Studies on the Progesterone Receptor Content and Steroid Metabolism in Normal and Pathological Human Breast Tissues*

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Abstract
Breast tissues from 44 patients who had normal tissues (9) or pathologic tissues designated as fibrocystic disease (8), fibroadenoma (1), and carcinoma (26) were examined for receptor content and metabolism of progesterone. The last 7-consecutive cases of carcinoma were also examined for testosterone metabolism. When the dextran-coated charcoal assay technique was used to analyze the progesterone receptor content of the cytosols, 3 of 9 normal breast tissues (33%), 1 of 8 tissues with fibrocystic disease (12%), and 10 of 26 breast carcinomas (38%) had progesterone receptor levels greater than 10 fmol/mg protein. In the presence of 30% glycerol and 1 μM cortisol, the dissociation constant for the [3H]progesterone-receptor complex was 1.9 ± 1.1 (SE) nM. Although 4 of 5 cases analyzed by sucrose density gradient sedimentation showed only a 4S peak for the progesterone receptor complex, 1 of 5 cases studied with [3H]progesterone and the 2 cases studied with [3H]R5020 (3Hlabeled 17α,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione) had radioactive peaks in the 7-8S and the 4S regions of the sucrose gradients. After incubation of minced tissues with [3H]progesterone, 5α pregnane-3,20-dione, 3α-hydroxy-5α-pregnan-20-one, 20α-hydroxy-pregn-4-en-3-one, 20α-hydroxy-5α-pregnan-3-one, and 5α pregnane-3α-20α-diol were found, indicating the presence of 5α reductase, 20α-hydroxysteroid dehydrogenase, and 3α-hydroxysteroid dehydrogenase activities. Normal breast tissues had the lowest levels of all three enzyme activities, while tissues with fibrocystic disease had the highest 5α-reductase activity. Carcinoma tissues had intermediate levels of 5α-reductase and the highest levels of the other two enzyme activities. There was increased production of 5α-reduced metabolites with increasing epithelial cellularity. After incubation of breast carcinoma tissues with [3H]testosterone, 5α-androstane-3α, 17β-diol, 17β-hydroxy-5α-androstan-3-one, and androstenedione were found. The presence of NADPH in the incubation medium increased the amounts of 5α reduced products formed. 5α-Dihydroprogesterone, the principal metabolite of progesterone in these studies, competed for the progesterone receptor in 2-h competition studies using the dextran-coated charcoal method, but with lower affinity than R5020 or progesterone. These results indicate that detectable levels of progesterone receptors are present in normal as well as pathologic breast tissues and that 5a-reductase and other enzyme activities are present in variable amounts in different types of breast tissues. (J Clin Endocrinol Metab48: 585, 1979)