ESTRONE SULFATE-SULFATASE AND 17-BETA-HYDROXYSTEROID DEHYDROGENASE-ACTIVITIES - A HYPOTHESIS FOR THEIR ROLE IN THE EVOLUTION OF HUMAN BREAST-CANCER FROM HORMONE-DEPENDENCE TO HORMONE-INDEPENDENCE

The evaluation of estrogens (estrone, estradiol, and their sulfates) in the breast tissue of postmenopausal patients with breast cancer indicates high levels, particularly of estrone sulfate (E(1)S) which is 15-25 times higher than in the plasma. Breast cancer tissue contains the enzymes necessary for focal synthesis of estradiol and it was demonstrated that, despite the presence of the sulfatase and its messenger in hormone-dependent and hormone-independent breast cancer cells, this enzyme operates particularly in hormone-dependent cells. Different progestins: Nomegestrol acetate, Promegestone, progesterone, as well as Danazol, can block the conversion of E(1)S to E(2) very strongly in hormone-dependent breast cancer cells. The last step in the formation of estradiol is the conversion of E(1) to this estrogen by the action of 17 beta-hydroxysteroid dehydrogenase. This activity is preferentially in the reductive direction (formation of E(2)) in hormone-dependent cells, but oxidative (E(2)-->E(1)) in hormone-independent cells. Using intact hormone-dependent cells it was observed that Nomegestrol acetate can block the conversion of E(1) to E(2). It is concluded, firstly, that in addition to ER mutants other factors are involved in the transformation of hormone-dependent breast cancer to hormone-independent, this concerns the enzymatic activity in the formation of E(2); it is suggested that stimulatory or repressive factor(s) involved in the enzyme activity are implicated as the cancer evolves to hormone-independence; secondly, different drugs can block the conversion of E(1)S to E(2). Clinical trials of these ''anti-enzyme'' substances in breast cancer patients could be the next step to investigate new therapeutic possibilities for this disease.