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Abundance of reactive oxygen species (ROS) is associated with tumor aggressiveness, immune response, and worse survival in breast cancer

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Reactive oxygen species (ROS) are oxygen-containing molecules that have high reactivity and play roles in protection or harm the cancer cells. We aimed to clarify the clinical relevance of ROS in breast cancer (BC) tumor microenvironment (TME). We hypothesized that it is associated with worse BC patient outcomes.

Methods

ROS score was generated by Gene Set Variation Analysis of Hallmark ROS pathway gene set and a total of 6245 BC patients were analyzed.

Results

High ROS BC significantly enriched cell proliferation-related gene sets (MYC targets v1 and v2, G2M checkpoint, E2F targets), pro-cancer-related gene sets (DNA repair, unfolded protein response, MTORC1 signaling, PI3K/AKT/MTOR signaling, glycolysis, and oxidative phosphorylation), immune-related gene sets (inflammatory response, allograft rejection, interferon-α and γ responses, complement, and IL6/JAK/STAT3 signaling), and infiltrated immune cells (CD4+ memory and CD8+ T cells, Th1 and Th2, dendritic cells, Tregs, M1 and M2 macrophages) and B cells, as well as elevated cytolytic activity consistently in both METABRIC and GSE96058 cohorts. Cancer cells were the major source of ROS in BC TME of single-cell sequence (GSE75688) cohort. High ROS was associated with intratumor heterogeneity, homologous recombination defects, mutation rates, and neoantigens, and with clinical aggressiveness in AJCC stage, Nottingham grade and Ki67 expression, as well as worse overall survival in both GSE96058 and METABRIC, and with worse disease-specific survival in METABRIC.

Conclusion

Abundant ROS in BC patients is associated with abundant mutations, aggressive cancer biology, immune response, and worse survival.

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Data availability

The datasets generated during and analyzed during the current study are available from the original source as they are publicly available deidentified databases.

Abbreviations

AJCC:

American Joint Committee on Cancer

DFS:

Disease-free survival

DSS:

Disease-specific survival

ER:

Estrogen receptor

FDR:

False discovery rate

GSEA:

Gene set enrichment analysis

GSVA:

Gene set variation analysis

HER2:

Human epidermal growth factor receptor 2

METABRIC:

Molecular Taxonomy of Breast Cancer International Consortium

NES:

Normalized enrichment score

OS:

Overall survival

TNBC:

Triple-negative breast cancer

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Funding

This research was supported by National Institutes of Health, USA grant number R37CA248018, R01CA250412, R01CA251545, R01EB029596, as well as US Department of Defense BCRP grant number W81XWH-19–1-0674 and W81XWH-19–1-0111 to K.T. National Cancer Institute, cancer center support grant P30CA016056 supports Roswell Park Comprehensive Cancer Center. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award numbers KL2TR001413 and UL1TR001412. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Masanori Oshi, Yoshihisa Tokumaru, Rongrong Wu & Kazuaki Takabe

  2. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan

    Masanori Oshi, Akimitsu Yamada, Ryusei Matsuyama, Itaru Endo & Kazuaki Takabe

  3. Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Shipra Gandhi & Kazuaki Takabe

  4. Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Li Yan

  5. Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan

    Yoshihisa Tokumaru

  6. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, 160-8402, Japan

    Kazuaki Takabe

  7. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8520, Japan

    Kazuaki Takabe

  8. Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan

    Kazuaki Takabe

  9. Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, 14263, USA

    Kazuaki Takabe

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  1. Masanori Oshi
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Contributions

Conceptualization was performed by AY, IE, KT, MO, and RM. Methodology was performed by KT, MO, and YT. Formal Analysis was performed by MO. The first draft of the manuscript was written by MO, and all authors commented on previous versions of the manuscript. Supervision and project administration were performed by KT. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kazuaki Takabe.

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The authors have no relevant financial or non-financial interests to disclose.

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Institutional review board (IRB) approval at Roswell Park Comprehensive Cancer Center (Buffalo, New York, United States of America) was waived as publicly available deidentified databases were used.

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Oshi, M., Gandhi, S., Yan, L. et al. Abundance of reactive oxygen species (ROS) is associated with tumor aggressiveness, immune response, and worse survival in breast cancer. Breast Cancer Res Treat 194, 231–241 (2022). https://doi.org/10.1007/s10549-022-06633-0

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