Comparison of the in vitro conversion of estradiol-17β to estrone of normal and neoplastic human breast tissue

Pollow, K.; Boquoi, E; Baumann, J.; Schmidt-Gollwitzer, M.; Pollow, Barbara

doi:10.1016/0303-7207(77)90108-3

Cited by 64 publications

(23 citation statements)

References 27 publications

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“…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.…”

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confidence: 99%

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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confidence: 99%

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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“…This evidence is also relevant for other target cells of steroids (Carruba et al, 1997 (Pollow et al, 1977;Strobl and Lippman, 1979;Tait et al, 1989;Poutanen et al, 1993). The oestrogen receptor status is critical for the genesis and/or evolution of a transformed cell phenotype and.…”

Section: Discussionmentioning

confidence: 88%

“…Interconversion of E, and E, has been reported to be altered in the neoplastic breast tissue owing to a change in intrinsic 17p3-HSD activity (Pollow et al, 1977;Prudhomme et al, 1984;Gompel et al, 1986;Vermeulen et al, 1986;Tait et al, 1989;Poutanen et al, 1992;Pasqualini et al, 1996), which also appears to be different according to the hormone-responsive status of cancer cells (Castagnetta et al, 1995(Castagnetta et al, , 1996. This evidence is also relevant for other target cells of steroids (Carruba et al, 1997 (Pollow et al, 1977;Strobl and Lippman, 1979;Tait et al, 1989;Poutanen et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Alteration of oestradiol metabolism in myc oncogene-transfected mouse mammary epithelial cells

Telang

Arcuri²,

Granata³

et al. 1998

Br J Cancer

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Summary Targeted overexpression of the c-myc oncogene induces neoplastic transformation in immortalized, non-tumorigenic mouse mammary epithelial cells (MMEC). Experiments in the present study were conducted to examine whether cellular transformation induced by c-myc oncogene is associated with altered metabolism of 17,-oestradiol (E2). The Keywords: c-myc expression; oestradiol metabolism; mammary carcinogenesis It is well recognized that oestrogens exert a profound influence on mammary epithelial cell growth, differentiation and neoplastic transformation Prudhomme et al, 1984;Mauvais-Jarvis et al, 1986;Siiteri et al, 1986). The molecular and biochemical mechanisms important for oestrogen responsiveness and the influence of altered oestrogen responsiveness on mammary cell carcinogenesis, however, are not fully understood. Our earlier studies on immortalized, non-tumorigenic mouse mammary epithelial cell lines have shown that transfection of the cell line with myc or Ras oncogenes results in neoplastic transformation. Before tumorigenesis in vivo, myc as well as Ras transfectants exhibit aberrant hyperproliferation in vitro (Telang et al, 1990(Telang et al, , 1991Suto et al, 1992). Thus, persistent oncogene expression and aberrant hyperproliferation may represent molecular and cellular biomarkers for neoplastic transformation.The conventionally recognized markers for oestrogen responsiveness include (1) functional activity of oestrogen receptor as determined by receptor-ligand binding; (2) modulation of transcriptional activity, growth and induction of progesterone receptor (Prudhomme et al, 1984;Mauvais-Jarvis et al, 1986;Siiteri et al, 1986;Dubik and Shiu, 1992); (3) (Telang et al, 1991Suto et al, 1993). In addition, it has been proposed that the oestrogenmediated stimulation of growth of breast tumour-derived MCF7 cells may involve transactivation in the c-mvc promoter region (Dubik and Shiu, 1992). It is not clear whether these molecular and metabolic alterations characterize the initiated phenotype or represent a late-occurring, post-initiational event in a rapidly growing tumour cell phenotype.The experiments in the present study were designed to (1) establish the validity of oestrogen metabolism as an endocrine biomarker for tumorigenic transformation in mnyc oncogene-transfected mammary epithelial cells; and (2) elucidate the relationship between myc expression, the extent of cellular metabolism of E, and tumorigenic transformation. To this end, we have compared the extent of EB metabolism in the spontaneously immortalized, non-tumorigenic mammary epithelial cell line MMEC and the stable transfectant MMEC/myc3 that expresses activated c-myc proto-oncogene and is highly tumorigenic.1549

