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Biology of Aromatase in the Mammary Gland

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Abstract

While the ovaries are the principal source of systemic estrogen in the premenopausal nonpregnant woman, other sites of estrogen biosynthesis are present throughout the body and these become the major sources of estrogen beyond menopause. These sites include the mesenchymal cells of the adipose tissue and skin, osteoblasts, and perhaps chondrocytes in bone, vascular endothelial and aortic smooth muscle cells, as well as a number of sites in the brain including the medial preoptic/anterior hypothalamus, the medial basal hypothalamus and the amygdala. These extragonadal sites of estrogen biosynthesis possess several fundamental features which differ from those of the ovaries. Principally, the estrogen synthesized within these compartments is probably only biologically active at a local tissue level in a paracrine or `intracrine' fashion. Thus the total amount of estrogen synthesized by these extragonadal sites may be small, but the local tissue concentrations achieved are probably quite high, and exert significant biological influence locally. Thus these sources of estrogen play an important but hitherto largely unrecognized, physiological and pathophysiological role.

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REFERENCES

  1. E. R. Simpson, Y. Zhao, V. R. Agarwal, M. D. Michael, S. E. Bulun, M. M. Hinshelwood, S. Gramah-Lorence, S. Sun, T. Fisher, and C. R. Mendelson (1997). Aromatase expression in health and disease. Rec. Prog. Horm. Res. 52:185–213.

    Google Scholar 

  2. H. R. Bruch, L. Wolf, R. Budde, G. Romalo, H. U. Schweikert (1992). Androstenedione metabolism in cultured human osteoblast-like cells. J. Clin. Endocrinol. Metab. 75:101–105.

    Google Scholar 

  3. F. Bayard, S. Clamens, G. Delsol, N. Blaes, A. Maret, and J. C. Faye (1995). Oestrogen biosynthesis, oestrogen metabolism and functional oestrogen receptors in bovine aortic endothelial cells. Ciba Found. Symp. 191: 122–132.

    Google Scholar 

  4. H. Sasano, G, Murakami, S. Shizawa, S. Satomi, H. Nagura, and N. Harada (1999). Aromatase and sex steroid receptors in human vena cava. Endocrinol. J. 46: 233–242.

    Google Scholar 

  5. F. Naftolin, K. J. Ryan, I. J. Davies, V. V. Reddy, F. Flores, Z. Petro, M. Kuhn, R. J. White, Y. Takaoka, and L. Wolin (1975). The formation of estrogens by central neuroendocrine tissues. Recent Prog. Hor. Res. 31:295–319.

    Google Scholar 

  6. F. Labrie, A. Belanger, L. Cusan, and B. Candas (1997). Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: Intracrinology. J. Clin. Endocrinol. Metab. 82:2403–2409.

    Google Scholar 

  7. P. K. Siiteri and P. C. MacDonald (1973). Role of extraglandular estrogen in human endocrinology. In R. O. Greep and E. B. Astwood (eds.), Handbook of Physiology, Vol. 2. Washington, American Physiology Society, pp. 619–629.

    Google Scholar 

  8. L. J. Melton (1997). Epidemiology of spinal osteoporisis. Spine 22:2S–11S.

    Google Scholar 

  9. Z. Huang, S. E. Hankinson, G. A. Colditz, M. J. Stampfner, D. J. Hunter, J. E. Manson, C. H. Hennekens, B. Rosner, F. E. Speizer, and W. C. Willett (1997). Dual effects of weight and weight gain on breast cancer risk. JAMA 278:1407–1411.

    Google Scholar 

  10. D. L. Hemsell, J. M. Grodin, P. F. Brenner, P. K. Siiteri, and P. C. MacDonald (1974). Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J. Clin. Endocrinol. Metab. 38: 476–479.

    Google Scholar 

  11. C. H. Tsai-Morris, D. R. Aquilana, and M. L. Dufau (1985). Cellular localization of rat testicular aromatase activity during development. 116:38–46.

    Google Scholar 

  12. H. Nitta, D. Bunick, R. A. Hess, L. Janulis, S. C. Newton, C. F. Millette, Y. Osawa, Y. Shizuta, K. Toda, and J. M. Bahr (1993). Germ cells of the mouse testis express P450 aromatase. Endocrinology 132:1395–1401.

