Adrenal precursor C19 steroids are potent stimulators of growth of androgen-sensitive mouse mammary carcinoma Shionogi cells in vitro.
Since there is convincing evidence for a role of adrenal steroids as precursors of active sex steroids in peripheral tissues, especially prostate cancer, we have studied the effect of the four main adrenal steroids, namely dehydroepiandrosterone sulfate (DHEA-S), DHEA, 5-androstene-3 beta,17 beta-diol (delta 5-diol) and 4-androstene-3,17-dione (delta 4-dione) on the growth of an androgen-sensitive clone (SEM-1) of the mouse mammary carcinoma Shionogi. From a control doubling time of 6.69 +/- 0.03 days, 0.1 microM DHT, 1.0 microM delta 4-dione, 10 microM delta 5-diol, 10 microM DHEA-S and 10 microM DHEA decreased generation time to 1.60 +/- 0.01, 1.69 +/- 0.01, 1.95 +/- 0.01, 4.37 +/- 0.02 and 5.66 +/- 0.03 days, respectively (P less than 0.01 vs. control). The same compounds exerted their stimulatory effects on cell growth at the following ED50 values: 0.06 nM, 16 nM, 90 nM, 150 nM and 16 microM for DHT, delta 4-dione, DHEA, delta 5-diol and DHEA-S, respectively. The stimulatory effect of all compounds was inhibited in a competitive manner by the pure antiandrogen hydroxyflutamide. Further evidence for an action of the adrenal steroids through the androgen receptor is indicated by competition of [3H]testosterone uptake in the tumor cells at the following IC50 values: 0.21 nM, 0.63 nM, 50 nM, 75 nM and 680 nM for DHT, testosterone, delta 4-dione, delta 5-diol and DHEA, respectively. The present data show that the four main adrenal steroids present in the serum of adult men can exert potent stimulatory effects on the growth of an androgen-sensitive cancer cell line through an androgen receptor-mediated mechanism.
Bégin
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MRC Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
Luthy
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Labrie
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D000728:Androgens / Q000494:pharmacology; D015114:Androstenediol / Q000494:pharmacology*; D000734:Androstenediols / Q000494:pharmacology*; D000735:Androstenedione / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate; D005485:Flutamide / Q000494:pharmacology; D006128:Growth / Q000187:drug effects*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000503:physiopathology; D051379:Mice; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000728:Androgens; D000734:Androstenediols; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D005485:Flutamide; D015114:Androstenediol