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Progesterone receptor modulates ERα action in breast cancer

Author

Listed:
  • Hisham Mohammed

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • I. Alasdair Russell

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Rory Stark

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Oscar M. Rueda

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Theresa E. Hickey

    (Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide)

  • Gerard A. Tarulli

    (Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide)

  • Aurelien A. Serandour

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Stephen N. Birrell

    (Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide)

  • Alejandra Bruna

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Amel Saadi

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Suraj Menon

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • James Hadfield

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Michelle Pugh

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Ganesh V. Raj

    (University of Texas, Southwestern Medical Center at Dallas)

  • Gordon D. Brown

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Clive D’Santos

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Jessica L. L. Robinson

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Grace Silva

    (Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill)

  • Rosalind Launchbury

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Charles M. Perou

    (Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill)

  • John Stingl

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Carlos Caldas

    (Cancer Research UK Cambridge Institute, University of Cambridge
    Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre
    Cambridge Experimental Cancer Medicine Centre)

  • Wayne D. Tilley

    (Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide)

  • Jason S. Carroll

    (Cancer Research UK Cambridge Institute, University of Cambridge)

Abstract

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.

Suggested Citation

  • Hisham Mohammed & I. Alasdair Russell & Rory Stark & Oscar M. Rueda & Theresa E. Hickey & Gerard A. Tarulli & Aurelien A. Serandour & Stephen N. Birrell & Alejandra Bruna & Amel Saadi & Suraj Menon & , 2015. "Progesterone receptor modulates ERα action in breast cancer," Nature, Nature, vol. 523(7560), pages 313-317, July.
    • Handle: RePEc:nat:nature:v:523:y:2015:i:7560:d:10.1038_nature14583
    DOI: 10.1038/nature14583
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    Cited by:

    1. Valentina Scabia & Ayyakkannu Ayyanan & Fabio Martino & Andrea Agnoletto & Laura Battista & Csaba Laszlo & Assia Treboux & Khalil Zaman & Athina Stravodimou & Didier Jallut & Maryse Fiche & Philip Buc, 2022. "Estrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Sasagu Kurozumi & Hiroshi Matsumoto & Kenichi Inoue & Katsunori Tozuka & Yuji Hayashi & Masafumi Kurosumi & Tetsunari Oyama & Takaaki Fujii & Jun Horiguchi & Hiroyuki Kuwano, 2018. "Impact of combining the progesterone receptor and preoperative endocrine prognostic index (PEPI) as a prognostic factor after neoadjuvant endocrine therapy using aromatase inhibitors in postmenopausal," PLOS ONE, Public Library of Science, vol. 13(8), pages 1-11, August.
    3. Zheqi Li & Olivia McGinn & Yang Wu & Amir Bahreini & Nolan M. Priedigkeit & Kai Ding & Sayali Onkar & Caleb Lampenfeld & Carol A. Sartorius & Lori Miller & Margaret Rosenzweig & Ofir Cohen & Nikhil Wa, 2022. "ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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