cancer. Nat Rev Clin Oncol 17(1):33–48
Patergnani S et al (2020) Various aspects of calcium signaling in the regulation of apoptosis, autophagy, cell proliferation, and cancer. Int J Mol Sci 21(21):8323
Pizzolato JF, Saltz LB (2003) The camptothecins. Lancet 361(9376):2235–2242
Qiu P et al (2021) Characterization of exosome-related gene risk model to evaluate the tumor immune microenvironment and predict prognosis in triple-negative breast cancer. Front Immunol 12:736030
Rickard BP et al (2023) Methods to evaluate changes in mitochondrial structure and function in cancer. Cancers (Basel) 15(9):2564
Sainero-Alcolado L et al (2022) Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ 29(7):1304–1317
Saltz LB (1998) Irinotecan in the first-line treatment of colorectal cancer. Oncology (Williston Park) 12(8 Suppl 6):54–58
Seetharam R, Sood A, Goel S (2009) Oxaliplatin: pre-clinical perspectives on the mechanisms of action, response and resistance. Ecancermedicalscience 3:153
Shen DW et al (2012) Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev 64(3):706–721
Siegel RL et al (2023) Cancer statistics, 2023. CA Cancer J Clin 73(1):17–48
Sun Z et al (2022a) FABP7 inhibits proliferation and invasion abilities of cutaneous squamous cell carcinoma cells via the Notch signaling pathway. Oncol Lett 24(2):254
Sun L et al (2022b) Lapatinib induces mitochondrial dysfunction to enhance oxidative stress and ferroptosis in doxorubicin-induced cardiomyocytes via inhibition of PI3K/AKT signaling pathway. Bioengineered 13(1):48–60
Suo J et al (2021) A retrospective analysis of the effect of irinotecan-based regimens in patients with metastatic breast cancer previously treated with anthracyclines and taxanes. Front Oncol 11:654974
Thomas R et al (2019) ACSL1 regulates TNFalpha-induced GM-CSF production by breast cancer MDA-MB-231 Cells. Biomolecules 9(10):555
Trapani D et al (2022) Global challenges and policy solutions in breast cancer control. Cancer Treat Rev 104:102339
Vasan K, Werner M, Chandel NS (2020) Mitochondrial metabolism as a target for cancer therapy. Cell Metab 32(3):341–352
Wang S et al (2021) Nilotinib, a discoidin domain receptor 1 (DDR1) inhibitor, induces apoptosis and inhibits migration in breast cancer. Neoplasma 68(5):975–982
Wang Y et al (2022a) Mitochondrial-related transcriptome feature correlates with prognosis, vascular invasion, tumor microenvironment, and treatment response in hepatocellular carcinoma. Oxid Med Cell Longev 2022:1592905
Wang Y et al (2022b) ROS-induced DCTPP1 upregulation contributes to cisplatin resistance in ovarian cancer. Front Mol Biosci 9:838006
Winters S et al (2017) Breast cancer epidemiology, prevention, and screening. Prog Mol Biol Transl Sci 151:1–32
Wu J et al (2021) A risk model developed based on tumor microenvironment predicts overall survival and associates with tumor immunity of patients with lung adenocarcinoma. Oncogene 40(26):4413–4424
Xia LL et al (2016) DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically. Oncotarget 7(42):68623–68637
Yang Y et al (2016) Mitochondria and mitochondrial ROS in cancer: novel targets for anticancer therapy. J Cell Physiol 231(12):2570–2581
Zhang J et al (2020) Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target. Theranostics 10(18):8315–8342
Zhang H et al (2023a) Identification of MTHFD2 as a prognostic biomarker and ferroptosis regulator in triple-negative breast cancer. Front Oncol 13:1098357
Zhang Q et al (2023b) ACSL1-induced ferroptosis and platinum resistance in ovarian cancer by increasing FSP1 N-myristylation and stability. Cell Death Discov 9(1):83
Zhao B et al (2022) The role of PPARs in breast cancer. Cells 12(1):130
Funding
This study was sponsored by Quanzhou City Science & Technology Program of China (2019N086S).
Author information
Authors and Affiliations
Contributions
Conceptualization: ZH and YL. Data curation: HY and BZ. Formal analysis: HY and SY. Funding acquisition: SY. Writing of the manuscript: ZH and YL. Supervision: YL and BZ.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest.
Ethical Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
All authors consent to submit the manuscript for publication.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lin, Y., Huang, Z., Zhang, B. et al. Construction and Analysis of a Mitochondrial Metabolism-Related Prognostic Model for Breast Cancer to Evaluate Survival and Immunotherapy. J Membrane Biol 257, 63–78 (2024). https://doi.org/10.1007/s00232-024-00308-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-024-00308-1