Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease

Heidi N Hilton; Tram B Doan; J Dinny Graham; Samantha R Oakes; Audrey Silvestri; Nicole Santucci; Silke Kantimm; Lily I Huschtscha; Christopher J Ormandy; John W Funder; Evan R Simpson; Elizabeth S Kuczek; Peter J Leedman; Wayne D Tilley; Peter J Fuller; George E O Muscat; Christine L Clarke

doi:10.18632/oncotarget.2354

Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease

Oncotarget. 2014 Sep 30;5(18):8651-64. doi: 10.18632/oncotarget.2354.

Authors

Heidi N Hilton¹, Tram B Doan¹, J Dinny Graham¹, Samantha R Oakes², Audrey Silvestri¹, Nicole Santucci¹, Silke Kantimm¹, Lily I Huschtscha³, Christopher J Ormandy², John W Funder⁴, Evan R Simpson⁴, Elizabeth S Kuczek⁵, Peter J Leedman⁶, Wayne D Tilley⁷, Peter J Fuller⁴, George E O Muscat⁸, Christine L Clarke¹

Affiliations

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. St Vincent's Clinical School, St Vincent's Hospital and University of New South Wales, Darlinghurst NSW, Australia.
³ Children's Medical Research Institute, Westmead, New South Wales, Australia.
⁴ MIMR-PHI Institute, Clayton, Victoria, Australia.
⁵ Sydney Medical School, University of Sydney, Westmead, NSW, Australia.
⁶ 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.
⁷ Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, Hanson Institute, University of Adelaide, Adelaide, South Australia, Australia.
⁸ Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / mortality
Breast Neoplasms / pathology
Carcinoma, Intraductal, Noninfiltrating / genetics
Carcinoma, Intraductal, Noninfiltrating / metabolism*
Carcinoma, Intraductal, Noninfiltrating / mortality
Carcinoma, Intraductal, Noninfiltrating / secondary
Case-Control Studies
Cell Lineage
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Epithelial Cells / metabolism*
Epithelial Cells / pathology
Female
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Kaplan-Meier Estimate
Mammary Glands, Animal / metabolism*
Mammary Glands, Human / metabolism*
Mammary Glands, Human / pathology
Prognosis
RNA, Messenger / metabolism
Receptor Cross-Talk
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism*
Receptors, Progesterone / genetics
Receptors, Progesterone / metabolism*
Signal Transduction*
Time Factors

Substances

Biomarkers, Tumor
RNA, Messenger
Receptors, Estrogen
Receptors, Progesterone