    Google Scholar 

  13. C. Carani, K. Qin, M. Simoni, M. Fanstini-Fustini, S. Serpanti, J. Boyd, K. Korach, and E. R. Simpson (1997). Aromatase deficiency in the male: Effect of testosterone and estradiol treatment. New Eng. J. Med. 337:91–95.

    Google Scholar 

  14. A. Morishima, M. M. Grumbach, E. R. Simpson, C. Fisher, and K. Qin (1995). Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J. Clin. Endocrinol. Metab. 80:3689–3698.

    Google Scholar 

  15. E. P. Smith, J. Boyd, G. R. Frank, H. Takahashi, R. M. Cohen, B. Specker, T. C. Williams, D. B. Lubahn, and K. S. Korach (1994). Estrogen resistance caused by a mutation in the estrogenreceptor gene in a man. N. Engl. J. Med. 331:1056–1061.

    Google Scholar 

  16. O. K. Oz, J. Zerwekh, C. R. Fisher, K. N. Graves, L. Nanu, R. Millsaps, and E. R. Simpson (2000). Bone has a sexually dimorphic response to aromatase deficiency. J. Bone Mineral Res. (in press).

  17. K. Yaffe, G. Sawaya, L. Lieberburg, and D. Grady (1998). Estrogen therapy in postmenopausal women: Effects on cognitive function and dementia. JAMA 279:688–695.

    Google Scholar 

  18. F. Labrie, A. Belanger, V. Luu-The, C. Labrie, J. Simond, L. Cusan, J. L. Gomez, and B. Candas (1998). DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: Its role during agina. Steroids 63:322–328.

    Google Scholar 

  19. F. Labrie, A. Belanger, L. Cusan, J. L. Gomez, and B. Candas (1997). Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J. Clin. Endocrinol. Metab. 82:2396–2402.

    Google Scholar 

  20. H. Sasano, A. R. Frost, R. Saitoh, N. Harada, M. Poutanen, R. Vihko, S. E. Bulun, S. G. Silverberg, and H. Nagura (1996). Aromatase and 17β-hydroxysteroid dehydrogenase Type 1 in human breast carcinoma. J. Clin. Endocrinol. Metab. 81:4042–4046.

    Google Scholar 

  21. H. Sasano, M. Uzuki, T. Sawai, H. Nagura, G. Matsunaga, O. Kashimoto, and N. Harada (1997). Aromatase in human bone tissue. J. Bone Mineral Res. 12:1416–1423.

    Google Scholar 

  22. A. M. Corbould, S. J. Judd, and R. J. Rodgers (1998). Expression of types 1,2, and 3. Mbeta-hydroxysteroid dehydrogenase in subcutaneous abdominal and intraabdominal adipose tissue in women. J. Clin. Endocrinol. Metab. 83:187–194.

    Google Scholar 

  23. S. E. Bulun, and E. R. Simpson (1994). Competitive RT-PCR analysis indicates levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J. Clin. Endocrinol. Metab. 78:428–432.

    Google Scholar 

  24. C. D. Edman and P. C. MacDonald (1976). The role of extraglandular estrogen in women in health and disease. In. James M. Serio and G. Giusti (eds.), The Endocrine Function of the Human Ovary Academic Press, London, pp.135–140.

    Google Scholar 

  25. D. W. Killinger, E. Perel, D. Daniilescu, L. Kherlip, and W. R. N. Lindsay (1987). The relationship between aromatase activity and body fat distribution. Steroids 50:61–72.

    Google Scholar 

  26. S. E. Bulun, T. M. Price, M. S. Mahendroo, J. Aitken, and E. R. Simpson (1993). A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J. Clin. Endocrinol. Metab. 77:1622–1628.

    Google Scholar 

  27. V. R. Agarwal, S. E. Bulun, M. Leitch, R. Rohrich, E. R. Simpson (1996). Use of alternative promoters to express the aromatase cytochrome P450 (CYP19) gene in breast adipose tissues of cancer-free and breast cancer patients. J. Clin. Endocrinol. Metab. 81:3843–3849.

