STEROID-HORMONE REGULATION OF PROSTATE-SPECIFIC ANTIGEN GENE-EXPRESSION IN BREAST-CANCER

We have recently reported that about 30-40% of female breast tumours p roduce prostate-specific antigen (PSA) and that PSA production is asso ciated with the presence of oestrogen (ER) and progesterone (PR) recep tors. We have now developed a tissue culture system to study the regul ation of the PSA gene in breast cancer. The breast carcinoma cell line T-47D produces PSA when stimulated by androgens, progestins and gluco corticoids/mineralocorticaids but not oestrogens. PSA mRNA appears app roximately 2 h after stimulation; PSA protein appears after 4-8 h. Amo ng 38 compounds tested, only androgens and progestins were able to sti mulate PSA production at concentrations below 10(-9) M. Evidence that the progesterone and androgen receptors can regulate the PSA gene inde pendently was provided as follows: (a) the progestin norgestimate, whi ch does not bind to the androgen receptor, up-regulates the PSA gene a t concentrations as low as 10(-10) M; (b) triamicinolone acetonide, wh ich does not bind to the androgen receptor (AR) but binds to the PR, a cts similarly to norgestimate; (c) the antiandrogen cyproterone acetat e, which blocks the androgen receptor but has progestational activity, up-regulates the PSA gene at concentrations as low as 10(-10) M; (d) the antiprogestin mifepristone completely blocks the stimulation of th e specific progestin norgestimate. Our tissue culture system identifie d androgen - progestin agonist activities of 17 alpha-ethinyloestradio l, the antioestrogen RU56, 187 and the antiprogestin mifepristone. Our data suggest that the expression of the PSA gene in the female breast is under the control of androgens and progestins. Our tissue culture system is a highly sensitive in vitro method for evaluating the biolog ical activity of candidate compounds having agonist and antagonist ste roid hormone activity.