Breast Cancer Research and Treatment

, Volume 165, Issue 3, pp 633–643 | Cite as

The effect of 14-3-3ζ expression on tamoxifen resistance and breast cancer recurrence: a Danish population-based study

  • Jake E. Thistle
  • Ylva Hellberg
  • Kristina Mortensen
  • Stephen Hamilton–Dutoit
  • Anders Kjærsgaard
  • Deirdre Cronin–Fenton
  • Henrik Toft Sørensen
  • Timothy L. LashEmail author



Overexpression of 14-3-3ζ has been linked to breast cancer recurrence in several studies, including studies assessing its effect on tamoxifen resistance. The study was performed to estimate the effect of 14-3-3ζ and differentiate potential prognostic or predictive utility.


A case–control study, nested in a population of 11,251 females residing on the Jutland Peninsula of Denmark, was performed. Participants were aged 35–69, diagnosed with stage I, II, or III breast cancer between 1985 and 2001, and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent breast cancer cases with estrogen receptor-positive disease treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 cases with estrogen receptor-negative disease never treated with tamoxifen (ER−/TAM−). We matched cases to controls on ER/TAM status, date of surgery, menopausal status, stage, and county. 14-3-3ζ expression was assessed using immunohistochemistry on tissue microarrays. We computed the odds ratio (OR) associating 14-3-3ζ expression with breast cancer recurrence adjusting for confounding using logistic regression. A quantitative bias analysis was performed to account for bias due to expression assay methods.


Associations for cytoplasmic and nuclear 14-3-3ζ staining above the 50th percentile were near null in both ER+/TAM+ and ER−/TAM− patients. When examining combined 14-3-3ζ staining, the association increased in the ER+/TAM+ group (adjusted OR 1.44, 95% confidence interval (CI) 1.05, 1.99). A nearly twofold increase in odds of recurrence was observed in above the 75th percentile staining of combined 14-3-3ζ, both for ER+/TAM+ patients (adjusted OR 1.93, 95% CI 1.15, 3.24) and ER−/TAM− patients (adjusted OR 1.93, 95% CI 1.03, 3.62), indicating potential prognostic utility.


Evidence is lacking to conclude that 14-3-3ζ is a useful marker of tamoxifen resistance; however, 14-3-3ζ expression is a potentially useful prognostic marker of breast cancer recurrence. Independent utility beyond established prognostic markers needs to be determined.


14-3-3ζ Tamoxifen Breast cancer recurrence Prognostic marker Predictive marker 



This study was supported by funding from the National Cancer Institute (R01 CA118708 and R01 CA166825) awarded to Timothy L. Lash, the Danish Cancer Society (DP06117) awarded to Stephen Hamilton-Dutoit, the Lundbeck Foundation (R167-2013-15861) awarded to Deirdre Cronin-Fenton, the Danish Medical Research Council (DOK 1158869) awarded to Timothy L. Lash, the Karen Elise Jensen Foundation awarded to Henrik Toft Sørensen, and the Program for Clinical Research Infrastructure established by the Lundbeck and the Novo Nordisk Foundations awarded to Henrik Toft Sørensen.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The research was approved by the regional ethical board in Denmark and by Institutional Review Boards in the US. This study does not contain any animal experiments performed by any of the authors.

Informed consent

Informed consent was not required. Registry-based research is exempt from informed consent requirements according to Danish law.

Supplementary material

10549_2017_4289_MOESM1_ESM.docx (26 kb)
Supplementary material 1 (DOCX 25 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Jake E. Thistle
    • 1
  • Ylva Hellberg
    • 2
  • Kristina Mortensen
    • 2
  • Stephen Hamilton–Dutoit
    • 2
  • Anders Kjærsgaard
    • 3
  • Deirdre Cronin–Fenton
    • 3
  • Henrik Toft Sørensen
    • 3
  • Timothy L. Lash
    • 1
    • 3
    Email author
  1. 1.Department of Epidemiology, Rollins School of Public HealthEmory UniversityAtlantaUSA
  2. 2.Institute of PathologyAarhus University HospitalAarhusDenmark
  3. 3.Department of Clinical EpidemiologyAarhus University HospitalAarhusDenmark

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