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

Pasqualini, Jörge R.

doi:10.1210/jc.81.4.1460

Cited by 270 publications

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“…Sulfatase mRNA levels were 10 2 -fold higher than aromatase mRNA in the present study and sulfatase activity has also been reported to be 400-to 500-fold higher than aromatase activity. 24,25 These results indicate that the sulfatase pathway is more important than aromatase pathway in the production of E1 in most breast tumors. However, Reed et al 26 demonstrated the presence of postmenopausal breast cancers in which the aromatase pathway can be more important than the sulfatase pathway by 3 H-androstendione and 14 Cestrone uptake study in patients.…”

Section: Discussionmentioning

confidence: 87%

Involvement of up-regulation of 17?-hydroxysteroid dehydrogenase type 1 in maintenance of intratumoral high estradiol levels in postmenopausal breast cancers

et al. 2001

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Estradiol (E2) and estrone (E1) levels as well as mRNA expression levels of aromatase, sulfatase and 17␤-hydroxysteroid dehydrogenase type 1 (17␤-HSD1) in breast cancer tissues were studied to elucidate the mechanism involved in the maintenance of the intratumoral high E2 levels in postmenopausal patients with very low serum E2 levels. Intratumoral E2 levels of postmenopausal patients (127.2 ؎ 17.5 pg/g) (mean ؎ SE) were not significantly different from those of premenopausal patients (110.1 ؎ 10.1 pg/g) (p ‫؍‬ 0.36). The mRNA expression levels of aromatase and sulfatase, determined by a quantitative real-time PCR, were not significantly different between premenopausal and postmenopausal breast cancers, but 17␤-HSD1 mRNA expression levels were significantly higher in postmenopausal than premenopausal breast cancers (p < 0.05). Intratumoral E2/E1 ratios were significantly higher in postmenopausal than premenopausal breast cancers (p < 0.01). These results demonstrate that the increased conversion from E1 to E2 catalyzed by 17␤-HSD1 may play an important role in the maintenance of the intratumoral high E2 levels in postmenopausal patients. © 2001 Wiley-Liss, Inc. Key words: breast cancer; estrogens; aromatase; sulfatase; 17␤-HSD1It has been shown that estrogens play an important role in the growth of hormone-dependent breast cancers. 1,2 In premenopausal women, the major source of estrogens is the ovary, and estrogens produced in the ovary are taken up by tumors and stimulate tumor growth. After menopause, serum estradiol (E2) levels decrease to be as low as about 1/10 of that of premenopausal women. 3,4 However, it has been reported that, even after menopause, intratumoral E2 levels are maintained at high levels that are equivalent to those in premenopausal women. 4 High intratumoral E2 levels in postmenopausal women are supposed to be maintained by the intratumoral biosynthesis of estrogens. [5][6][7] E2 is synthesized in breast cancer tissues through 2 pathways (aromatase and sulfatase pathways). 8 -10 In the aromatase pathway, androstenedione taken up by the tumor from the blood is aromatized into estrone (E1) and then catalyzed into E2 by 17-␤hydrox-ysteroid dehydrogenase type 1 (17-␤ HSD1). [11][12][13] In the sulfatase pathway, estrone sulfate (E1S) taken up by the tumor from the blood is converted into E1 and then catalyzed into E2 by 17␤-HSD1. Several studies have demonstrated the intratumoral expression of these enzymes involved in E2 biosynthesis and stressed the importance of aromatase in the intratumoral biosynthesis of E2. 14 -16 Thus, it is speculated that expression of these enzymes, especially aromatase, is enhanced in postmenopausal women as compared with premenopausal women in order to maintain the high E2 levels in tumors. However, it still remains to be established which enzyme(s) is responsible for the high E2 levels in tumors in postmenopausal women.In the present study, we measured the E2 and E1 levels in breast cancer tissues and investigated the association of the E2 and E1 levels with v...

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Section: Discussionmentioning

confidence: 87%

Involvement of up-regulation of 17?-hydroxysteroid dehydrogenase type 1 in maintenance of intratumoral high estradiol levels in postmenopausal breast cancers

et al. 2001

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“…However, another approach to this type of therapy has been to regulate ER responses by modulating the availability of endogenous ER ligand within tumour tissue. Local synthesis of oestrogens as a result of endogeneous aromatase, 17β-HSD and oestrone sulphatase activity has been demonstrated in endometrial (Maentausta et al, 1992), prostate (Elo et al, 1996) and breast tumours (Pasqualini et al, 1996). As a consequence, novel anti-cancer therapies have been aimed at controlling the local build-up of oestrogens in tumours by inhibiting the activity of specific steroidogenic enzymes, particularly aromatase and oestrone sulphatase (Brodie et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

