Control Of Sult Activities In Normal And Cancerous Breast

Estrogen Sulfates (in pmol/mg DNA)

Cell Lines In the Cells In the Culture Medium

MCF-7 T-47D

MDA-MB-231

Quoted from Chetrite GS, Kloosterboer HJ, Philippe J-C, Pasqualini JR, Anticancer Research 19: 269-276, 1999b. With permission.

The control of the formation of estrogen sulfoconjugates represents an important mechanism to modulate the biological effect of the hormone in breast tissue as it is well established that estrogen sulfates are biologically inactive. Here we summarize the action of various substances that may inhibit or stimulate SULTs in breast tissue.

Effect of Progestins

Different progestins have been tested on the effect of the SULT activities in breast cancer cells. Medrogestone, a synthetic pregnane derivative that is used in the treatment of pathological deficiency of the natural progesterone, has a biphasic effect on SULT activity in MCF-7 and T47-D breast cancer cells: at a low concentration (5 x 10-8 mol/L), it stimulates the formation of estrogen sulfates, whereas at a high concentration (5 x 10-5 mol/L), the SULT activity is not modified in the MCF-7 cells or inhibited in T47-D cells. Other progestins, promegestone (R-5020), nomegestrol acetate at low concentration, can also increase SULT activity in breast cancer cells (Chetrite et al., 1999a; Figure 8.3). In relation to these findings, it is interesting to mention that the natural progesterone can induce SULT1E1 activity in the Ishikawa human endometrial adenocarcinoma cells, as well as in the excretory endometrial tissue (Clarke et al., 1982; Falany and Falany, 1996b; Tseng and Liu, 1981).

120 80 40

Control R-5020 Norn. Ac. TX-525 Medrog.

FIGURE 8.3 Comparative effects of various progestins on the conversion of estrone (E1) to estrogen sulfates (ES) in the hormone-dependent T-47D human breast cancer cell line. Results (pmol of ES formed in culture medium per mg DNA from E1) are expressed in percent (%) of control value considered as 100%. The data represent the mean ± S.E.M. of duplicate determinations of three to six independent experiments. R-5020: promegestone; Nom.Ac.: nomegestrol acetate; TX-525: a 19-nor progestin of Theramex Laboratories; Medrog.: medrogestone. * P < 0.05 vs control value; ** P < 0.01 vs control value.

120 80 40

FIGURE 8.3 Comparative effects of various progestins on the conversion of estrone (E1) to estrogen sulfates (ES) in the hormone-dependent T-47D human breast cancer cell line. Results (pmol of ES formed in culture medium per mg DNA from E1) are expressed in percent (%) of control value considered as 100%. The data represent the mean ± S.E.M. of duplicate determinations of three to six independent experiments. R-5020: promegestone; Nom.Ac.: nomegestrol acetate; TX-525: a 19-nor progestin of Theramex Laboratories; Medrog.: medrogestone. * P < 0.05 vs control value; ** P < 0.01 vs control value.

Effect of Tibolone and Its Metabolites

Tibolone (the active substance in Livial®) is a 19-nortestosterone derivative with estrogenic, androgenic, and progestagenic properties used to prevent climacteric symptoms and postmenopausal bone loss (Bjarnason et al., 1996; Kicovic et al., 1982).

Tibolone is largely metabolized in three main derivatives: the 3a-and-3p hydroxy, which are estrogenic, and the 4-en isomer, which is progestagenic. These compounds also provoke a dual effect on SULT activity in breast cancer cells: stimulatory at low doses (5 x 10-8 mol/L), inhibitory at high doses (5 x 10-5 mol/L). The 3p-hydroxy derivative is the most potent compound in the stimulatory effect of the SULT activity in both the MCF-7 and T-47D breast cancer cells (Chetrite et al., 1999b; Figure 8.4).

As the apparent affinities of SULT1E1 for estrogens are in the same order as those of Kd for the ER (nanomolar concentrations), it was postulated that SULT1E1 can compete with ER for estradiol binding and abolish the steroid action after processing of ligand-charged ER (Anderson and Howell, 1995; Hobkirk, 1993; Hobkirk et al., 1985; Roy, 1992; Saunders et al., 1989). In support of this hypothesis, it is interesting to remark that a significant sequence homology was observed between the ligand domain of the ER and putative estrogen-binding domain deduced from bovine placental SULT1E1 cDNA (Nash et al., 1988).

