Control and expression of oestrone sulphatase activities in human breast cancer.
Oestradiol (E2) is one of the most important factors supporting the growth and evolution of breast cancer; consequently, to block this hormone 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 (E1S) which is 15-25 times higher than in the plasma. Two main pathways are involved in the formation of oestrogens the sulphatase pathway which transforms E1,S into oestrone (E1), and the aromatase pathway which converts androgens into oestrogens. Comparative studies in breast cancer tissues show that the sulphatase pathway is 50-300 times more important than that of the aromatase pathway. Using intact cells and physiological concentrations of E1S (5 x 10(9)M) the conversion to oestradiol was very intense with the hormone-dependent (T-171). MCF-7) breast cancer cells, but very little or no E2 was obtained with the hormone-independent (MDA-MB-231, MDA-MB-436) cells. However, when the latter cells were homogenized, the oestrone sulphatase became very intense. This contradiction in the comparison of the sulphatase activity of the intact cell and the homogenate of the hormone-independent cells can be explained by the presence of inhibitory factors or the absence of positive factor(s) involved in the enzyme activity, which could be related to the evolution of the cancer to hormone-independence. Testing different substances, it was proven that promegestone (R-5020), and danazol, as well as decapeptyl in the presence of heparin, are very active in inhibiting sulphatase activity in hormone-dependent breast cancer cells. Using reverse 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-471) and MDA-MB-231 than in the other cell lines. A correlation of this mRNA with the enzymatic activities of oestrone sulphate was observed. The progestagen, R-5020, can significantly decrease the sulphatase mRNA in MCF-7 and T-471) cells. As this progestagen can also inhibit the enzyme itself, it is suggested that the decrease in sulphatase activity by antisulphatase agents in breast cancer cells is a complex mechanism involving not only the effect on the enzyme but also the transcriptional factor(s). It is concluded that in addition to the control of aromatase, specific inhibition of oestrone sulphatase with antisulphatase agents can open new possibilities in breast cancer treatment.
Pasqualini
J R
JR
CNRS Steroid Hormone Research Unit, Paris, France.
Chetrite
G
G
Nestour
E L
EL
D001943:Breast Neoplasms / Q000201:enzymology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D006801:Humans; D013429:Sulfatases / Q000378:metabolism*
C031555:estradiol sulfate; D004970:Estrone; D004958:Estradiol; D013429:Sulfatases; C020121:estrone sulfatase; C017296:estrone sulfate