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Eukaryotic translation initiation factor 4E (eIF4E) expression is associated with breast cancer tumor phenotype and predicts survival after anthracycline chemotherapy treatment

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Abstract

Abnormal translation of mRNAs frequently occurring during carcinogenesis is among the mechanisms that can affect the expression of proteins involved in tumor development and progression. Eukaryotic initiation factor eIF4E is a key regulator of translation of many cancer-related transcripts and its expression is altered in various cancers and has been associated with worse survival. We determined the eIF4E protein levels using immunohistochemistry (IHC) in 1,233 breast tumors on tissue microarrays. We analyzed the effects of the IHC expression level on tumor characteristics and patient survival, also with stratification by adjuvant chemotherapy treatment. In 1,085 successfully stained tumors, high level of eIF4E protein expression was associated with features of aggressive tumor phenotype, namely grade, estrogen and progesterone receptor negativity, HER2 receptor positivity, and high expression of p53 and Ki67, and with triple negative subtype (p < 0.001). High eIF4E expression was associated with worse breast cancer-specific survival with a hazard ratio (HR) of 1.99 (95 % CI 1.32–3.00, p = 0.0008) and was in a multivariate analysis an independent prognostic factor. High eIF4E expression was associated with worse outcome also after detection of distant metastasis (HR = 1.88, 95 % CI 1.20–2.94, p = 0.0060). In the subgroup analysis the survival effect was strongest among patients treated with anthracycline chemotherapy (HR = 3.34, 95 % CI 1.72–6.48, p = 0.0002), whereas no such effect was seen among patients who had not received anthracycline with significant difference in heterogeneity between the two groups (p = 0.0358). High expression of eIF4E is associated with adverse tumor characteristics and predicts poor breast cancer-specific survival. This effect is emphasized in patients treated with anthracycline chemotherapy. eIF4E as a treatment predictive factor warrants further studies.

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Abbreviations

4E-BP:

eIF4E-binding protein

CEF:

Cyclophosphamide, epirubicin, and fluorouracil treatment

CISH:

Chromogenic in situ hybridization

CMF:

Cyclophosphamide, methotrexate, and fluorouracil treatment

eIF4E:

Eukaryotic initiation factor 4E

ER:

Estrogen receptor

HR:

Hazard ratio

IHC:

Immunohistochemistry

mAb:

Monoclonal antibody

MMP-9:

Matrix metalloptotease 9

mTOR:

Mammalian target for rapamycin

OR:

Odds ratio

PI3K:

Phosphatidylinositol-3-kinase

PR:

Progesterone receptor

PTEN :

Phosphatase and tensin homolog

TLK1B:

Tousled-like kinase 1B

TMA:

Tissue microarray

VEGF:

Vascular endothelial growth factor

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Acknowledgments

We thank research nurses Irja Erkkilä and Virpi Palola for their assistance with data management, and the Finnish Cancer Registry for the cancer diagnostic and follow-up data. The study was supported by funding from the Helsinki University Central Hospital Research Fund, the Sigrid Juselius Foundation, the Finnish Cancer Society, and the Academy of Finland (132473), and for TH by the Finnish Cultural Foundation, Paulo foundation, Ida Montin foundation, and Orion-Farmos research foundation. TK is a member of Turku doctoral program of biomedical sciences.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, P.O. Box 700, 00029, Helsinki, Finland

    Tuomas Heikkinen, Rainer Fagerholm, Sofia Khan & Heli Nevanlinna

  2. Department of Pathology and Medicity Laboratory, University of Turku, Turku, Finland

    Taina Korpela & Olli Carpén

  3. Turku University Hospital, 20521, Turku, Finland

    Olli Carpén

  4. Department of Clinical Genetics, Helsinki University Central Hospital, P.O. Box 140, 00029, Helsinki, Finland

    Kristiina Aittomäki

  5. Department of Pathology, Helsinki University Central Hospital, P.O. Box 400, 00029, Helsinki, Finland

    Päivi Heikkilä

  6. Department of Oncology, Helsinki University Central Hospital, P.O. Box 180, 00029, Helsinki, Finland

    Carl Blomqvist

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  1. Tuomas Heikkinen
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  2. Taina Korpela
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Correspondence to Tuomas Heikkinen.

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Heikkinen, T., Korpela, T., Fagerholm, R. et al. Eukaryotic translation initiation factor 4E (eIF4E) expression is associated with breast cancer tumor phenotype and predicts survival after anthracycline chemotherapy treatment. Breast Cancer Res Treat 141, 79–88 (2013). https://doi.org/10.1007/s10549-013-2671-2

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  • DOI: https://doi.org/10.1007/s10549-013-2671-2

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