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

Martin Haar Pedersen, Brian L Hood, Hans Christian Beck, Thomas P Conrads, Henrik Ditzel, Rikke Leth-Larsen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
Artikelnummere1305531
TidsskriftOncoImmunology
Vol/bind6
Udgave nummer5
Antal sider14
ISSN2162-4011
DOI
StatusUdgivet - 16. mar. 2017

Fingeraftryk

Antigen Presentation
Down-Regulation
Neoplasms
Proteins
Tumor-Infiltrating Lymphocytes
Intrinsic Factor
Growth
Paraffin
Formaldehyde
Lymph Nodes
Cell Proliferation
Databases

Citer dette

@article{af0c0889c985476b91d52e7fd8da4d3b,
title = "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.",
author = "Pedersen, {Martin Haar} and Hood, {Brian L} and Beck, {Hans Christian} and Conrads, {Thomas P} and Henrik Ditzel and Rikke Leth-Larsen",
year = "2017",
month = "3",
day = "16",
doi = "10.1080/2162402X.2017.1305531",
language = "English",
volume = "6",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Taylor & Francis",
number = "5",

}

Downregulation of antigen presentation-associated pathway proteins is linked to poor outcome in triple-negative breast cancer patient tumors. / Pedersen, Martin Haar; Hood, Brian L; Beck, Hans Christian; Conrads, Thomas P; Ditzel, Henrik; Leth-Larsen, Rikke.

I: OncoImmunology, Bind 6, Nr. 5, e1305531, 16.03.2017.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Downregulation of antigen presentation-associated pathway proteins is linked to poor outcome in triple-negative breast cancer patient tumors

AU - Pedersen, Martin Haar

AU - Hood, Brian L

AU - Beck, Hans Christian

AU - Conrads, Thomas P

AU - Ditzel, Henrik

AU - Leth-Larsen, Rikke

PY - 2017/3/16

Y1 - 2017/3/16

N2 - 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.

AB - 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.

U2 - 10.1080/2162402X.2017.1305531

DO - 10.1080/2162402X.2017.1305531

M3 - Journal article

VL - 6

JO - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

IS - 5

M1 - e1305531

ER -