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 s timulated by high concentrations (10(-6) M) of the synthetic progestin s gestodene and 3-ketodesogestrel, but not by Org2058, comparable to t he stimulation by low dosages of estradiol (10(-10) M). At physiologic al concentrations of the progestins (10(-10) M) only T47D cells respon ded. Using specific antihormones it was shown that the effect at pharm acological dosages is mediated by a crossreaction of these compounds w ith the estrogen receptor (ER), while the stimulation of T47D cells at physiological concentrations seems progesterone receptor (PR) mediate d. This was further substantiated using transient transfection assays with ER- and PR-inducible reporter constructs and mRNA induction of th e 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 t hat the level of transcriptionally active PR is a major determinant fo r the response to physiological concentrations of progestins in human breast cancer cells.