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Breast Cancer Research and Treatment

, Volume 147, Issue 2, pp 295–309 | Cite as

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

  • Bharath Rudraraju
  • Marjolein Droog
  • Tarek M. A. Abdel-Fatah
  • Wilbert Zwart
  • Athina Giannoudis
  • Mohammed I. Malki
  • David Moore
  • Hetal Patel
  • Jacqui Shaw
  • Ian O. Ellis
  • Steve Chan
  • Greg N. Brooke
  • Ekaterina Nevedomskaya
  • Christiana Lo Nigro
  • Jason Carroll
  • R. Charles Coombes
  • Charlotte Bevan
  • Simak Ali
  • Carlo Palmieri
Preclinical study

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.

Keywords

Breast cancer Activating transcription factor-2 Phosphorylation Tamoxifen 

Notes

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.

Supplementary material

10549_2014_3098_MOESM1_ESM.pdf (982 kb)
Supplementary material 1 (PDF 981 kb)
10549_2014_3098_MOESM2_ESM.pdf (330 kb)
Supplementary material 2 (PDF 330 kb)
10549_2014_3098_MOESM3_ESM.docx (13 kb)
Supplementary material 3 (DOCX 13 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Bharath Rudraraju
    • 1
  • Marjolein Droog
    • 2
  • Tarek M. A. Abdel-Fatah
    • 3
  • Wilbert Zwart
    • 2
  • Athina Giannoudis
    • 1
  • Mohammed I. Malki
    • 1
  • David Moore
    • 4
  • Hetal Patel
    • 5
  • Jacqui Shaw
    • 4
  • Ian O. Ellis
    • 6
  • Steve Chan
    • 3
  • Greg N. Brooke
    • 7
  • Ekaterina Nevedomskaya
    • 2
    • 8
  • Christiana Lo Nigro
    • 9
  • Jason Carroll
    • 10
  • R. Charles Coombes
    • 5
  • Charlotte Bevan
    • 5
  • Simak Ali
    • 5
  • Carlo Palmieri
    • 1
    • 11
    • 12
  1. 1.Department of Molecular and Clinical Cancer Medicine, Institute of Translational MedicineUniversity of LiverpoolLiverpoolUK
  2. 2.Division of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Division of Pathology, School of Molecular Medical SciencesNottingham University Hospitals and University of NottinghamNottinghamUK
  4. 4.Department of Cancer Studies and Molecular MedicineUniversity of LeicesterLeicesterUK
  5. 5.Cancer Research UK Laboratories, Division of CancerImperial College LondonLondonUK
  6. 6.Division of Pathology, School of Molecular Medical SciencesUniversity of NottinghamNottinghamUK
  7. 7.School of Biological SciencesUniversity of EssexEssexUK
  8. 8.Department of Molecular CarcinogenesisThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  9. 9.Laboratory of Cancer Research and Translational Oncology, Oncology DepartmentS. Croce General HospitalCuneoItaly
  10. 10.Cancer Research UK, Cambridge Research InstituteCambridgeUK
  11. 11.Liverpool & Merseyside Academic Breast UnitRoyal Liverpool University HospitalLiverpoolUK
  12. 12.Academic Department of Medical OncologyClatterbridge Cancer Centre NHS Foundation TrustWirralUK

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