Hostname: page-component-848d4c4894-8bljj Total loading time: 0 Render date: 2024-06-21T05:25:50.506Z Has data issue: false hasContentIssue false
  • English
  • Français

The regulation of oestrogen biosynthesis in human adipose tissue

Published online by Cambridge University Press:  05 December 2011

E. R. Simpson  and
C. R. Mendelson
E. R. Simpson
Affiliation:
The Cecil H. & Ida Green Center for Reproductive Biology Sciences and the Departments of Obstetrics-Gynecology and Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235, U.S.A.
C. R. Mendelson
Affiliation:
The Cecil H. & Ida Green Center for Reproductive Biology Sciences and the Departments of Obstetrics-Gynecology and Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235, U.S.A.
Get access

Synopsis

The enzyme complex responsible for the conversion of androgens to oestrogens is called aromatase. This enzyme is expressed in a number of tissue sites, including granulosa cells, placenta, hypothalamus and adipose. Oestrogen formation in adipose tissue has been implicated in the aetiology of endometrial and breast cancer. Aromatase comprises two components: a member of the cytochrome P-450 gene family known as aromatase cytochrome P-450, and a flavoprotein, NADPH-cytochrome P-450 reductase. We have recently obtained a full-length cDNA insert encoding human aromatase cytochrome P-450 and have expressed it in COSI monkey kidney tumour cells. The resulting transcript encodes a protein which is capable of converting androstenedione, testosterone and 16α-hydroxyandrostenedione to the corresponding oestrogens. Furthermore, characterisation of the aromatase cytochrome P-450 gene indicates that in humans there is only one such gene, which spans about 30kb and has at least nine exons. From these results we conclude that there is only one aromatase enzyme in humans. Study of the expression of this enzyme in human adipose stromal cells indicates that it is subject to regulation by a number of factors including cAMP, phorbol esters, and the growth factors, EGF, TGF-α, TGF-β, TNF and 1Lβ. Since several of these growth factors are produced by breast cancer cells in response to oestrogens, the possibility exists for paracrine and autocrine feedback loops within the breast, in which the growth of a tumour is regulated by oestrogen produced locally in the adipose cells of the surrounding tissue, and this in turn is regulated by the growth factors produced by the tumour as a result of oestrogen action.

Type
Research Article
Information
Proceedings of the Royal Society of Edinburgh, Section B: Biological Sciences , Volume 95: Oestrogen and the Human Breast , 1989 , pp. 153 - 159
Copyright
Copyright © Royal Society of Edinburgh 1989

