Abstract
Triple Negative Breast Cancer (TNBC) is recognised as heterogeneous, with distinct subtypes specified by histopathologic and gene expression analysis. However, these do not align closely to treatment response and there is an on-going need for both clinically applicable biomarkers and new effective treatments. Comprehensive profiling of the TNBC tissue proteome has potential to bring new perspective to these challenges. We report global proteomic profiles of 312 TNBC cases derived from Data Independent Acquisition-Mass Spectrometry (DIA-MS) analysis, coupled with gene expression profiling in a subset of cases (n = 97). This showed differential expression of protein cassettes reflecting the key features of 1) cellular growth and proliferation, 2) immune activation, 3) mesenchymal elements and 4) luminal androgen receptor phenotype. In combination, these cassettes distinguished TNBC subtypes that align to potential treatments. We also found an association between immune activation and improved survival that was influenced by the presence of lymph node metastases. In our cohort and in a validation dataset, the combination of a five protein immune activation signature with lymph node status was highly predictive of survival, suggesting that a combination of tissue proteomics with clinical features could be an informative guide to TNBC management. This large proteomic study forms a resource to progress this goal.
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Acknowledgements
This work was supported by the National Breast Cancer Foundation (NBCF) of Australia. ProCan® is supported by the Australian Cancer Research Foundation, Cancer Institute NSW (2017/TPG001, REG171150), NSW Ministry of Health (CMP-01), University of Sydney, Cancer Council NSW (IG 18-01), Ian Potter Foundation, the Medical Research Futures Fund (MRFF-PD) National Health and Medical Research Council (NHMRC) of Australia European Union grant (GNT1170739, a companion grant to support the European Commission’s Horizon 2020 Program, H2020-SC1-DTH-2018-1, ’iPC—individualizedPaediatricCure’). The work at ProCan was done under the auspices of a Memorandum of Understanding between Children’s Medical Research Institute and the U.S. National Cancer Institute’s International Cancer Proteogenomics Consortium (ICPC), that encourages cooperation among institutions and nations in proteogenomic cancer research in which datasets are made available to the public. P.J.R. is supported by the NHMRC Fellowship (GNT1137064). Research conducted at the Westmead Institute for Medical Research (WIMR) was supported by Tour de Cure and the Cancer Institute NSW (CINSW) through the Sydney West Translational Cancer Research Centre (SW-TCRC, 15/TRC/1-01). Tissues were received from the Australian Breast Cancer Tissue Bank (ABCTB), which is generously supported by the NHMRC, the Cancer Institute NSW and the NBCF. The ABCTB makes tissues and samples available to researchers on a non-exclusive basis. Supportive contributions from research team members at ProCan® and the Centre for Cancer Research at WIMR are gratefully acknowledged. In particular, the authors thank Dr Mohashin Pathan for assistance with quality analysis of proteomic data.
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Rosemary L Balleine has received research support from Illumina for unrelated work. The other authors declare no competing financial or non-financial interests.
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Doan, T.B., Wouters, M.A., Hu, J. et al. Potential treatment targets in the whole-tissue proteome of triple negative breast cancer. npj Breast Cancer (2026). https://doi.org/10.1038/s41523-026-00976-3
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DOI: https://doi.org/10.1038/s41523-026-00976-3
