Norelgestromin as selective estrogen enzyme modulator in human breast cancer cell lines: Effect on sulfatase activity in comparison to medroxyprogesterone acetate

Human breast cancer tissue contains enzymes (estrone sulfatase, 17β-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol (E2) formation. In this tissue, E2 can be synthesized by two main pathways: (1) sulfatase—transforms estrogen sulfates into bioactive E2, and the (2) aromatase—converts androgens into estrogens. Quantitative assessment of E2 formation in human breast tumors indicates that metabolism of estrone sulfate (E1S) via the sulfatase pathway produces 100–500 times more E2 than androgen aromatization.In the present study, we demonstrated in T-47D and MCF-7 human breast cancer cells that norelgestromin (NGMN) (a metabolite of norgestimate) is a potent inhibitory agent of the estrone sulfatase activity. After 24 h incubation of physiological concentrations of E1S (<F>5×10−9</F> mol/l) the inhibitory effect of NGMN at concentrations of <F>5×10−9</F>, <F>5×10−7</F> and <F>5×10−5</F> mol/l was <F>43±7</F>, <F>74±4</F> and <F>97±2</F>%, respectively, in T-47D cells; <F>25±4</F>, <F>57±5</F> and <F>96±2</F>% respectively, in MCF-7 cells. Comparative studies using medroxyprogesterone acetate (MPA) showed that this progestin also has an inhibitory effect on sulfatase activity, but significantly less intense than that of NGMN. The inhibition for MPA at concentrations of <F>5×10−9</F>, <F>5×10−7</F> and <F>5×10−5</F> mol/l was <F>31±5</F>, <F>47±3</F> and <F>61±3</F>%, respectively, for T-47D cells; <F>6±3</F>, <F>20±3</F> and <F>63±4</F>%, respectively, for MCF-7 cells.In conclusion, the present data show that NGMN is a very potent inhibitory agent for sulfatase activity in the hormone-dependent breast cancer cells, resulting in decreased tissue concentration of E2. The clinical significance of this finding remains to be elucidated. [Copyright &y& Elsevier]