Synthetic progestins induce proliferation of breast tumor cell lines via the progesterone or estrogen receptor

Proliferation of the human breast tumor cell lines T47D and MCF7 was stimulated by high concentrations (10^-6 M) of the synthetic progestins gestodene and 3-ketodesogestrel, but not by Org2058, comparable to the stimulation by low dosages of estradiol (10^-10 M). At physiological concentrations of the progestins (10 ^-10 M) only T47D cells responded. Using specific antihormones it was shown that the effect at pharmacological dosages is mediated by a crossreaction of these compounds with the estrogen receptor (ER), while the stimulation of T47D cells at physiological concentrations seems progesterone receptor (PR) mediated. This was further substantiated using transient transfection assays with ER- and PR-inducible reporter constructs and mRNA induction of the ER- and PR-target genes pS2 and fatty acid synthetase, respectively. Using a whole cell ligand binding assay, 20-fold higher amounts of PR were measured in T47D compared to MCF7 cells. This was in line with a much higher PR-dependent transactivation in T47D cells and suggests that the level of transcriptionally active PR is a major determinant for the response to physiological concentrations of progestins in human breast cancer cells.