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“…In vitro studies have shown that human mammary tumours cultured in the presence of either labelled oestrone or oestradiol-173 showed higher ratios of oestradiol-17,B to oestrone than did normal or benign tissues (Willcox & Thomas, 1972;Geier et al, 1975). The specific activities of oestradiol-178 dehydrogenase in subcellular fractions of breast-cancer tissues are lower than those from non-malignant tissue (Pollow et al, 1977). Thus, whilst a decrease in oestradiol-17/ dehydrogenase could explain the decrease in oestradiol-17/ metabolism in neoplastic mammary tissue, it is inconsistent with the observed higher conversions of oestrone to oestradiol-17,.…”

Section: Discussionmentioning

confidence: 99%

Effect of hormone manipulation on oxidation, reduction and sulphurylation of dehydroepiandrosterone and oestrone in DMBA-induced rat mammary tumours

Li¹,

Chandra²,

Pewnim³

et al. 1980

Br J Cancer

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Summary.-Using the DMBA-induced mammary tumour as a model, the effect of hormone manipulation on steroid sulphurylation and on oxidative and reductive metabolism has been investigated. or oestradiol-17p + progesterone, administered to oophorectomized animals, had no effect on adenosine-3'-phosphate-5'-phosphosulphate formation in the tumours. Dehydroepiandrosterone sulphotransferase was also unaffected. A large increase in oestrogen sulphotransferase following administration of oestrogen + progesterone was observed in some but not all tumours, and the overall results were not statistically significant. The major metabolities of dehydroepiandrosterone, by both human and carcinogen-induced rat mammary tumours in vitro, are 7-oxygenated derivatives. Oestrogen administration led to a significantly decreased production of total 7-oxygenated derivatives of dehydroepiandrosterone. Conversion to 5-androstene-3p,17p-diol was unaffected by the hormones. The rate of formation of oestradiol-17p from oestrone was increased 5-fold in growing tumours from animals receiving oestrogen, or oestrogen+proges-terone, compared to regressing tumours in oophorectomized control animals.A HYPOTHESIS has been presented implicating adrenal dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) in the aetiology of human breast cancer (Adams, 1977). The main metabolites of DHEA, produced by in vitro incubation with human mammary tumours, are 7-oxygenated derivatives (7a-hydroxy DH-EA, 7P-hydroxy DHEA and 7-oxo DHEA) and 5-androstene-3g, 17/-diol (Li et al., 1978). The latter can cause translocation of the oestrogen receptor in both the uterus and mammary tumours Nicholson et al., 1978). Although it is difficult to be certain of the exact role played by the 7-hydroxylation system in mammary tissue, it has been suggested ) that it could function as an inactivation step to modify oestrogen receptor translocation by 33-hydroxy-A5-androstenes, which are known to occur in relatively high concentrations in human mammary tumours (Maynard et al., 1977). Thus high levels of DHEAS in the blood could lead to high intracellular levels of DHEA and its metabolites formed in situ in mammary tissue.Pathways of DHEA metabolism similar to those established in human mammary tumours also occur in 7,12-dimethylbenz-(a)anthracene (DMBA)-induced rat mammary tumours (Li et al., 1976). It was thus of interest to use this as a model to study the influence of an altered sexhormone milieu in tumour-bearing rats upon subsequent DHEA metabolism in the tumour. In parallel studies, the influence of an altered hormone milieu on oestrogen metabolism by these tumours has been investigated.One other aspect of DHEA metabolism by human mammary tumours, i.e. formation of the sulphate ester, is of relevance when considered together with the sulphurylation of oestradiol-17/. Measurement of these conversions by the tumour

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Comparison of the in vitro conversion of estradiol-17β to estrone of normal and neoplastic human breast tissue

Cited by 64 publications

References 27 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

Alteration of oestradiol metabolism in myc oncogene-transfected mouse mammary epithelial cells

Effect of hormone manipulation on oxidation, reduction and sulphurylation of dehydroepiandrosterone and oestrone in DMBA-induced rat mammary tumours

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