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Improved relapse-free survival on aromatase inhibitors in breast cancer is associated with interaction between oestrogen receptor-α and progesterone receptor-b

British Journal of Cancervolume 119pages13161325 (2018) | Download Citation



Recent pre-clinical studies indicate that activated progesterone receptor (PR) (particularly the PR-B isoform) binds to oestrogen receptor-α (ER) and reprogrammes transcription toward better breast cancer outcomes. We investigated whether ER and PR-B interactions were present in breast tumours and associated with clinical parameters including response to aromatase inhibitors.


We developed a proximity ligation assay to detect ER and PR-B (ER:PR-B) interactions in formalin-fixed paraffin-embedded tissues. The assay was validated in a cell line and patient-derived breast cancer explants and applied to a cohort of 229 patients with ER-positive and HER2-negative breast cancer with axillary nodal disease.


Higher frequency of ER:PR-B interaction correlated with increasing patient age, lower tumour grade and mitotic index. A low frequency of ER:PR-B interaction was associated with higher risk of relapse. In multivariate analysis, ER:PR-B interaction frequency was an independent predictive factor for relapse, whereas PR expression was not. In subset analysis, low frequency of ER:PR-B interaction was predictive of relapse on adjuvant aromatase inhibitor (HR 4.831, p = 0.001), but not on tamoxifen (HR 1.043, p = 0.939).


This study demonstrates that ER:PR-B interactions have utility in predicting patient response to adjuvant AI therapy.

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Ethics approval and consent to participate: for patient-derived explant studies, tumour samples were obtained following informed consent from women undergoing surgery for breast cancer at the Burnside War Memorial Hospital, Adelaide. This study was approved by the University of Adelaide Human Research Ethics Committee (approval numbers: H-065-2005; H-169-2011). For the retrospective cohort, the use of clinical information and tumour blocks was approved by the Mater Health Services Human Research Ethics Committee with a waiver of consent (approval number: HREC/15/MHS/123). The study was performed in accordance with the Declaration of Helsinki.


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The authors thank the following people for their contributions to this study: Yanlin Liu for assembly of the database used to collate patient information. Lauren Furnas for help with block retrieval. Brenton Seidl for help with retrieving patient information. Geraldine Lavin-Law for technical work involving the patient-derived explants. This work was supported by grants from the Royal College of Pathologists of Australasia Foundation (CS), National Health and Medical Research Council of Australia (NHMRC) (ID 1130077 WDT and TEH), and Cancer Australia/National Breast Cancer Foundation (ID 1043497; WDT, TEH). CS is supported by a Betty McGrath Fellowship from Mater Foundation. CL is a recipient of PhD scholarships from the Australian Government (Australian Postgraduate Award) and Royal College of Pathologists of Australasia (RCPA Foundation Postgraduate Research Fellowship). WDT is also supported by a grant from the National Breast Cancer Foundation (PS-15-041). TEH is supported by a Career Development Fellowship from the Royal Adelaide Hospital Research Foundation (Adelaide, Australia). The project also has received funding from the Mater Foundation (Queensland, Australia) and The Hospital Research Foundation (Adelaide, Australia). The Translational Research Institute is supported by a grant from the Australian Government.

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Author notes

  1. These authors contributed equally: Jane E. Armes, Wayne D. Tilley.


  1. Cancer Pathology Research Group, Mater Research Institute—The University of Queensland, Translational Research Institute, Woolloongabba, QLD, 4102, Australia

    • Cameron E. Snell
    •  & Madeline Gough
  2. Department of Anatomical Pathology, Mater Pathology, Mater Hospital Brisbane, South Brisbane, QLD, 4101, Australia

    • Cameron E. Snell
    • , Madeline Gough
    • , Cheng Liu
    •  & Jane E. Armes
  3. Department of Medical Oncology, Mater Hospital Brisbane, South Brisbane, QLD, 4101, Australia

    • Kathryn Middleton
    • , Catherine Shannon
    •  & Natasha Woodward
  4. Department of Breast and Endocrine Surgery, Mater Hospital Brisbane, South Brisbane, QLD, 4101, Australia

    • Christopher Pyke
  5. Mater Research Institute—The University of Queensland, Translational Research Institute, Woolloongabba, QLD, 4102, Australia

    • Kathryn Middleton
    • , Christopher Pyke
    • , Catherine Shannon
    •  & Natasha Woodward
  6. Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, 5000, Australia

    • Theresa E. Hickey
    •  & Wayne D. Tilley


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C.E.S, J.A, T.E.H. and W.D.T. conceived the study. C.E.S, M.G. and T.E.H. performed the experiments. C.E.S. and C.L. scored the slides. C.E.S. and M.G. performed statistical analyses. Patient data was collected by K.M, C.P, C.S. and N.W. C.E.S. wrote the paper with major editing from W.D.T, T.E.H. and J.E.A. and minor editing and final approval of the submitted version by all authors.

Competing interests

KM reports receiving travel expenses from Roche. CS reports receiving compensation for being on advisory boards for Roche and AstraZeneca. NW reports stock ownership (CSL), receiving travel/expenses from Roche and research funding from Medivation. The remaining authors declare that they have no conflict of interest.

Availability of data and materials

To protect patient privacy, all patient data have been de-identified and reported in aggregate. De-identified patient data are available from the authors on request by e-mail.


This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

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Correspondence to Cameron E. Snell.

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