Human mammary cancer as a site of sex steroid metabolism

Abstract

Oestrogen-progesterone imbalance in favour of the oestrogens is considered to be an important factor in the development of mammary cancer, although oestrogens are not directly mitogenic. Moreover, this promoter effect of carcinogenesis may be limited in time. Except for increased plasma (free) oestradiol levels, plasma sex hormone levels in breast cancer patients are comparable to those in normal women, matched for age and weight. In both benign and malignant breast tissue, sex hormone concentrations (ng/g) are significantly higher than in plasma (ng/mg), except for dehydroepiandrosterone sulphate, oestrone sulphate and testosterone, but in breast cancer tissues, dehydroepiandrosterone sulphate (DHEAS), 5 alpha-androstane-3 alpha-17 beta-diol and progesterone concentrations are lower than in normal breast tissue. As to the origin of these sex hormones in breast tissue, a positive arteriovenous gradient across the breast tissue has been observed for androstenedione and oestradiol, suggesting uptake from plasma by the tissues. Aromatization of androstenedione, on the other hand, is probably only a minor source of oestrogens in breast tissue. Hydrolysis of oestrone sulphate taken up from the blood, or oestradiol-17 beta fatty acid esters may be another source, but data are too scarce at present to draw a final conclusion as to their role as source of tissue oestrogens. 17 beta-hydroxysteroid dehydrogenase activity, inactivating oestradiol into oestrone, may be an important determinant of tissue oestradiol concentration. This enzyme activity was found to be higher in oestrogen receptor positive than in oestrogen receptor negative tissues and was negatively correlated with DHEA and DHEAS concentrations. As it was shown that the latter two steroids are non-competitive inhibitors of the 17 beta-hydroxysteroid dehydrogenase as well as of the oestrogen-sulphotransferase, it appears that DHEA may be an important modulator of tissue oestradiol concentration, whereas the 17 beta-hydroxysteroid dehydrogenase might constitute an additional marker of hormone dependency of breast cancer.