Downregulation of antigen presentation-associated pathway proteins is linked to poor outcome in triple-negative breast cancer patient tumors

ABSTRACT

Triple-negative breast cancer (TNBC) is a heterogeneous subtype with varying disease outcomes. Tumor-infiltrating lymphocytes (TILs) are frequent in TNBC and have been shown to correlate with outcome, suggesting an immunogenic component in this subtype. However, other factors intrinsic to the cancer cells may also influence outcome. To identify proteins and molecular pathways associated with recurrence in TNBC, 34 formalin-fixed paraffin-embedded (FFPE) primary TNBC tumors were investigated by global proteomic profiling using mass spectrometry. Approximately, half of the patients were lymph node-negative and remained free of local or distant metastasis within 10 y follow-up, while the other half developed distant metastasis. Proteomic profiling identified >4,000 proteins, of which 63 exhibited altered expression in primary tumors of recurrence versus recurrence-free patients. Importantly, downregulation of proteins in the major histocompatibility complex (MHC) class I antigen presentation pathways were enriched, including TAP1, TAP2, CALR, HLA-A, ERAP1 and TAPBP, and were associated with significantly shorter recurrence-free and overall survival. In addition, proteins involved in cancer cell proliferation and growth, including GBP1, RAD23B, WARS and STAT1, also exhibited altered expression in primary tumors of recurrence versus recurrence-free patients. The association between the antigen-presentation pathway and outcome were validated in a second sample set of 10 primary TNBC tumors and corresponding metastases using proteomics and in a large public gene expression database of 249 TNBC and 580 basal-like breast cancer cases. Our study demonstrates that downregulation of antigen presentation is a key mechanism for TNBC cells to avoid immune surveillance, allowing continued growth and spread.

KEYWORDS:

• Basal-like breast cancer
• biomarker
• formalin-fixed paraffin embedded
• major histocompatibility complex
• mass spectrometry
• MHC class I antigen presentation pathway
• proteomics
• triple-negative breast cancer

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

This work was supported by the Danish Council for Independent Research (DFF), The Danish Cancer Society, the Region of Southern Denmarks Research Council, the Foundation for the Advancement of Medical Research (A.P. Møller Foundation), Race Against Breast Cancer, NEXT bioinformatic (National Experimental Therapy Partnership) financed by Innovation Fund Denmark, Manufacturer Einar Willumsens Memorial Foundation, Therese Maria Hansen born Beers Foundation, the Neye Foundation and Engineer K. A. Rohde and wife Foundation.