et al. 2000

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Summary Epidemiological data suggest that oestrogen contributes to the aetiology of colonic cancer. Furthermore, recent studies have suggested that local hormone metabolism may play a key role in determining colonic responsiveness to oestrogen. To further clarify this mechanism we have characterized the expression and regulation of isozymes of 17β-hydroxysteroid dehydrogenase (17β-HSD) in vitro and in situ. Immunohistochemistry was used to confirm expression of the type 2 and 4 isozymes of 17β-HSD (17β-HSD2 and 4) in normal colonic epithelial cells. Parallel studies suggested that both isozymes were abnormally expressed in colonic tumours and this was confirmed by Western blot analyses. Abnormal expression of 17β-HSD2 and 4 proteins was also observed in Caco-2, HT-29 and SW620 colonic cancer cell lines, although the overall pattern of oestrogen metabolism in these cells was similar to that seen in primary colonic mucosal tissue. The predominant activity (conversion of oestradiol to oestrone) was highest in Caco-2>SW620>HT-29, which correlated inversely with the rate of proliferation of the cell lines. Regulatory studies using SW620 cells indicated that the most potent stimulator of oestradiol to oestrone inactivation was the antiproliferative agent 1,25-dihydroxyvitamin D 3 (1,25D 3 ), whilst oestradiol itself inhibited 17β-HSD activity. Both oestradiol and 1,25D 3 decreased mRNA for 17β-HSD2 and 4. Data indicate that the high capacity for inactivation of oestrogens in the colon is associated with the presence of 17β-HSD2 and 4 in epithelial cells. MATERIALS AND METHODS Immunohistochemical studiesColonic tumour and paired normal mucosal tissue were obtained with agreement from the local ethical approval committee. Fivemicron thick, formalin-fixed tissue sections were cut and placed on coated glass slides. Sections were de-waxed and endogenous peroxidase activity quenched with 3% hydrogen peroxide. Sections were then incubated in donkey serum (Binding Site, Birmingham, UK) diluted 1/10 in PBS (15 min), followed by primary antibody diluted in PBS (1 hour). Antisera used were as follows: 17β-HSD2 monoclonal antiserum (1/500 dilution), a kind gift of Dr S Andersson (South Western Medical Center, Dallas, USA), was produced with a synthetic carboxyterminal peptide [C]RALRMP-NYKKKAT, corresponding to amino acids 375-387 in the human 17β-HSD2 protein; 17β-HSD4 monoclonal antibody (1:200 dilution), a kind gift of Dr J Adamski (GSF, Neuherberg, Germany) was prepared against the porcine 17β-HSD4 which cross-reacts with human, rat and mouse tissues. After washing, slides were incubated for 30 min with a biotinylated universal secondary antibody (Binding Site), diluted 1/100 in PBS, and binding visualised using ABC reagent (Binding Site) and 3,3′-diaminobenzidine (Sigma Chemical Co, Poole, UK). After staining, slides were washed and counterstained in Mayer's haematoxylin. Cell cultureColonic carcinoma cell lines (SW620, Caco-2 and HT-29) were routinely maintained in Dulbecco's Modified Eagles Medium (DMEM), supplemented wit...

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“…Cells were incubated for 1 day and thereafter treated with or without 10 À8 M oestradiol (17b-oestradiol; Apoteket, Umeå, Sweden), 10 À6 M tamoxifen (Sigma, St Louis, MO, USA) or a combination of oestradiol and tamoxifen. The dose of oestradiol may be considered physiological, taking into consideration the local production and accumulation of oestradiol in human breast tumours in vivo (van Landeghem et al, 1985;Vermeulen et al, 1986;Pasqualini et al, 1996). The concentration of tamoxifen is equivalent to therapeutic serum concentrations found in breast cancer patients.…”

Section: Cells and Culture Conditionsmentioning

confidence: 99%

Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells

Garvin¹,

Nilsson²,

Dabrosin³

2005

Br J Cancer

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Angiogenesis is regulated by the balance between pro-and antiangiogenic factors. Vascular endothelial growth factor (VEGF), acting via the receptors VEGFR-1 and VEGFR-2, is a key mediator of tumour angiogenesis. The soluble form of the VEGF receptor-1 (sVEGFR-1) is an important negative regulator of VEGF-mediated angiogenesis. The majority of breast cancers are oestrogen dependent, but it is not fully understood how oestrogen and the antioestrogen, tamoxifen, affect the balance of angiogenic factors. Angiogenesis is a result of the interplay between cancer and endothelial cells, and sex steroids may exert effects on both cell types. In this study we show that oestradiol decreased secreted sVEGFR-1, increased secreted VEGF, and decreased the ratio of sVEGFR-1/ VEGF in MCF-7 human breast cancer cells. The addition of tamoxifen opposed these effects. Moreover, human umbilical vein endothelial cells (HUVEC) incubated with supernatants from oestradiol-treated MCF-7 cells exhibited higher VEGFR-2 levels than controls. In vivo, MCF-7 tumours from oestradiol þ tamoxifen-treated nude mice exhibited decreased tumour vasculature. Our results suggest that tamoxifen and oestradiol exert dual effects on the angiogenic environment in breast cancer by regulating cancer cell-secreted angiogenic ligands such as VEGF and sVEGFR-1 and by affecting VEGFR-2 expression of endothelial cells.

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

Cited by 270 publications

References 0 publications

Involvement of up-regulation of 17?-hydroxysteroid dehydrogenase type 1 in maintenance of intratumoral high estradiol levels in postmenopausal breast cancers

Involvement of up-regulation of 17?-hydroxysteroid dehydrogenase type 1 in maintenance of intratumoral high estradiol levels in postmenopausal breast cancers

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells

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