It was demonstrated in previous studies in this laboratory that medrogestone, as well as tibolone and its metabolites, at low doses can block the sulfatase activity in the conversion of E1S to estradiol. As these compounds also stimulate SULT1E1 activity in the same concentration range, this dual effect can contribute to decreasing

FIGURE 8.4 Comparative effects of tibolone (Org OD14; active substance of Livial®) and of its main metabolites on the conversion of estrone (E1) to estrogen sulfates (ES) in the hormone-dependent MCF-7 human breast cancer cell line. Results (pmol of ES formed in culture medium per mg DNA from E1) are expressed in percent (%) of control value considered as 100%. The data represent the mean ± S.E.M. of duplicate determinations of three to four experiments. Org OM38: 4-en isomer of tibolone; Org 4094: 3a-hydroxy derivative of tibolone; Org 30126: 3p-hydroxy derivative of tibolone. * P < 0.05 vs control value [3H]-E1 alone. Quoted from Chetrite, GS, Kloosterboer, HJ, Philippe, J-C, Pasqualini, JR, Anticancer Research, 19: 269-276, 1999b.

FIGURE 8.4 Comparative effects of tibolone (Org OD14; active substance of Livial®) and of its main metabolites on the conversion of estrone (E1) to estrogen sulfates (ES) in the hormone-dependent MCF-7 human breast cancer cell line. Results (pmol of ES formed in culture medium per mg DNA from E1) are expressed in percent (%) of control value considered as 100%. The data represent the mean ± S.E.M. of duplicate determinations of three to four experiments. Org OM38: 4-en isomer of tibolone; Org 4094: 3a-hydroxy derivative of tibolone; Org 30126: 3p-hydroxy derivative of tibolone. * P < 0.05 vs control value [3H]-E1 alone. Quoted from Chetrite, GS, Kloosterboer, HJ, Philippe, J-C, Pasqualini, JR, Anticancer Research, 19: 269-276, 1999b.

the estrogenic stimulation by encouraging the excretion of estrogens to the sulfate form. If a similar action can operate in vivo, we have a new possibility to block estradiol with interesting clinical applications.

The mechanism implicated for the different dose-response effects observed with medrogestone or tibolone and its metabolites remains to be elucidated. However, there are a substantial number of examples where a hormone or antihormone produced an opposite effect according to its concentration.

Effect of Quercetin and Resveratrol

Epidemiological studies have suggested that dietary phytoestrogens (e.g., soya products, tea, fruit, etc.) rich in flavonoids, isoflavonoids, and other phenolic compounds can protect against hormone-dependent breast cancer. One of the mechanisms implicated for this chemoprotective effect is the ability of phytoestrogens to inhibit human cytosolic SULTs as the sulfation process is a key step in the metabolic activation of some dietary or environmental procarcinogens and promutagens in mammary tissues (Banoglu, 2000; Kirk et al., 2001; Pai et al., 2001).

Quercetin and resveratrol are dietary flavonoids that can inhibit estrogen sulfatase activity (Huang et al., 1997). It was demonstrated that these flavonoids are also potent inhibitors of the human SULT1A1 (Eaton et al., 1996; Walle et al., 1995)

Otake et al. (2000) observed that quercetin and resveratrol are substrates for EST in the normal HME cells, with Km values similar to their K¡ values for inhibition of estradiol sulfation. Quercetin is 25 times more potent in inhibiting SULT1E1 in the HME cells than in inhibiting SULT1A1 activity in the intact human hepatoma cell line Hep G2, which has SULT1A1 expression levels similar to the human liver (Shwed et al., 1992). The mechanism for this potent inhibition is unclear. Otake et al. (2000) proposed that it could involve 1) a mechanism concentrating quercetin inside the breast cell; 2) bioactivation to a more potent form, e.g., by O-methylation; 3) inhibition of synthesis of the cosubstrate PAPS; or 4) inhibition of some factor involved in the regulation of EST expression.

The IC50 of 0.1 ^M corresponds to a quercetin concentration of about 30 ng/mL, which is 5 to 10 times lower than concentrations in plasma reported in humans after consuming common foodstuffs rich in quercetin, such as onions and apples (Hollman et al., 1997). Inhibition of SULT1E1 by quercetin resulted in elevated estradiol levels in the normal breast cell, which can be a potentially harmful effect. However, it is interesting to note that in the HME cells, SULT1E1 could catalyze the bioactivation of the cooked food mutagen and procarcinogen N-hydroxy-2-amino-1-methyl-6-phenylimidazol (4,5-b)pyridine (N-OH-PhIP) and its subsequent binding to genomic DNA (Lewis et al., 1998). It has been reported that resveratrol (50 ^M) leads to a decrease in PhIP-DNA adducts from 31 to 69% in primary cultures of HME cells. In breast cancer cell lines (MCF-7, ZR-75-1), resveratrol suppresses O-acetyltrans-ferase and SULT activities (Dubuisson et al., 2002).

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