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Bradshaw, K. D., Waterman, M. R., Couch, R. T., Simpson, E. R. & Zuber, M. X. 1987. Characterization of complementary DNA for human adrenocortical 17α-hydroxylase: A probe for analysis of 17α-hydroxylase deficiency. Molecular Endocrinology 1, 348–354.CrossRefGoogle Scholar
Chua, S. C., Szabo, P., Vitek, A., Grzeschik, K. H., John, M. E. & White, P. C. 1987. Cloning of cDNA encoding steroid 11β-hydroxylase (P-450c11). Proceedings of the National Academy of Sciences of the U.S.A. 84, 7193–7197.CrossRefGoogle Scholar
Chung, B. C., Picardo-Leonard, J., Haniu, M., Bienkowski, M., Hall, P. F., Shively, J. E. & Miller, W. L. 1987. Cytochrome P-450c17: Cloning of human adrenal and testis cDNAs indicated the same gene is expressed in both tissues. Proceedings of the National Academy of Sciences of the U.S.A. 84, 407–411.CrossRefGoogle Scholar
Corbin, C. J., Graham-Lorence, S., McPhaul, M., Mason, J. I., Mendelson, C. R. & Simpson, E. R. 1988. Isolation of a full-length cDNA insert encoding human aromatase cytochrome P-450 and its expression in non-steroidogenic cells. Proceedings of the National Academy of Sciences of the U.S.A. (in press).CrossRefGoogle Scholar
Grodin, J. M., Siiteri, P. K. & MacDonald, P. C. 1973. Source of estrogen production in the postmenopausal women. Journal of Clinical Endocrinology and Metabolism 36, 207–214.CrossRefGoogle ScholarPubMed
Higashi, Y., Yoshioka, H., Yamane, M., Gotoh, O. & Fujii-Kurayama, Y. 1986. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: A pseudogene and a genuine gene. Proceedings of the National Academy of Sciences of the U.S.A. 83, 2841–2845.CrossRefGoogle Scholar
John, M. E., Okamura, T., Dee, A., Adler, B., John, M. C., White, P. C., Simpson, E. R. & Waterman, M. R. 1986. Bovine steroid 21-hydroxylase: Regulation of biosynthesis. Biochemistry 25, 2846–2853.CrossRefGoogle Scholar
Knabbe, C., Lippman, M. E., Wakefield, L. M., Flanders, K. C., Kasid, A., Derynck, R. & Kickson, R. B. 1987. Evidence that transforming growth factor-β is a hormonally-regulated negative growth factor in human breast cancer cells. Cell 48, 417–428.CrossRefGoogle ScholarPubMed
MacDonald, P. C., Edman, C. D., Hemsell, D. L., Porter, J. C. & Siiteri, P. K. 1978. Effect of obesity on conversion of plasma androstenedione to estrone in postmenopausal women with and without endrometrial cancer. American Journal of Obstetrics and Gynecology 130, 448–455.CrossRefGoogle Scholar
McPhaul, M., Noble, J. F., Simpson, E. R., Mendelson, C. R. & Wilson, J. D. 1988. The expression of a functional cDNA encoding the chicken cytochrome P-450AROM that catalyses the formation of estrogen from androgen. Journal of Biological Chemistry (in press).CrossRefGoogle Scholar
Mendelson, C. R., Corbin, C. J., Smith, M. E., Smith, J. & Simpson, E. R. 1986. Growth factors suppress and phorbol esters potentiate the action of dibutyryl adenosine 3',5'-monophosphate to stimulate aromatase activity of human adipose stromal cells. Endocrinology 118, 968–973.CrossRefGoogle ScholarPubMed
Morohashi, K., Fujii-Kurayama, Y., Okada, Y., Sagawa, K., Horose, T., Inayama, S. & Omura, T. 1984. Molecular cloning and nucleotide sequence of cDNA for mRNA of mitochondrial cytochrome P-450 (SCC) of bovine adrenal cortex. Proceedings of the National Academy of Sciences of the U.S.A. 81, 4647–4651.CrossRefGoogle ScholarPubMed
O'Neill, J. S., Elton, R. A. & Miller, W. R. 1988. Aromatase activity in adipose tissue from breast quadrants: A link with tumour site. British Medical Journal 296, 741–743.CrossRefGoogle ScholarPubMed
Simpson, E. R., Ackerman, G. E., Smith, M. E. & Mendelsom, C. R. 1981. Estrogen formation in stromal cells of adipose tissue of women: Induction by glucocorticoids. Proceedings of the National Academy of Sciences of the U.S.A. 78, 5690–5694.CrossRefGoogle Scholar
Thompson, E. A. Jr., & Siiteri, P. K. 1974a. Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. Journal of Biological Chemistry 249, 5364–5372.CrossRefGoogle ScholarPubMed
Thompson, E. A. Jr., & Siiteri, P. K. 1974b. The involvement of human placental microsomal cytochrome P-450 in aromatization. Journal of Biological Chemistry 249, 5373–5378.CrossRefGoogle ScholarPubMed
White, P. C., New, M. I. & Dupont, B. 1986. Structure of human steroid 21-hydroxylase genes. Proceedings of the National Academy of Sciences of the U.S.A. 83, 5111–5115.CrossRefGoogle ScholarPubMed
Zuber, M. X., John, M. E., Okamura, T., Simpson, E. R. & Waterman, M. R. 1986. Bovine adrenocortical cytochrome P-45017α: Regulation of gene expression by ACTH and elucidation of primary sequence. Journal of Biological Chemistry 261, 2475–2482.CrossRefGoogle Scholar