CONTROL AND EXPRESSION OF ESTRONE SULFATASE ACTIVITIES IN HUMAN BREAST-CANCER

Oestradiol (E(2)) is one of the most important factors supporting the growth and evolution of breast cancer; consequently, to block this hor mone has been one of the main targets in recent years. The evaluation of oestrogens (oestrone, oestradiol and their sulphates) in the breast tissue of post-menopausal patients with breast cancer indicates high levels, particularly of oestrone sulphate (E(1)S) which is 15-25 times higher than in the plasma. Two main pathways are involved in the form ation of oestrogens: the sulphatase pathway which transforms E(1)S int o oestrone (E(1)), and the aromatase pathway which converts androgens into oestrogens. Comparative studies in breast cancer tissues show tha t the sulphatase pathway is 50-300 times more important than that of t he aromatase pathway. Using intact cells and physiological concentrati ons of E(1)S (5 x 10(-9) M) the conversion to oestradiol was very inte nse with the hormone-dependent (T-47D, MCF-7) breast cancer cells, but very Little or no E(2) was obtained with the hormone-independent (MDA -MB-231, MDA-MB-436) cells. However, when the latter cells were homoge nized, the oestrone sulphatase became very intense. This contradiction in the comparison of the sulphatase activity of the intact cell and t he homogenate of the hormone-independent cells can be explained by the presence of inhibitory factors or the absence of positive factor(s) i nvolved in the enzyme activity, which could be related to the evolutio n of the cancer to hormone-independence. Testing different substances, it was proven that promegestone (R-5020), and danazol, as well as dec apeptyl in the presence of heparin, are very active in inhibiting sulp hatase activity in hormone-dependent breast cancer cells. Using revers e transcriptase-PCR it was possible to detect the presence of oestrone sulphatase mRNA in different mammary cancer cells. The expression of this mRNA is significantly higher in T-47D and MDA-MB-231 than in the other cell lines. A correlation of this mRNA with the enzymatic activi ties of oestrone sulphate was observed. The progestagen, R-5020, can s ignificantly decrease the sulphatase mRNA in MCF-7 and T-47D cells. As this progestagen can also inhibit the enzyme itself, it is suggested that the decrease in sulphatase activity by antisulphatase agents in b reast cancer cells is a complex mechanism involving not only the effec t on the enzyme but also the transcriptional factor(s). It is conclude d that in addition to the control of aromatase, specific inhibition of oestrone sulphatase with antisulphatase agents can open new possibili ties in breast cancer treatment.