Effect of Org OD14 (Livial®) and its metabolites on human estrogen sulphotransferase activity in the hormone-dependent MCF-7 and T-47D, and the hormone-independent MDA-MB-231, Breast cancer cell lines

The concentration of estrogen sulphates (ES) is particularly high in tumoural breast tissues in post-menopausal women. It is well known that during the post-menopausal phase the levels of circulating estrogens are very low, suggesting the local production of these hormones in the breast cancer tissue itself Breast cancer cells possess all the enzymes involved in the last steps of estradiol (E 2 ) formation, as well as in its transformation (e.g sulphotransferase). As ES are not biologically active, the formation of this conjugate is an important transformation pathway in the control of E 2 . Consequently, it was interesting to investigate the factors which regulate the sulphotransferase activity. In the present study, we explored the effect of Org OD14; the active substance in Livial®, and of its main metabolites (Org 4094, Org 30126, Org OM-38) on the estrogen sulphotransferase activity in the hormone-dependent: MCF-7, T-47D, and hormone-independent: MDA-MB-231, human breast cancer cell lines. After 24 hours incubation at 37°C of physiological concentrations of estrone ([ 3 H]-El: 5×10 -9 mol/l), it was observed that the sulphotransferase activity is detectable in MCF-7 and T-47D cells, since the concentrations of ES found were 14.90 and 17.30 pmol/mg DNA, respectively, whereas in MDA-MB-231 cells the concentration of ES found was only 2.01 pmol/mg DNA. Sulphates are found exclusively in the culture medium, which suggests that as soon as the sulphate is biosynthesized it is secreted into the medium. Org OD14, Org 30126, and Org 4094 have a biphasic effect on sulphotransferase activity in the hormone-dependent cells only. At low doses (5×10 -8 mol/l) these compounds stimulate this enzyme by 63, 101, and 51%, respectively in the MCF-7 cells, and by 41, 102, and 80%, respectively in the T-47D cells. No stimulatory effect was detected with Org OM-38. At high concentrations (5×10 -5 mol/l) Org OD14 and its three metabolites inhibit the sulphotransferase activity in MCF-7 and T-47D cells by 50-70%. In conclusion, the stimulatory effect provoked at low doses by Org OD14 and its metabolites (Org 4094, Org 30126) on the estrogen sulphotransferase involved in the biosynthesis of the inactive estrogen sulphates in estrogen-dependent breast cancer cells, can contribute to the protection of breast tissue in postmenopausal women with hormone replacement therapy.