The effect of aromatase inhibitor 4-hydroxyandrostenedione on steroid receptors in hormone-dependent tissues of the rat.
In previous studies, we observed that aromatase inhibitor 4-hydroxy-androstenedione (4-OHA) treatment significantly decreased estrogen (ER) and progesterone receptor (PR) concentrations in the uterus of ovariectomized (OVX) rats. To investigate whether similar effects occur in mammary tumors, we have studied the hormone-dependent, carcinogen (DMBA)-induced tumors of the rat. After 2 weeks of 4-OHA treatment both ER and PR were reduced in mammary tumors, as well as in uteri of intact animals (P < 0.05). Following ovariectomy, receptor levels were also reduced. A further reduction in receptor concentration in mammary tumors occurred with 4-OHA treatment in OVX animals (P < 0.001). Treatment of OVX rats with estradiol (0.2 microgram/ml) restored tumor PR concentrations to the level of the control, whereas ER levels were increased to concentrations slightly higher than the control. 4-OHA treatment partially inhibited this increase in ER in mammary tumors of OVX rats treated with estradiol. In contrast to ER concentrations, mRNA ER levels in the uterus were not decreased significantly by ovariectomy although mRNA levels were reduced in the tumors. Ovariectomy was without effect on mRNA PR in either tissue. Treatment with 4-OHA reduced mRNA levels of ER and PR in uterus and tumors in intact and OVX animals. Levels of tumor mRNA of both ER and PR were inhibited by 4-OHA treatment in estradiol treated OVX rats. Thus, 4-OHA appears to inhibit ER and PR concentrations in mammary tumors of the rat by reducing transcription. Although aromatase inhibition which results in decreased estrogen production, is the major antitumor effect of 4-OHA, reduction in ER and PR could contribute to effective estrogen blockade and limit tumor growth by antagonizing estrogen action as well as production.
Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore 21201.
J L
JL
Zhou
A
A
Brodie
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D010052:Ovariectomy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*
D047072:Aromatase Inhibitors; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D000735:Androstenedione; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; C014594:formestane