Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients.

This report concerns the evaluation of various estrogens, estrone (El), estradiol (E2), and estrone sulfate (E1S), as well as E1S-sulfatase and aromatase activities in pre- and postmenopausal women with breast cancer. The levels (in picomoles per g; mean +/- SEM) of the various estrogens in the breast tissue from premenopausal patients (n = 11) are: El, 1.4 +/- 0.5; E2, 1.2 +/- 0.6; and E1S, 1.2 +/- 0.3. In postmenopausal patients (n = 23), the values are, respectively, 1.0 +/- 0.4, 1.4 +/- 0.7, and 3.3 +/- 1.9. These concentrations of estrogens in the tumors of postmenopausal patients are significantly higher than those found in plasma. The activity of E1S-sulfatase in both pre- and postmenopausal patients was 50-200 times higher than that of aromatase. E1S-sulfatase and aromatase activities are significantly higher in post-menopausal than in cycling patients. It is concluded that despite the low levels of circulating estrogens in postmenopausal patients, the tissue concentrations of these steroids are several-fold higher than those in plasma, suggesting tumor accumulation of these estrogens. The physiopathology and clinical significance of these high levels of the various estrogens (E1, E2, and E1S) as well as sulfatase and aromatase activities in postmenopausal patients with breast cancer is yet to be explored.

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 post-menopausal patients with breast cancer indicates high levels, particularly of estrone sulfate (E1S) which is 15-25 times higher than in the plasma. Breast cancer tissue contains the enzymes necessary for local 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 E1S to E2 very strongly in hormone-dependent breast cancer cells. The last step in the formation of estradiol is the conversion of E1 to this estrogen by the action of 17 beta-hydroxysteroid dehydrogenase. This activity is preferentially in the reductive direction (formation of E2) in hormone-dependent cells, but oxidative (E2-->E1) in hormone-independent cells. Using intact hormone-dependent cells it was observed that Nomegestrol acetate can block the conversion of E1 to E2. 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 E2; 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 E1S to E2. Clinical trials of these "anti-enzyme" substances in breast cancer patients could be the next step to investigate new therapeutic possibilities for this disease.

Transcriptional activation of the c-myc oncogene in the T-47D mammary cancer cells by conditioned media from embryonic mouse fibroblasts (BALB/c-3T3). Effect of the antiestrogen ICI 164,384.

The effects of the conditioned medium (CM) of embryonic mouse fibroblast (BALB/c-3T3) cells (clone A31) on the mRNA of the c-myc oncogene of the hormone-dependent T-47D mammary cancer cells were explored. After 6h incubation a significant stimulation of c-myc expression was observed with a 10% v/v concentration of CM, and the effect was even higher using a CM concentration of 30% v/v. It is suggested that this action of CM could be related to the stimulatory effect on proliferation and DNA synthesis induced by the CM, as was recently demonstrated for the T-47D cells. It was also observed that the antiestrogen ICI 164,384 (5 x 10(-6) M) can inhibit the stimulatory action of CM on c-myc expression. It is concluded that the fibroblast mouse embryonic cells contain and secrete factor(s) involved in the mechanism of proliferation of human hormone-dependent mammary cancer cells.

Effect of the progestagen Promegestone (R-5020) on mRNA of the oestrone sulphatase in the MCF-7 human mammary cancer cells.

Using reverse transcriptase polymerase chain reaction amplification it was possible to detect the presence of oestrogen sulphatase mRNA in different hormone-dependent (MCF-7, T-47D) and hormone-independent (MDA-MB-231, MDA-MB-468) mammary cancer cell lines. The expression of this mRNA is significantly higher in T-47D and MDA-MB-231 than in the other cell lines, and a correlation of this expression with the enzymatic activities was observed. The progestagen Promegestone (R-5020) can significantly decrease the mRNA of the sulphatase in MCF-7 cells. As this progestagen can also inhibit the enzyme itself in the same mammary cancer cell line, it is suggested that for the decrease in the sulphatase activity not only the effect on the enzyme, but also the effect on transcriptional factor(s) which express this enzyme are involved. The present data not only contribute to the knowledge of the mechanism of the sulphatase activity, but also can open new possibilities in breast cancer treatment.