Mediation by the androgen receptor of the stimulatory and antiandrogenic actions of 17 beta-estradiol on the growth of androgen-sensitive Shionogi mammary carcinoma cells in culture.

Increasing concentrations of 17 beta-estradiol (E2) led to a maximal 7-fold stimulation of growth of the highly androgen-sensitive clone (SEM-1) of the mammary carcinoma Shionogi cell line. Half-maximal stimulation by the estrogen was observed at 100 nM E2. Diethylstilbestrol (DES), on the other hand, a synthetic estrogen with no affinity for the androgen receptor, had no significant stimulatory effect on cell growth but caused growth inhibition at concentrations above 1 microM. Mediation of the action of E2 by the androgen receptor is indicated by the absence of interference of E2 action by the antiestrogen LY156758 while the antiandrogen hydroxyflutamide (3 microM) caused a 50% inhibition of E2 action. While increasing concentrations of E2 led to a progressive increase in cell growth, a progressive shift in the ED50 value of action of dihydrotestosterone (DHT) was observed at intermediate (10-100 nM) concentrations of E2 while 10 microM E2 completely inhibited DHT action. At those high E2 concentrations, however, E2 itself led to a stimulation of cell growth equivalent to approximately 50% of the maximal value achieved by DHT. E2 competed with the specific uptake of [3H]testosterone in intact cells at an inhibition constant (Ki) value of 15 nM, thus indicating direct interaction of E2 with the androgen receptor. Preincubation with E2 had no influence on the apparent affinity of testosterone for the androgen receptor nor on the number of androgen binding sites. The present data demonstrate that both the stimulatory and antiandrogenic action of E2 on the growth of the androgen-sensitive mammary carcinoma cell line SEM-1 are mediated through direct interaction of the estrogen with the androgen receptor. Such data may offer an explanation for the subjective improvements reported in prostate cancer patients receiving a high dose of E2 when relapsing after castration.