The therapeutic and prognostic role of cuproptosis-related genes in triple negative breast cancer

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Abstract

Background

This study aimed to observe the potential impact of known cuproptosis-related genes (CRGs) on triple negative breast cancer (TNBC) development, as well as their associated molecular mechanisms, immune infiltration mechanisms and potential therapeutic agents.

Results

Based on the Cox Proportional Hazard Model, 11 CRGs may be especially important in TNBC development and progression (considered as the Key-TNBC-CRGs). The expression of several Key-TNBC-CRGs (e.g., ATP7A, PIK3CA, LIAS, and LIPT) are associated with common mutations. The SCNA variation of 11 Key-TNBC-CRGs are related to differences immune infiltration profiles. In particular, depletion of ATP7A, ATP7B, CLS, LIAS, and SCL31A1 and while high amplification of NLRP3 and LIPT2 are correlated with decreased immune infiltration. In our Cox proportional hazards regression model, there is a significant difference in the overall survival between high-risk and low-risk groups. The HR in the high-risk group is 3.891 versus the low-risk group. And this model has a satisfactory performance in Prediction of 5–15-year survival, in particular in the 10-year survival (AUC = 0.836). Finally, we discovered some potential drugs for TNBC treatment based on the strategy of targeting 11 Key-TNBC-CRGs, such as Dasatinib combined with ABT-737, Erastin or Methotrexate, and Docetaxel/Ispinesib combination.

Conclusion

In conclusion, CRGs may play important roles in TNBC development, and they can impact tumor immune microenvironment and patient survival. The Key-TNBC-CRGs interact mutually and can be influenced by common BC-related mutations. Additionally, we established a 11-gene risk model with a robust performance in prediction of 5–15-year survival. As well, some new drugs are proposed potentially effective in TNBC based on the CRG strategy.

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Most cited references 39

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Copper induces cell death by targeting lipoylated TCA cycle proteins

Peter Tsvetkov, Shannon Coy, Boryana Petrova … (2022)

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms. Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al . investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK Lipoylation determines sensitivity to copper-induced cell death.

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Mitochondria as multifaceted regulators of cell death

Florian J. Bock, Stephen Tait (2019)

Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.

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Is Open Access

A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma

Zilong Bian, Rong Fan, Lingmin Xie (2022)

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, which is characterized by metabolic reprogramming. Cuproptosis, a novel form of cell death, is highly linked to mitochondrial metabolism and mediated by protein lipoylation. However, the clinical impacts of cuproptosis-related genes (CRGs) in ccRCC largely remain unclear. In the current study, we systematically evaluated the genetic alterations of cuproptosis-related genes in ccRCC. Our results revealed that CDKN2A, DLAT, DLD, FDX1, GLS, PDHA1 and PDHB exhibited differential expression between ccRCC and normal tissues (|log2(fold change)| > 2/3 and p < 0.05). Utilizing an iterative sure independence screening (SIS) method, we separately constructed the prognostic signature of CRGs for predicting the overall survival (OS) and progression-free survival (PFS) in ccRCC patients. The prognostic score of CRGs yielded an area under the curve (AUC) of 0.658 and 0.682 for the prediction of 5-year OS and PFS, respectively. In the Kaplan−Meier survival analysis of OS, a higher risk score of cuproptosis-related gene signature was significantly correlated with worse overall survival (HR = 2.72 (2.01–3.68), log-rank p = 1.76 × 10−7). Patients with a higher risk had a significantly shorter PFS (HR = 2.83 (2.08–3.85), log-rank p = 3.66 × 10−7). Two independent validation datasets (GSE40435 (N = 101), GSE53757 (N = 72)) were collected for meta-analysis, suggesting that CDKN2A (log2(fold change) = 1.46, 95%CI: 1.75–2.35) showed significantly higher expression in ccRCC tissues while DLAT (log2(fold change) = −0.54, 95%CI: −0.93–−0.15) and FDX1 (log2(fold change) = −1.01, 95%CI: −1.61–−0.42) were lowly expressed. The expression of CDKN2A and FDX1 in ccRCC was also significantly associated with immune infiltration levels and programmed cell death protein 1 (PD-1) expression (CDKN2A: r = 0.24, p = 2.14 × 10−8; FDX1: r = −0.17, p = 1.37 × 10−4). In conclusion, the cuproptosis-related gene signature could serve as a potential prognostic predictor for ccRCC patients and may offer novel insights into the cancer treatment.

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Author and article information

Contributors

Zhenyu Cui: cuizhenyu615@163.com

Journal

Journal ID (nlm-ta): BMC Bioinformatics

Journal ID (iso-abbrev): BMC Bioinformatics

Title: BMC Bioinformatics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2105

Publication date (Electronic): 31 May 2023

Publication date PMC-release: 31 May 2023

Publication date Collection: 2023

Volume: 24

Electronic Location Identifier: 223

Affiliations

[1 ]GRID grid.459324.d, Color Ultrasound Room, , Affiliated Hospital of Hebei University, ; Baoding, Hebei China

[2 ]GRID grid.459324.d, Medical Engineering Center, , Affiliated Hospital of Hebei University, ; Baoding, Hebei China

[3 ]GRID grid.459324.d, Department of Integrated Traditional Chinese and Western Medicine, , Affiliated Hospital of Hebei University, ; Baoding, Hebei China

[4 ]GRID grid.459324.d, Department of Urology Surgery, , Affiliated Hospital of Hebei University, ; Baoding, Hebei China

Article

Publisher ID: 5348

DOI: 10.1186/s12859-023-05348-3

PMC ID: 10234018

PubMed ID: 37259036

SO-VID: 01b6d09d-f27a-4e4b-9f9f-e4b86b7a87fe

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 7 February 2023

Date accepted : 23 May 2023

Funding

Funded by: Medical Science Foundation of Hebei University

Award ID: 2021X07

Award Recipient : Zhenyu Cui

Custom metadata

ScienceOpen disciplines: Bioinformatics & Computational biology

Keywords: triple negative breast cancer,cuproptosis,bioinformatics,immune infiltration,survival,drug sensitivity

Data availability:

ScienceOpen disciplines: Bioinformatics & Computational biology

Keywords: triple negative breast cancer, cuproptosis, bioinformatics, immune infiltration, survival, drug sensitivity

The therapeutic and prognostic role of cuproptosis-related genes in triple negative breast cancer

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Most cited references 39

Copper induces cell death by targeting lipoylated TCA cycle proteins

Mitochondria as multifaceted regulators of cell death

A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma

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