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Synthesis and Regulation of Sex Hormones in Breast Tissue During Pre- and Postmenopause

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Synthesis and Regulation of Sex Hormones in Breast Tissue During Pre- and Postmenopause JOURNAL FÜR MENOPAUSE PASQUALINI JR Synthesis and regulation of sex hormones in breast tissue during pre- and postmenopause Journal für Menopause 2001; 8 (Supplementum 2) (Ausgabe für Schweiz), 10-13 Homepage: www.kup.at/menopause Online-Datenbank mit Autoren- und Stichwortsuche TERIUMTE IM KLIMAKZEITSCHRIFTISCHE ASPEKT FÜR DIAGNOSTISCHE, THERAPEUTISCHE UND PROPHYLAK Indexed in EMBASE/ Krause & Pachernegg GmbH · VERLAG für MEDIZIN und WIRTSCHAFT · A-3003 Gablitz Excerpta Medica SYNTHESIS AND J. R. Pasqualini REGULATION OF SEX HORMONES IN BREAST SYNTHESIS AND REGULATION OF SEX TISSUE DURING HORMONES IN BREAST TISSUE DURING PRE- AND POSTMENOPAUSE PRE- AND POSTMENOPAUSE and the “sulphatase pathway” which INTRODUCTION converts E1S into E1 by the estrone- ESTRONE SULPHATASE sulphatase (EC: 3.1.6.1) [8–10]. The final step of steroidogenesis is the ACTIVITY IN BREAST CANCER Most breast cancers (~ 95 %) are in conversion of the weak E1 to the AND ITS CONTROL their early stage hormone-sensitive, potent biologically active E2 by the where the estrogen estradiol (E2) action of a reductive 17β-hydroxy- plays an important role in the gen- steroid dehydrogenase type 1 activity For many years the endocrine therapy esis and development of this tumour (17β-HSD-1, EC 1.1.1.62) [11–12]. in breast cancer has been mainly by [1, 2]. About two thirds of breast the utilization of antiestrogens (e.g. cancers occur during the postmeno- Quantitative evaluation indicates Nolvadex, tamoxifen citrate) which pausal period when the ovaries have that in human breast tissue E1S “via block the estrogen receptor. ceased to be functional. Despite the sulphatase” is a much more likely low levels of circulating estrogens, precursor for E2 than is androsten- More recently, another endocrine the tissular concentrations of estrone edione “via aromatase” (Fig. 2) [4, 5, therapy has been explored by inhib- (E1), E2 and their sulphates (E1S, 13]. It is also well established that iting the tissular E2 production using E2S) are several times higher than steroid sulphotransferases, which different anti-enzyme agents in- those found in the plasma or in the convert estrogens into their sul- volved in the biosynthesis of this area of the breast considered as nor- phates, are also present in breast hormone. At present, the positive mal tissue (Fig. 1) suggesting a spe- cancer tissues [14, 15]. This informa- effect of anti-aromatase compounds cific tissular biosynthesis and accu- tion extends the concept of “intra- on the benefit in breast cancer pa- mulation of these hormones [3–5]. crinology” where a hormone can tients is well documented [16–17]. There is substantial information that have its biological response in the However, as E1S in human breast the mammary gland, normal or same organ as it is produced. cancer is quantitatively the most pathological, contains all the en- important precursor of E2, new pos- zymes responsible for the local bio- sibilities can be opened to block E2 synthesis of E2 from circulating pre- which is originated through this con- cursors. Two principal pathways are Figure 2: Comparative effects of jugate via the “sulphatase pathway”. implicated in the last steps of E2 various progestins on the inhibition of formation in breast tissues: the the estrone sulphate (E1S) conver- In human hormone-dependent breast “aromatase pathway” which trans- sion to estradiol (E2) in the hor- cancer cells (MCF-7, T-47D), the forms androgens into estrogens [6–7] mone-dependent T-47D human breast estrone sulphatase activity is high. cancer cell line. In contrast, hormone-independent breast cancer cells (MDA-MB-231, Figure 1: Concentrations of estrone Preconfluent cells were incubated 24 h at 37 °C with a physiological concentration (5 × 10-9 MDA-MB-468) show very low sul- (E1), estradiol (E2) and their mol/l) of [3H]-E1S alone or in the presence of phatase activity in intact cells [18]. sulphates (E1S, E2S) in the tumoral progestins at the concentration of 5 × 10-7 The sulphatase mRNAs are present in tissue and the tissue considered as mol/l. Results (pmol of E2 formed/mg DNA both the hormone-dependent and normal of patients with breast cancer. from E1S) are expressed in percent (%) of hormone-independent breast cancer control value considered as 100 %. The data are The different estrogens were evaluated by RIA. cells and the expression of this mRNA the means ± SEM of duplicate determinations Values (in pg/g tissue) are expressed as the of 3–7 experiments. Prog. = progesterone; correlates with the sulphatase activ- mean ± SEM (n = 14). *p = 0.025 vs. E2 in TX-525 and TX-541 are 19-norprogestins of ity [19]. the normal tissue. **p = 0.05 vs. E1S in the Theramex laboratories; R-5020 = promege- normal tissue. Quoted from [5]. stone; Nom.Ac. = nomegestrol