Defining the role of progesterone receptor and progestin in luminal breast cancer cells
Date of Issue2018-09-05
School of Biological Sciences
Progesterone is a steroid hormone essential for the reproduction and the development of the mammary gland. Its effects are mediated by progesterone receptor (PR) which is induced by estrogen in most target tissues. In humans and mice, PR is expressed as two major isoforms: PRA and PRB. Although progesterone has been implicated in breast cancer its role in the development of breast cancer remains controversial. There is evidence for the increased risk of breast cancer incidence in post-menopausal women receiving estrogen plus progestin replacement therapy compared to estrogen therapy alone. However, progestin demonstrated therapeutic benefits for metastatic breast cancer. In laboratory studies, progestin can stimulate or inhibit cell growth depending on experimental conditions and cell models. It has been reported that progesterone inhibits estrogen-induced growth of ER and PR-positive luminal breast cancer cells MCF-7 in xenograft model and this is mediated by modulating the activity of ER. However, the role of PR in mediating the effect of progestin in this most commonly used ER and PR-positive model is controversial. This is partly due to the fact that PR expression is estrogen-dependent and the level of estrogen-induced PR is relatively low. As a result, the effect of progestin treatment is often marginal. In order to better understand PR-mediated effect of progestin in luminal breast cancer, the main aim of the study was to establish MCF-7 luminal breast cancer cells overexpressing PRB and define the molecular and cellular aspects of PRB-mediated effect of progestin in this MCF-7 cell model. We hypothesize that progestin exerts the inhibitory effect on MCF-7 cells expressing PR independent estrogen. The study demonstrated that progestin R5020 causes drastic cell growth inhibition. More interestingly, R5020 completely abolished estrogen-induced cell growth. Furthermore, the R5020-treated cells in three dimensional (3D) Matrigel culture were unable to form proper mammospheres and almost the entire population underwent apoptosis after 1-2 weeks in 3D culture. Thus, progestin R5020 strongly suppresses the growth of luminal breast cancer cells when there is an abundant expression of PRB. Taken together, our study demonstrated a powerful anti-tumoral effect of R5020 on breast cancer cells expressing high levels of PR and future in vivo studies could lead to improved outcomes in breast cancer patients.