    Google Scholar 

  28. J. S. O'Neill, R. A. Elton, and W. R. Miller (1988). Aromatase activity in adipose tissue from breast quadrants: A link with tumor site. Brit. Med. J. 296:741–743.

    Google Scholar 

  29. M. J. Reed, L. Topping, N. G. Woldham, A. Purohit, M. W. Ghilchik, and V. H. T. James (1993). Control of aromatase activity in breast cancer cells: The role of cytokines and growth factors. J. Steroid. Biochem. Molec. Biol. 44:589–596.

    Google Scholar 

  30. H. Sasano, H. Nagura, N. Harada, Y. Goukon, and M. Kimura (1994). Immunolocalization of aromatase and other steroido genic enzymes in human breast disorders. Hum. Pathol. 25:530–535.

    Google Scholar 

  31. T. Price, J. Aitken, J. Head, M. S. Mahendroo, G. D. Means, and E. R. Simpson (1992). Determination of aromatase cytochrome P450 messenger RNA in human breast tissues by competitive polymerase chain reaction (PCR) amplification. J. Clin. Endocrinol. Metab. 74:1247–1252.

    Google Scholar 

  32. G. E. Ackerman, M. E. Smith, C. R. Mendelson, P. C. Mac-Donald, and E. R. Simpson (1981). Aromatization of androstenedione by human adipose tissue stromal cells in monolayer culture. J. Clin. Endocrinol. Metab. 53:412–417.

    Google Scholar 

  33. E. R. Simpson, G. E. Ackerman, M. E. Smith, and C. R. Mendelson (1981). Estrogen formation in stromal cells of adipose tissue of women: Induction by glucocorticosteroids. Proc. Natl. Acad. Sci. U.S.A. 78:5690–5694.

    Google Scholar 

  34. M. S. Mahendroo, C. R. Mendelson, and E. R. Simpson (1993). Tissue-specific and hormonally-controlled alternative promoters regulate aromatase cytochrome P450 gene expression in human adipose tissue. J. Biol. Chem. 268:19463–19470.

    Google Scholar 

  35. Y. Zhao, C. R. Mendelson, and E. R. Simpson (1995a). Characterization of the sequences of the human CYP19 (aromatase) gene that mediate regulation by glucocorticoids in adipose stromal cells and fetal hepatocytes. Mol. Endocrinol. 9: 340–349.

    Google Scholar 

  36. J. E. Darnell, Jr., I. M. Kerr, and G. R. Stark (1994). Jak_STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1420.

    Google Scholar 

  37. C. Schindler, X-Y Fu, T. Improta, R. Aebersold, and J. E. Darnell, Jr. (1992). Proteins of transcription factor ISGF-3:One gene encodes the 91-and 84 kDA ISGF-3 proteins that are activated by interferon alpha. Proc. Natl. Acad. Sci. U.S.A. 89:7836–7839.

    Google Scholar 

  38. Z. Zhong, Z. Wen, and J. E. Darnell (1994). Members of the family of signal transducers and activators of transcription. Proc. Natl. Acad. Sci. U.S.A. 91:4806–4810.

    Google Scholar 

  39. Y. Zhao, J. E. Nichols, S. E. Bulun, C. R. Mendelson, and E. R. Simpson (1995b). Aromatase P450 gene expression in human adipose tissue. Role of a Jak/STAT pathway in regulation of the adipose-specific promoter. J. Biol. Chem. 270: 16449–164xx.

    Google Scholar 

  40. N. Stahl, T. G. Boulton, T. Farruggella, N. Y. Ip, S. Davis, B. A. Witthuhn, F. W. Quelle, O. Silvenoinen, G. Barbieri, S. Pellegrini, J. N, Ihle, and G. D. Yancopoulos (1994). Association and activation of Jak-Tyk kinases by CNTF-LIF-OSMIL-6 beta receptor components. Science 263:92–95.

    Google Scholar 

  41. N. Stahl and G. D. Yancopoulos (1993). The alphas, betas and kinases of cytokine receptor complexes. Cell 74:587–590.

