posters International Association for Breast Cancer Research 2014

ER and PR are functionally non-overlapping in normal breast but converge in breast cancer (#33)

Heidi N. Hilton 1 , Tram B. Doan 1 , J. Dinny Graham 1 , Audrey Silvestri 1 , Nicole Santucci 1 , Silke Kantimm 1 , Lily Huschtscha 2 , John Funder 3 , Evan Simpson 3 , Elizabeth S. Kuczek 4 , Peter J. Leedman 5 , Wayne D. Tilley 6 , Peter J. Fuller 3 , George E.O. Muscat 7 , Christine L. Clarke 1
  1. Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia
  2. Childrens Medical Research Institute, Sydney, NSW, Australia
  3. Prince Henry's Institute of Medical Research, Melbourne, VIC, Australia
  4. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  5. University of Western Australia, Perth, WA, Australia
  6. Hanson Institute, University of Adelaide, Adelaide, SA, Australia
  7. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, USA
Cumulative exposure to the cycling levels of estrogen (E) and progesterone (P) throughout a woman’s reproductive life significantly influences the lifetime risk of developing breast cancer, and women exposed to progestin-containing hormone replacement therapy (HRT) have an increased breast cancer risk compared to women taking estrogen (E) alone, or no HRT at all. How exposure to these hormones increases breast cancer risk, however, is unknown. Despite the pervasive dogma that P in the breast merely serves as a marker of an active estrogen receptor (ER), and an inhibitor of the proliferative actions of E, it is now clear that in the normal breast P increases proliferation independently of E action. Using a 3D culture model of primary human breast cells to recapitulate the structure of the breast in vivo, as well as a cohort of normal breast tissue samples, we have shown that the progesterone receptor (PR) is expressed in different epithelial populations compared with ER in the normal human breast. In addition, we have shown that PR becomes highly correlated with ER in breast cancer, supporting the view that the mechanisms of E and P action are distinct in the normal breast, but that they converge in breast cancer. Importantly, the findings of this study were obtained using a combination of transcript and protein data, multiple sample cohorts, and in vitro, in vivo and in silico methodologies. The data presented here challenge the established paradigm that ER and PR are co-expressed in normal breast, and have significant implications regarding not only our understanding of normal biology in the human breast, but also regarding diagnosis, prognosis and/or treatment options in breast cancer patients.