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Ferritin heavy chain in triple negative breast cancer : a favorable prognostic marker that relates to a cluster of differentiation 8 positive (CD8+) effector T-cell response

Liu, Ning Qing; De Marchi, Tommaso LU ; Timmermans, Annemieke M; Beekhof, Robin; Trapman-Jansen, Anita M A C; Foekens, Renée; Look, Maxime P.; van Deurzen, Carolien H. M.; Span, Paul N. and Sweep, Fred C G J, et al. (2014) In Molecular and Cellular Proteomics 13(7). p.27-1814
Abstract

Ferritin heavy chain (FTH1) is a 21-kDa subunit of the ferritin complex, known for its role in iron metabolism, and which has recently been identified as a favorable prognostic protein for triple negative breast cancer (TNBC) patients. Currently, it is not well understood how FTH1 contributes to an anti-tumor response. Here, we explored whether expression and cellular compartmentalization of FTH1 correlates to an effective immune response in TNBC patients. Analysis of the tumor tissue transcriptome, complemented with in silico pathway analysis, revealed that FTH1 was an integral part of an immunomodulatory network of cytokine signaling, adaptive immunity, and cell death. These findings were confirmed using mass spectrometry (MS)-derived... (More)

Ferritin heavy chain (FTH1) is a 21-kDa subunit of the ferritin complex, known for its role in iron metabolism, and which has recently been identified as a favorable prognostic protein for triple negative breast cancer (TNBC) patients. Currently, it is not well understood how FTH1 contributes to an anti-tumor response. Here, we explored whether expression and cellular compartmentalization of FTH1 correlates to an effective immune response in TNBC patients. Analysis of the tumor tissue transcriptome, complemented with in silico pathway analysis, revealed that FTH1 was an integral part of an immunomodulatory network of cytokine signaling, adaptive immunity, and cell death. These findings were confirmed using mass spectrometry (MS)-derived proteomic data, and immunohistochemical staining of tissue microarrays. We observed that FTH1 is localized in both the cytoplasm and/or nucleus of cancer cells. However, high cytoplasmic (c) FTH1 was associated with favorable prognosis (Log-rank p = 0.001), whereas nuclear (n) FTH1 staining was associated with adverse prognosis (Log-rank p = 0.019). cFTH1 staining significantly correlated with total FTH1 expression in TNBC tissue samples, as measured by MS analysis (Rs = 0.473, p = 0.0007), but nFTH1 staining did not (Rs = 0.197, p = 0.1801). Notably, IFN γ-producing CD8+ effector T cells, but not CD4+ T cells, were preferentially enriched in tumors with high expression of cFTH1 (p = 0.02). Collectively, our data provide evidence toward new immune regulatory properties of FTH1 in TNBC, which may facilitate development of novel therapeutic targets.

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keywords
Adult, Aged, Apoferritins, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Cell Nucleus, Cytoplasm, Female, Ferritins, Humans, Interferon-gamma, Middle Aged, Prognosis, Protein Interaction Maps, Proteomics, Tissue Array Analysis, Triple Negative Breast Neoplasms, Journal Article, Research Support, Non-U.S. Gov't
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Molecular and Cellular Proteomics
volume
13
issue
7
pages
14 pages
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • scopus:84904088682
ISSN
1535-9484
DOI
10.1074/mcp.M113.037176
language
English
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no
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8c369c63-84cc-417c-9137-8ad690316f5d
date added to LUP
2017-06-27 14:27:57
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2017-09-10 05:20:46
@article{8c369c63-84cc-417c-9137-8ad690316f5d,
  abstract     = {<p>Ferritin heavy chain (FTH1) is a 21-kDa subunit of the ferritin complex, known for its role in iron metabolism, and which has recently been identified as a favorable prognostic protein for triple negative breast cancer (TNBC) patients. Currently, it is not well understood how FTH1 contributes to an anti-tumor response. Here, we explored whether expression and cellular compartmentalization of FTH1 correlates to an effective immune response in TNBC patients. Analysis of the tumor tissue transcriptome, complemented with in silico pathway analysis, revealed that FTH1 was an integral part of an immunomodulatory network of cytokine signaling, adaptive immunity, and cell death. These findings were confirmed using mass spectrometry (MS)-derived proteomic data, and immunohistochemical staining of tissue microarrays. We observed that FTH1 is localized in both the cytoplasm and/or nucleus of cancer cells. However, high cytoplasmic (c) FTH1 was associated with favorable prognosis (Log-rank p = 0.001), whereas nuclear (n) FTH1 staining was associated with adverse prognosis (Log-rank p = 0.019). cFTH1 staining significantly correlated with total FTH1 expression in TNBC tissue samples, as measured by MS analysis (Rs = 0.473, p = 0.0007), but nFTH1 staining did not (Rs = 0.197, p = 0.1801). Notably, IFN γ-producing CD8+ effector T cells, but not CD4+ T cells, were preferentially enriched in tumors with high expression of cFTH1 (p = 0.02). Collectively, our data provide evidence toward new immune regulatory properties of FTH1 in TNBC, which may facilitate development of novel therapeutic targets.</p>},
  author       = {Liu, Ning Qing and De Marchi, Tommaso and Timmermans, Annemieke M and Beekhof, Robin and Trapman-Jansen, Anita M A C and Foekens, Renée and Look, Maxime P. and van Deurzen, Carolien H. M. and Span, Paul N. and Sweep, Fred C G J and Brask, Julie Benedicte and Timmermans-Wielenga, Vera and Debets, Reno and Martens, John W. M. and Foekens, John A. and Umar, Arzu},
  issn         = {1535-9484},
  keyword      = {Adult,Aged,Apoferritins,Biomarkers, Tumor,CD8-Positive T-Lymphocytes,Cell Nucleus,Cytoplasm,Female,Ferritins,Humans,Interferon-gamma,Middle Aged,Prognosis,Protein Interaction Maps,Proteomics,Tissue Array Analysis,Triple Negative Breast Neoplasms,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {7},
  pages        = {27--1814},
  publisher    = {American Society for Biochemistry and Molecular Biology},
  series       = {Molecular and Cellular Proteomics},
  title        = {Ferritin heavy chain in triple negative breast cancer : a favorable prognostic marker that relates to a cluster of differentiation 8 positive (CD8+) effector T-cell response},
  url          = {http://dx.doi.org/10.1074/mcp.M113.037176},
  volume       = {13},
  year         = {2014},
}