• A Corrigendum to this article was published on 05 August 2015


Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

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Gene Expression Omnibus

Data deposits

All microarray and ChIP-seq data are deposited in GEO with the accession number GSE68359. All proteomic data are deposited with the PRIDE database with the accession number PXD002104.


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The authors would like to thank S. Leigh-Brown, the staff in the genomic core facility, S. Halim, the proteomic core facility and the bioinformatic core facility at Cancer Research UK. We acknowledge S. Jindal for pathology review, N. Ryan for technical assistance and S. Edwards for statistical analysis with ex vivo culture. The MCF7-LucYFP cells were a kind gift from N. Benaich. We thank H. Gronemeyer for the PR-A and PR-B expressing vectors. We would like to acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. Research reported in this manuscript was supported by the National Cancer Institute of the National Institutes of Health under award number 5P30CA142543 (to University of Texas Southwestern) and Department of Defense grants W81XWH-12-1-0288-03 (GVR). W.D.T. is supported by grants from the National Health and Medical Research Council of Australia (ID 1008349; ID 1084416) and Cancer Australia (ID 627229) T.E.H. held a Fellowship Award from the US Department of Defense Breast Cancer Research Program (BCRP; W81XWH-11-1-0592) and currently is supported by a Florey Fellowship from the Royal Adelaide Hospital Research Foundation. J.S.C. is supported by an ERC starting grant and an EMBO Young investigator award.

Author information

Author notes

    • Wayne D. Tilley
    •  & Jason S. Carroll

    These authors jointly supervised this work.


  1. Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK

    • Hisham Mohammed
    • , I. Alasdair Russell
    • , Rory Stark
    • , Oscar M. Rueda
    • , Aurelien A. Serandour
    • , Alejandra Bruna
    • , Amel Saadi
    • , Suraj Menon
    • , James Hadfield
    • , Michelle Pugh
    • , Gordon D. Brown
    • , Clive D’Santos
    • , Jessica L. L. Robinson
    • , Rosalind Launchbury
    • , John Stingl
    • , Carlos Caldas
    •  & Jason S. Carroll
  2. Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide, Adelaide, South Australia 5005, Australia

    • Theresa E. Hickey
    • , Gerard A. Tarulli
    • , Stephen N. Birrell
    •  & Wayne D. Tilley
  3. Department of Urology, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA

    • Ganesh V. Raj
  4. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, CB7295, Chapel Hill, North Carolina 27599, USA

    • Grace Silva
    •  & Charles M. Perou
  5. Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK

    • Carlos Caldas
  6. Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK

    • Carlos Caldas


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Experimental work was conducted by H.M., I.A.R., T.E.H., G.A.T., A.A.A.S., A.B., A.S., C.D., J.L.L.R., R.L. and G.S. Computational analysis was conducted by R.S., O.M.R., S.M. and G.D.B. Clinical samples, information and support was provided by S.N.B., G.V.R., C.M.P. and C.C. In vivo work was conducted by J.S. Genomic work was conducted by J.H. and M.P. All experiments were overseen by W.D.T. and J.S.C. The manuscript was written by H.M., I.A.R., T.E.H., W.D.T. and J.S.C. with help from the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Wayne D. Tilley or Jason S. Carroll.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This Supplementary table contains all RIME proteomic SILAC data from Figures 1a, Figure 1b and Extended data figure 1.

  2. 2.

    Supplementary Table 2

    Peak numbers following ERα, PR and p300 ChIP-seq in T-47D and MCF-7 cell lines. The number of peaks for the different conditions are shown, these include estrogen, estrogen plus progesterone and estrogen plus R5020 treatment. Also included are the common peaks observed under estrogen plus progesterone and estrogen plus R5020 conditions.

  3. 3.

    Supplementary Table 3

    Enriched pathways based on the ERα binding events induced by progesterone and R5020. The enriched pathways that occur in both T-47D and MCF-7 cells are shown. The values represent the Odds ratio.

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