A comparison of the in vivo uptake and metabolism of 3H‐oestrone and 3H‐oestradiol by normal breast and breast tumour tissues in post‐menopausal women

McNeill, Judith; Reed, Michael J.; Beranek, P.A.; Bonney, R. C.; Ghilchik, M.W.; Robinson, Dominic J.; James, V. H. T.

doi:10.1002/ijc.2910380208

Cited by 89 publications

(34 citation statements)

References 10 publications

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“…This may reflect the greater importance of this enzyme, also known as aldo-keto reductase 1C3, in androgen metabolism (21). Peripheral metabolism of estrogens normally strongly favors the inactivation of E 2 , but in women with breast cancer, E 1 can be preferentially converted to E 2 in tumor tissue (27). Our data indicate that the enhanced conversion of E 1 to E 2 may be mediated by the increased expression of HSD17B7.…”

Section: Discussionmentioning

confidence: 71%

“…Conversely, HSD17B2, HSD17B10, and HSD17B14 are thought to be the most important oxidative isoforms of the enzyme in breast tissue, inactivating E 2 by converting it to E 1 (24)(25)(26). Whereas the overall peripheral metabolism of estrogens strongly favors E 2 inactivation, the situation is opposite within tumor tissue where E 1 is preferentially converted to E 2 (27). Recent data from our group found HSD17B7 expression to be positively correlated with response to aromatase inhibition in advanced breast cancer (28).…”

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confidence: 99%

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Intratumoral Estrogen Disposition in Breast Cancer

Haynes

Straume

Geisler

et al. 2010

Clinical Cancer Research

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Purpose: The concentration of estradiol (E 2 ) in breast tumors is significantly higher than that in plasma, particularly in postmenopausal women. The contribution of local E 2 synthesis versus uptake of E 2 from the circulation is controversial. Our aim was to identify possible determinants of intratumoral E 2 levels in breast cancer patients.Experimental Design: The expression of genes involved in estrogen synthesis, metabolism, and signaling was measured in 34 matched samples of breast tumor and normal breast tissue, and their correlation with estrogen concentrations assessed.Results: ESR1 (9.1-fold; P < 0.001) and HSD17B7 (3.5-fold; P < 0.001) were upregulated in ER + tumors compared with normal tissues, whereas STS (0.34-fold; P < 0.001) and HSD17B5 (0.23-fold; P < 0.001) were downregulated. Intratumoral E 2 levels showed a strong positive correlation with ESR1 expression in all patients (Spearman r = 0.55, P < 0.001) and among the subgroups of postmenopausal (r = 0.76, P < 0.001; n = 23) and postmenopausal ER + patients (r = 0.59, P = 0.013; n = 17). HSD17B7 expression showed a significant positive correlation (r = 0.59, P < 0.001) whereas HSD17B2 (r = −0.46, P = 0.0057) and HSD17B12 (r = −0.45, P = 0.0076) showed significant negative correlations with intratumoral E 2 in all patients. Intratumoral E 2 revealed no correlation to CYP19, STS, and HSD17B1 expression. Multivariate models comprising ESR1 and plasma E 2 predicted between 50% and 70% of intratumoral E 2 variability.

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

Intratumoral Estrogen Disposition in Breast Cancer

Haynes

Straume

Geisler

et al. 2010

Clinical Cancer Research

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“…These are that (1) either tumours secrete factors capable of enhancing aromatase activity in adjacent tissue, or else ( 2 ) increased aromatase activity in breast adipose tissue encourages tumour development at this site. In a previous study the uptake and metabolism of 3H-oestrone by breast tissues was examined (McNeill et al, 1986). It was found that the tissue:plasma ratio for 3H-oestrone ranged from 3.9 to 6.1 for normal breast tissue and from 3.0 to 10.4 for tumour tissue.…”

Section: Discussionmentioning

confidence: 99%

in situ oestrone synthesis in normal breast and breast tumour tissues: Effect of treatment with 4‐hydroxyandrostenedione

Reed

Owen

Lai

et al. 1989

Intl Journal of Cancer

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148

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An isotopic infusion technique has been used in an attempt to determine the contribution that local, in situ, oestrone synthesis makes to the oestrogen content of breast tumours. 3H-Androstenedione and 14C-oestrone were infused into women with advanced breast cancer for 12 hr before operation. At surgery, normal breast and breast tumour biopsy samples were obtained and 3H-androstenedione, 3H-oestrone derived from 3H-androstenedione and 14C-oestrone were isolated and measured. DNA polymerase alpha activity, a marker of cellular proliferation, was also measured to examine whether local synthesis of oestrone exerted a biological effect. The study was repeated after patients had been treated with the aromatase inhibitor, 4-hydroxyandrostenedione, before undergoing further surgery for removal of their tumours. In 4/6 tumours examined, in situ synthesis of 3H-oestrone from 3H-androstenedione accounted for the major part (84.3 +/- 9.0%) of the 3H-oestrone detected, while no significant in situ synthesis occurred in 2 other tumours. Although treatment with 4-hydroxyandrostenedione did not significantly alter the uptake of 3H-androstenedione or 14C-oestrone into breast tissues, in situ formation of 3H-oestrone was only detected in one tumour sample after treatment. DNA polymerase alpha activity decreased in 4/6 tumours after treatment with 4-hydroxyandrostenedione. Overall, however, there was no significant correlation between the level of 3H-oestrone formed in situ and DNA polymerase alpha activity (r = 0.38, NS). It is concluded that in some, but not all, breast tumours in situ formation of oestrone can make an important contribution to the oestrogen content of breast tumours.

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“…1986, Wilson et al 1987, 1988, Farkas & Rosler 1993, Geissler et al 1994 (McNeill et al 1986, Vermeulen et al 1986). Because 17ß-estradiol enhances breast cell proliferation, 17ß-HSD is an attractive target for the design of inhibitors that may be effective antitumor agents.…”

Section: Introductionmentioning

confidence: 98%

17 -Hydroxysteroid dehydrogenase: inhibitors and inhibitor design

Penning¹

1996

Endocrine Related Cancer

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A comparison of the in vivo uptake and metabolism of ³H‐oestrone and ³H‐oestradiol by normal breast and breast tumour tissues in post‐menopausal women

Cited by 89 publications

References 10 publications

Intratumoral Estrogen Disposition in Breast Cancer

Intratumoral Estrogen Disposition in Breast Cancer

in situ oestrone synthesis in normal breast and breast tumour tissues: Effect of treatment with 4‐hydroxyandrostenedione

17 -Hydroxysteroid dehydrogenase: inhibitors and inhibitor design

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