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.
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 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.
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute, ‡‡Netherlands Proteomics Centre, Utrecht, The Netherlands; §§Postgraduate School of Molecular Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; ¶¶Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Ning Qing
authors.initials: NQ
authors.lastname: Liu
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute, §§Postgraduate School of Molecular Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors.forename: Tommaso
authors.initials: T
authors.lastname: De Marchi
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute.
authors.forename: Annemieke M
authors.initials: AM
authors.lastname: Timmermans
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute.
authors.forename: Robin
authors.initials: R
authors.lastname: Beekhof
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute.
authors.forename: Anita M A C
authors.initials: AM
authors.lastname: Trapman-Jansen
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute.
authors.forename: Renée
authors.initials: R
authors.lastname: Foekens
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute.
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.affiliation: §Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors.forename: Carolien H M
authors.initials: CH
authors.lastname: van Deurzen
authors.affiliation: ¶Department of Radiation Oncology.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.affiliation: ‖Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: **Department of Pathology, the Centre of Diagnostic Investigations, Copenhagen University Hospital, Copenhagen, Denmark;
authors.forename: Julie Benedicte
authors.initials: JB
authors.lastname: Brask
authors.affiliation: **Department of Pathology, the Centre of Diagnostic Investigations, Copenhagen University Hospital, Copenhagen, Denmark;
authors.forename: Vera
authors.initials: V
authors.lastname: Timmermans-Wielenga
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute.
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute, ‡‡Netherlands Proteomics Centre, Utrecht, The Netherlands;
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute, ‡‡Netherlands Proteomics Centre, Utrecht, The Netherlands;
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.affiliation: From the ‡Department of Medical Oncology, Erasmus MC Cancer Institute, ‡‡Netherlands Proteomics Centre, Utrecht, The Netherlands; a.umar@erasmusmc.nl.
authors.forename: Arzu
authors.initials: A
authors.lastname: Umar
mesh_terms: D000328:Adult; D000368:Aged; D001052:Apoferritins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008875:Middle Aged; D010088:Oxidoreductases; D011379:Prognosis; D060066:Protein Interaction Maps; D040901:Proteomics; D046888:Tissue Array Analysis; D064726:Triple Negative Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality
chemical_list: D014408:Biomarkers, Tumor; D007371:Interferon-gamma; D005293:Ferritins; D001052:Apoferritins; C454461:FTH1 protein, human; D010088:Oxidoreductases
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