Enzymatic control of estrogen production in human breast cancer: relative significance of aromatase versus sulfatase pathways.
One-third of the cases of breast cancer in postmenopausal women are hormone-dependent and the lesions regress upon treatment with antiestrogens or inhibition of estrogen biosynthesis. In these patients, estrogens are synthesized in extraglandular tissues from adrenal precursors and re-enter plasma to produce estrone levels of 52 +/- 6.5 pg/ml (mean +/- SEM) and estradiol concentrations of 13.1 +/- 0.7 pg/ml. However, the fact that the levels of estrogen in breast tumor tissue are an order of magnitude higher than plasma levels suggested the possibility of in situ estrogen production. To address this possibility, we measured several enzymes involved in estradiol biosynthesis in human tumors. Forty-eight of 61 tumors contained aromatase (estrogen synthetase) activity ranging from 5-80 pg/gm protein per hour. By comparison, the levels of estrone sulfatase were 10(6) higher, ranging from 0.8-125 micrograms/gm protein per hour. Because the sulfatase enzyme was of lower affinity (i.e., Km = 27 microM) than that of aromatase (i.e., 0.027 microM), the amount of estrogen formed under conditions of similar substrate concentrations was compared and found to be 10-fold higher via the sulfatase enzyme. In 41 additional tumors, the 17 beta-hydroxysteroid dehydrogenase enzyme, catalyzing the conversion of estrone to estradiol, was uniformly present. To test the biologic relevance of the estrone sulfate to estrone to estradiol pathway, estrogen-dependent nitrosomethylurea rat mammary tumors were grown in soft agar in the presence of estrone sulfate. Concentrations of estrone sulfate of 10(-6) microM significantly (p less than 0.01) stimulated colony formation in this system in which 75.5-98.6% of estrone sulfate was converted to estrone and 0.2 to 6% to estradiol. These data support the hypothesis that mammary carcinomas can synthesize estradiol in situ from circulating estrogen precursor and that local conversion is biologically important. On the basis of comparative data, the estrone sulfate to estrone to estradiol pathway is quantitatively more important than that involving androstenedione to estrone to estradiol.
D015067:17-Hydroxysteroid Dehydrogenases / Q000032:analysis; D000315:Adrenalectomy; D000616:Aminoglutethimide / Q000627:therapeutic use; D000735:Androstenedione / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D004958:Estradiol / Q000032:analysis; D004967:Estrogens / Q000096:biosynthesis*; D004970:Estrone / Q000031:analogs & derivatives / Q000032:analysis; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D051381:Rats; D013429:Sulfatases / Q000378:metabolism*; D013738:Testolactone / Q000031:analogs & derivatives / Q000494:pharmacology
D004967:Estrogens; D000616:Aminoglutethimide; D004970:Estrone; C018155:testololactone; D000735:Androstenedione; D004958:Estradiol; D013738:Testolactone; D015067:17-Hydroxysteroid Dehydrogenases; D001141:Aromatase; D013429:Sulfatases; C014594:formestane; C017296:estrone sulfate; D006854:Hydrocortisone