Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease
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Heidi N. Hilton1, Tram B. Doan1, J. Dinny Graham1, Samantha R. Oakes2,3, Audrey Silvestri1, Nicole Santucci1, Silke Kantimm1, Lily I. Huschtscha4, Christopher J. Ormandy2,3, John W. Funder5, Evan R. Simpson5, Elizabeth S. Kuczek6, Peter J. Leedman7, Wayne D. Tilley8, Peter J. Fuller5, George E. O. Muscat9 and Christine L. Clarke1
1 Westmead Millennium Institute, Sydney Medical School – Westmead, University of Sydney, NSW, Australia
2 Cancer Research Program and The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
3 St Vincent’s Clinical School, St Vincent’s Hospital and University of New South Wales, Darlinghurst NSW, Australia
4 Children’s Medical Research Institute, Westmead, New South Wales, Australia
5 MIMR-PHI Institute, Clayton, Victoria, Australia
6 Sydney Medical School, University of Sydney, Westmead, NSW, Australia
7 Laboratory for Cancer Medicine, Centre for Medical Research, Western Australian Institute for Medical Research and School of Medicine and Pharmacology, the University of Western Australia, Perth, Western Australia, Australia
8 Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, Hanson Institute, University of Adelaide, Adelaide, South Australia, Australia
9 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
Heidi Hilton, email:
Keywords: Estrogen receptor; progesterone receptor; breast cancer; human breast
Received: August 13, 2014 Accepted: August 15, 2014 Published: August 16, 2014
Cumulative exposure to estrogen (E) and progesterone (P) over the menstrual cycle significantly influences the risk of developing breast cancer. Despite the dogma that PR in the breast merely serves as a marker of an active estrogen receptor (ER), and as an inhibitor of the proliferative actions of E, it is now clear that in the breast P increases proliferation independently of E action. We show here that the progesterone receptor (PR) and ER are expressed in different epithelial populations, and target non-overlapping pathways in the normal human breast. In breast cancer, PR becomes highly correlated with ER, and this convergence is associated with signaling pathways predictive of disease metastasis. These data challenge the established paradigm that ER and PR function co-operatively in normal breast, and have significant implications not only for our understanding of normal breast biology, but also for diagnosis, prognosis and/or treatment options in breast cancer patients.
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