acetate; Control by progestins Medrog. = medrogestone; Noreth. = norethisterone. *p = 0.05 vs control value, Various progesterone derivatives **p = 0.01 vs control value. (e.g. medrogestone), as well as nor- progestins (e.g. nomegestrol acetate, promegestone) provoke a significant decrease of E2 formation when physiological concentrations of E1S are incubated with breast cancer cells (MCF-7 and T-47D) [18, 20]. Figure 2 gives a comparative study of the inhibitory effect of different progestins in the conversion of E1S 10 J. MENOPAUSE Supplement 2/2001 For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. SYNTHESIS AND REGULATION OF SEX HORMONES IN BREAST TISSUE DURING PRE- AND POSTMENOPAUSE to E2 in the T-47D hormone-depend- hormone-independent cells (MDA- breast cancer cells; tibolone and its ent breast cancer cells. MB-231, MDA-MB-468) the metabolites Org 30126 and Org oxidative activity is preferential sug- 4094 (at 5 × 10–7 M) significantly Effect of Tibolone and its metabolites gesting that there is a change in 17β- decrease the conversion of E1 to E2 HSD phenotype in neoplastic cells by the reductive 17β-HSD type 1 In another series of studies, the effect [23, 24]. activity (see Fig. 4). This inhibitory of tibolone on the estrone-sulphatase effect is dose-dependent. The 4-en activity was explored. Tibolone (Org Effect of progestins on 17β -HSD isomer of tibolone (Org OM-38) OD-14, active substance of Livial®) shows an inhibitory effect only at the is a synthetic steroid with a 19-nor- Using nomegestrol acetate or concentration of 5x10–6M [26]. testosterone derivative structure. This medrogestone, it was observed that compound has a tissue-specific ac- these substances decrease signifi- tion with weak estrogenic, progesta- cantly the reductive 17β-HSD activ- genic and androgenic properties and ity in hormone-dependent breast SULPHOTRANSFERASE ACTIVITY is extensively used to prevent cli- cancer cells [23, 25]. This effect is macteric symptoms and postmeno- more intense with the PR-rich T-47D IN BREAST CANCER AND ITS pausal bone loss. Tibolone and its cells. CONTROL metabolites Org 4094, Org 30126 (3α and 3β hydroxy derivatives) and Effect of tibolone and its metabolites its 4-en isomer (Org OM-38) are on 17β -HSD It is well established that estrogen potent sulphatase inhibitors at low sulphates do not bind to the estrogen concentrations in hormone-depend- After 24 h incubation with a physi- receptor and have no estrogenic ent breast cancer cells [21] (Fig. 3). ological concentration of [3H]-E1 effect, consequently increase of (5 × 10–9 M) in T-47D or MCF-7 sulphotransferase activities in breast Estradiol can inhibit estrone sulphatase in human breast cancer cells Figure 3: Comparative effects of tibo- Figure 4: Comparative effects of tibo- Very recent studies of this laboratory lone (Org OD14, active substance of lone (Org OD14, active substance of have demonstrated that E2 at a con- ® ® centration of 5 × 10-5–5 × 10–9 M has Livial ) and of its main metabolites Livial ) and of its main metabolites a significant inhibitory effect on the on the inhibition of the estrone on the inhibition of the estrone (E1) conversion of E1S to E2 in T-47D sulphate (E1S) conversion to estra- conversion to estradiol (E2) in the and MCF-7 breast cancer cells. diol (E2) in the hormone-dependent hormone-dependent T-47D human Estradiol inhibits this conversion at T-47D human breast cancer cell line. breast cancer cell line. very low doses (5 × 10–9 M) (57.5 % Preconfluent cells were incubated 24 h at 37 Preconfluent cells were incubated 24 h at 37 °C of inhibition) and this effect is dose- °C with 5 × 10-9 mol/l of [3H]-E1S alone or in with 5 × 10-9 mol/l of [3H]-E1 alone or in the dependent. The IC50 value (the E2 the presence of tibolone or its metabolites at presence of tibolone or its metabolites at the concentration of 5 × 10-7 mol/l. Results the concentration of 5 × 10-7 mol/l. Results concentration which corresponds to (pmol of E2 formed/mg DNA from E1S) are (pmol of E2 formed in cell compartment/mg × –9 50 % inhibition) is 1.85 10 M expressed in percent (%) of control values DNA from E1) are expressed in percent (%) [22]. considered as 100 %. The data are the means of control value considered as 100 %. The ± SEM of duplicate determinations of 3–5 data are the means ± SEM of duplicate experiments. Org OM38 = 4-en isomer of determinations of 3–4 experiments. Org tibolone; Org 4094 = 3α-hydroxy derivative OM38 = 4-en isomer of tibolone; Org 4094 β of tibolone; Org 30126 = 3β-hydroxy deri- = 3α-hydroxy derivative of tibolone; Org 17 -HYDROXYSTEROID vative of tibolone. *p = 0.001 vs control 30126 = 3β-hydroxy derivative of tibolone. DEHYDROGENASE (17β-HSD) value, **p = 0.0005 vs control value. *p = 0.05 vs control value. IN BREAST CANCER AND ITS CONTROL Studies on estrogen metabolism have demonstrated that the 17β-HSD (Type I) reductive activity is very high in hormone-dependent breast cancer cells (MCF-7, T-47D) whereas in J.
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