    Google Scholar 

  42. T. G. Boulton, N. S. Stahl, and G. D. Yancopoulos (1994). Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. J. Biol. Chem. 269:11648–11655.

    Google Scholar 

  43. N. Stahl, T. Farruggella, T. G. Boulton, Z. Zhong, J. E. Darnell, and G. D. Yancopoulos (1995). Modular tyrosine-based motifs in cytokine receptor specific choice of STATs and other substrates. Science 267:1349–1353.

    Google Scholar 

  44. Y. Zhao, J. E. Nichols, R. Valdez, C. R. Mendelson, and E. R. Simpson (1996). Tumor necrosis factor-α stimulates aromatase gene expression in human adipose stromal cells through use of an activating protein-1 binding site upstream of promoter I.4. Mol. Endocrinol. 10:1350–1357.

    Google Scholar 

  45. D. C. Keller, X. X. Du, E. F. Srour, R. Hoffman, and D. A. Williams (1993). Interleukin-11 inhibits adipogenesis and stimulates myelopoiesis in human long-term marrow cultures. Blood 82:1428–1435.

    Google Scholar 

  46. J. Wei, H. Xu, J. L. Davies, and G. P. Hemmings (1992). Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci. 51:1953–1956.

    Google Scholar 

  47. R. A. Daynes, B. A. Araneo, W. B. Ershler, C. Maloney, G. Z. Li, and S. Y. Ryu (1993). Altered regulation of IL-6 production with normal aging. J. Immunol. 150:5219–5230.

    Google Scholar 

  48. N. Harada, T. Utsume, and Y. Takagi (1993). Tissue-specific expression of the human aromatase cytochrome P450 gene by alternative use of multiple exons 1 and promoters, and switching of tissue-specific exons 1 in carcinogenesis. Proc. Natl. Acad. Sci. 90:11312–11316.

    Google Scholar 

  49. Y. Zhao, V. R. Agarwal, C. R. Mendelson, and E. R. Simpson (1996). Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase gene). Endocrinology 137:5739–5742.

    Google Scholar 

  50. M. P. Schrey, and K. V. Patel (1995). Prostaglandin E2 production and metabolism in human breast cancer cells and breast fibroblasts. Regulation by inflammatory mediators. Brit. J. Cancer. 72:1412–1419.

    Google Scholar 

  51. R. B. Dickson and M. E. Lippman (1987). Estrogenic regulation of growth and polypeptide growth factor secretion in human breast carcinoma. Endocrine Rev. 8:29–43.

    Google Scholar 

  52. G. L. Rubin, Y. Zhao, A. M. Kalus, and E. R. Simpson (2000). PPAR_ ligands inhibit estrogen biosynthesis in human breast adipose tissue—possible implications for breast cancer therapy. Cancer Res. (in press).

  53. J. R. Pasqualini, G. Chetrite, C. Blacker, M. C. Feinstein, L. De la Londe, M. Talbi, and C. Maloche (1996). Concentrations of estrone, estradiol and estrone sulfate and evaluation of sulfatase and aromatase activities in pre-and postmenopausal breast cancer patients. J. Clin. Endocrinol. Metab. 81:1460–1464.

    Google Scholar 

  54. Collaborative group on hormonal factors in breast cancer. (1997). Collaborative re-analysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,441 women without breast cancer. Lancet. 350:1047–1059.

    Google Scholar 

  55. R. F. Service (1998). New role for estrogen in cancer? Science 279:1631–1633.

    Google Scholar 

  56. R. E. Harris, K. K. Nauboodim, and W. K. Farrar (1996). Nonsteroidal anti-inflammatory drugs and breast cancer. Epidemiology 1:203–205.

    Google Scholar 

  57. S. E. Bulun, K. M. Zeitoun, K. Takayama, E. R. Simpson, and H. Sasano (1999). Aromatase as a therapeutic target in endometriosis. Trends Endocrinol. Metab. 11:22–27.

    Google Scholar 

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Simpson, E.R. Biology of Aromatase in the Mammary Gland. J Mammary Gland Biol Neoplasia 5, 251–258 (2000). https://doi.org/10.1023/A:1009590626450

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