Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Progesterone action in normal breast and breast cancer (#138)

J. Dinny Graham 1 , Heidi N Hilton 1 , Audrey Silvestri 1 , Nicole Santucci 1 , Tram Doan 1 , Lily Huschtscha 2 , Christine Clarke 1
  1. Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
  2. Children’s Medical Research Institute, Westmead, NSW, Australia

The ovarian hormone progesterone is a key regulator of a diversity of female reproductive tissue functions, acting as a physiological inhibitor of estrogen-induced proliferation in the uterus, but increasing mammary progenitors and driving lobular alveolar development in the breast. The finding that progestins in exogenous formulations (oral contraceptives, hormone replacement therapy (HRT)) increased breast cancer risk was completely unexpected, as was the lack of any increased risk associated with estrogen (E) in HRT. E was long believed to be the principal mitogen in the breast, whereas progestins were thought to be markers of E action in the breast, and by analogy with their action in the uterus, to be anti-estrogens through inhibition of E-mediated proliferation. The dogma that progesterone (P) is an anti-estrogen in the breast is challenged by the findings of the HRT trials; and by emerging evidence from our group and others that P is proliferative in the normal human breast; that P expands progenitor cells in human breast and mouse mammary gland; and that P augments cancer stem cells. These are obvious pathways of P influence on cell lineage in normal breast, and potential mechanisms for its deleterious impact in breast cancer. P acts through its nuclear receptor (PR), expressed as two isoforms, PRA and PRB, which are functionally different. PR forms both homodimers and heterodimers and all three dimer species are transcriptionally active. They are equivalently expressed in mature luminal cells in normal breast, however PRA is the predominant species in bipotent progenitors. This presentation will detail recent insights using a model of primary normal human breast as well as clinical cohorts, that modulation of PR isoform ratio represents a normal mechanism controlling P action in the normal breast, but that in breast cancer PR - via predominance of its isoform PRA – predicts poorer response to the ER-targeted agent tamoxifen, compared with aromatase inhibitors. These emerging data indicate major alterations in P signalling in breast cancer, and emphasise a clinically important convergence of ER and PR action in breast cancer.