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High PPFIA1 expression promotes cancer survival by suppressing CD8+ T cells in breast cancer: drug discovery and machine learning approach

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Abstract

Background

PTPRF-interacting protein alpha 1 (PPFIA1) plays an important role as a regulator of cell motility and tumor cell invasion and is frequently amplified in breast cancer. The aim of this study was to investigate the clinicopathologic features, survival, anticancer immunities and specific gene sets related to high PPFIA1 expression in patients with breast cancer. We verified the importance of PPFIA1 and survival rates using machine learning and identified drugs that can effectively reduce breast cancer cells with high PPFIA1 expression.

Methods

This study analyzed clinicopathologic factors, survival rates, immune profiles and gene sets according to PPFIA1 expression in 3457 patients with breast cancer from the Kangbuk Samsung Medical Center cohort (456 cases), Molecular Taxonomy of Breast Cancer International Consortium (1904 cases) and The Cancer Genome Atlas (1097 cases). We applied gene set enrichment analysis (GSEA), in silico cytometry, pathway network analyses, in vitro drug screening, and gradient boosting machine (GBM) analysis.

Results

High PPFIA1 expression in breast cancer was associated with worse prognosis, with reduced tumor-infiltrating lymphocytes, especially CD8+ T cells, and increased PD-L1 expression. In pathway network analysis, PPFIA1 was linked directly to the tyrosine-protein phosphatase pathway and indirectly to immune pathways. The importance of PPFIA1’s association with survival in GBM analysis was higher than that of perineural and lymphovascular invasion. In in vitro drug screening, expression of PPFIA1 on mRNA level positively correlated with sensitivity of cell lines to erlotinib.

Conclusion

High PPFIA1 in patients with breast cancer is related to poor prognosis and decreased anticancer immune response, and erlotinib may be promising for development of therapeutic approaches in patients with tumors overexpressing PPFIA1.

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Data availability

Public data used in this work can be acquired from the portal TCGA Research Network (https://gdc.cancer.gov/about-data/publications/pancanatlas). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author.

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Funding

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Author information

Authors and Affiliations

  1. Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunanro, Jongno-gu, Seoul, Republic of Korea

    Jinah Chu, Dong-Hoon Kim & Sung-Im Do

  2. Department of Pathology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Gyeonggi-do, Republic of Korea

    Kyueng-Whan Min

  3. Department of Internal Medicine, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Uijeongbu, Gyeonggi-do, Republic of Korea

    Byoung Kwan Son

  4. Division of Breast Surgery, Department of Surgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Gyeonggi-do, Republic of Korea

    Hyung Suk Kim

  5. Department of Obstetrics and Gynecology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Gyeonggi-do, Republic of Korea

    Un Suk Jung

  6. Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do, Republic of Korea

    Mi Jung Kwon

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  1. Jinah Chu
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Contributions

JC, K-WM, and D-HK conceived of the study and were responsible for the data curation, formal analysis, investigation, methodology, resources, software, validation, visualization, and writing—original draft. K-WM and D-HK conceived of the study, acquired funding, administered the project, supervised the study, and wrote and reviewed and edited the manuscript. JC, K-WM, and D-HK wrote, reviewed and edited the manuscript. S-ID, BKS, YHO, WYJ, HSK, USJ, and MJK verified the underlying data. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Kyueng-Whan Min or Dong-Hoon Kim.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of Kangbuk Samsung Medical Center (IRB No. 2020-09-015, Seoul, Korea).

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Informed consent was not obtained from all individual participants included in the study. IRB approved a request to waive the documentation of informed consent.

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Chu, J., Min, KW., Kim, DH. et al. High PPFIA1 expression promotes cancer survival by suppressing CD8+ T cells in breast cancer: drug discovery and machine learning approach. Breast Cancer 30, 259–270 (2023). https://doi.org/10.1007/s12282-022-01419-0

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