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Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer

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Abstract

Activating transcription factor-2 (ATF-2) has been implicated as a tumour suppressor in breast cancer (BC). c-JUN N-terminal kinase (JNK) and p38 MAPK phosphorylate ATF-2 within the activation domain (AD), which is required for its transcriptional activity. To date, the role of ATF-2 in determining response to endocrine therapy has not been explored. Effects of ATF-2 loss in the oestrogen receptor (ER)-positive luminal BC cell line MCF7 were explored, as well as its role in response to tamoxifen treatment. Genome-wide chromatin binding patterns of ATF-2 when phosphorylated within the AD in MCF-7 cells were determined using ChIP-seq. The expression of ATF-2 and phosphorylated ATF-2 (pATF-2-Thr71) was determined in a series of 1,650 BC patients and correlated with clinico-pathological features and clinical outcome. Loss of ATF-2 diminished the growth-inhibitory effects of tamoxifen, while tamoxifen treatment induced ATF-2 phosphorylation within the AD, to regulate the expression of a set of 227 genes for proximal phospho-ATF-2 binding, involved in cell development, assembly and survival. Low expression of both ATF-2 and pATF-2-Thr71 was significantly associated with aggressive pathological features. Furthermore, pATF-2 was associated with both p-p38 and pJNK1/2 (< 0.0001). While expression of ATF-2 is not associated with outcome, pATF-2 is associated with longer disease-free (p = 0.002) and BC-specific survival in patients exposed to tamoxifen (p = 0.01). Furthermore, multivariate analysis confirmed pATF-2-Thr71 as an independent prognostic factor. ATF-2 is important for modulating the effect of tamoxifen and phosphorylation of ATF-2 within the AD at Thr71 predicts for improved outcome for ER-positive BC receiving tamoxifen.

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Acknowledgments

Carlo Palmieri was supported by a clinician scientist fellowship from Cancer Research UK, Wilbert Zwart by a KWF Dutch Cancer Society Fellowship and a VENI scholarship from the Dutch Organisation for Scientific Research NWO, and Jason Carroll by an ERC starting grant and an EMBO Young investigator award. We thank Angie Gillies (University of Leicester) for technical help with immunohistochemistry. We would also like to acknowledge the support of Cancer Research UK Cambridge Research Institute, The Netherlands Cancer Institute and A Sisters Hope. The Department of Molecular and Clinical Cancer Medicine forms part of the North West Cancer Centre-University of Liverpool which is funded by North West Cancer Research. Research support is also received from The Clatterbridge Cancer Charity.

Conflict of Interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK

    Bharath Rudraraju, Athina Giannoudis, Mohammed I. Malki & Carlo Palmieri

  2. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Marjolein Droog, Wilbert Zwart & Ekaterina Nevedomskaya

  3. Division of Pathology, School of Molecular Medical Sciences, Nottingham University Hospitals and University of Nottingham, Nottingham, UK

    Tarek M. A. Abdel-Fatah & Steve Chan

  4. Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK

    David Moore & Jacqui Shaw

  5. Cancer Research UK Laboratories, Division of Cancer, Imperial College London, Du Cane Road, London, UK

    Hetal Patel, R. Charles Coombes, Charlotte Bevan & Simak Ali

  6. Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK

    Ian O. Ellis

  7. School of Biological Sciences, University of Essex, Colchester, Essex, UK

    Greg N. Brooke

  8. Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Ekaterina Nevedomskaya

  9. Laboratory of Cancer Research and Translational Oncology, Oncology Department, S. Croce General Hospital, Cuneo, Italy

    Christiana Lo Nigro

  10. Cancer Research UK, Cambridge Research Institute, Robinson Way, Cambridge, UK

    Jason Carroll

  11. Liverpool & Merseyside Academic Breast Unit, Royal Liverpool University Hospital, Liverpool, UK

    Carlo Palmieri

  12. Academic Department of Medical Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK

    Carlo Palmieri

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  1. Bharath Rudraraju
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  19. Carlo Palmieri
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Correspondence to Carlo Palmieri.

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Marjolein Droog and Tarek M.A. Abdel-Fatah are equal Contribution.

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Rudraraju, B., Droog, M., Abdel-Fatah, T.M.A. et al. Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer. Breast Cancer Res Treat 147, 295–309 (2014). https://doi.org/10.1007/s10549-014-3098-0

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