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Demonstration of aromatase activity and its regulation in breast tumor and benign breast fibroblasts


Breast tumors from post-menopausal women contain higher amounts of estradiol than would be predicted from levels circulating in plasma. This observation raised the hypothesis that tumors may synthesize estradiol in situ and increase their tissue estradiol levels via this mechanism. The key enzyme involved in tissue estrogen synthesis, aromatase, is present in breast tumors but, according to some investigators, not in sufficient concentration to be biologically meaningful. We postulated that foci of cells in breast tumors might contain high amounts of aromatase and this locally produced estrogen might act in a paracrine or autocrine fashion. To test this hypothesis, we utilized immunohistochemistry to localize the aromatase enzyme, an histological scoring system to quantitate it, and culture of isolated breast cells to demonstrate its potential regulation. In 26 archival breast tumors, 16 (62%) contained aromatase by radiometric assay. With the immunohistochemical method, we detected areas with staining in the stroma as well as tumor epithelial cells. Staining ranged from the intensity approaching that seen in placenta to levels just distinguishable from background. We adopted an histological scoring system (H-score) from that used to quantitate progesterone receptor levels in tissue and used it to quantitate aromatase activity. A higher histologic score was found in stromal spindle cells (13) than in tumor epithelial cells (4.8). The biochemical aromatase results correlated with the H-score of stromal but not epithelial cells. To further study stromal cells from tumors, we isolated stromal cells from breast tumors and the benign areas of breast distal to the tumor and grew them in culture. Addition of dexamethasone, phorbol esters, and cyclic AMP analogues stimulated aromatase enzyme and messenger RNA levels substantially. Use of aromatase enzyme inhibitors such as letrozole blocked estrogen production but did not alter aromatase message levels. Epithelial cells, whether nonmalignant or cancer derived, exhibited no regulation by dexamethasone, phorbol esters, or cAMP analogues.

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  1. Siiteri P: Review of studies on estrogen biosynthesis in the human. Cancer Res 42: 3269s–3273s, 1982

    PubMed  CAS  Google Scholar 

  2. Mendelson CR, Cleland WH, Smith ME, Simpson ER: Regulation of aromatase activity of stromal cells derived from human adipose tissue. Endocrinol 111: 1077–1085, 1992

    Article  Google Scholar 

  3. Adams JB, Li K: Biosynthesis of 17α-oestradiol in human breast carcinoma tissue and a novel method for its characterization. Br J Cancer 31: 429–433, 1975

    PubMed  CAS  Google Scholar 

  4. Thijssen JHH, Daroszewski J, Milewicz A, Blackenstein MA: Local aromatase activity in human breast tissues. J Steroid Biochem Mol Biol 44: 577–582, 1993

    Article  PubMed  CAS  Google Scholar 

  5. Santner SJ, Leszczynski D, Wright C, Manni A, Feil PD, Santen RJ: Estrone sulfate: a potential source of estradiol in human breast cancer tissues. Breast Cancer Res Treat 7: 35–44, 1986

    Article  PubMed  CAS  Google Scholar 

  6. Santen RJ, Martel J, Hoagland M et al.: Stromal spindle cells contain aromatase in human breast tumors. J Clin Endocrinol Metab 79: 627–632, 1994

    Article  PubMed  CAS  Google Scholar 

  7. McCarthy Jr KS, Miller LS, Cox EB, Konrath J, McCarthy Sr KS: Estrogen receptor analysis. Arch Pathol Lab Med 109: 716–721, 1985

    Google Scholar 

  8. Lipton A, Santen RJ, Santner SJ et al.: Correlation of aromatase activity with histological differentiation of breast cancer — a morphometric analysis. Breast Res Treat 12: 31–35, 1988

    Article  CAS  Google Scholar 

  9. Stampfer M, Hallowes RC, Hackett AJ: Growth of normal human mammary cells in culture. In vitro 16: 415–425, 1980

    PubMed  CAS  Google Scholar 

  10. Singer C, Rasmussen A, Smith HS, Lippman ME, Lynch HT, Cullen KJ: Malignant breast epithelium selects for insulinlike growth factor II expression in breast stroma: evidence for paracrine function. Cancer Res 55: 2448–2454, 1995

    PubMed  CAS  Google Scholar 

  11. Rønnov-Jessen I, Petersen OW, Koteliansky VE, Bissell MJ: The origin of myofibroblasts in breast cancer. J Clin Invest 95: 859–873, 1995

    Article  PubMed  Google Scholar 

  12. Lazard D, Sastre X, Frid MG, Glukhova MA, Thiery J-P, Koteliansky VE: Expressions of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci USA 90: 999–1003, 1993

    Article  PubMed  CAS  Google Scholar 

  13. Lipton A, Santen RJ, Santner SJ, Harvey HA, Sanders SI, Matthews YL: Prognastic value of breast cancer aromatase. Cancer 70: 1951–1955, 1992

    Article  PubMed  CAS  Google Scholar 

  14. Simpson ER, Merrill JC, Hollub AJ, Graham-Lorence S, Mendelson CR: Regulation of estrogen biosynthesis by human adipose cells. Endocr Rev 10: 136, 1989

    Article  PubMed  CAS  Google Scholar 

  15. Berkovitz GD, Chen S, Migeon CJ, Levine MA: Induction and superinduction of messenger ribonucleic acid specific for atomatase cytochrome P450 in cultured human skin fibroblasts. J Clin Endocrinol Metab 74: 629–634, 1992

    Article  PubMed  CAS  Google Scholar 

  16. Evans CT, Corbin CJ, Saunders CT, Merrill JC, Simpson ER, Mendelson, CR: Regulation of estrogen biosynthesis in human adipose stromal cells. J Biol Chem 262: 6914–6920, 1987

    PubMed  CAS  Google Scholar 

  17. Lephart ED, Peterson KG, Noble JF, George FW, McPahaul MJ: The structure of cDNA clones encoding the aromatase P450 isolated from a rat ovary and a neoplastic cell line. Mol Cell Endocrinol 70: 31–40, 1990

    Article  PubMed  CAS  Google Scholar 

  18. Esteban JM, Warsi Z, Haniu M, Hall P, Shively JE, Chen S: Detection of intratumoral aromatase in breast carcinoma. Am J Pathol 140: 337–343, 1992

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  20. Lu Q, Nakamura, Savinov A, Yue W, Weisz J, Dabbs D, Wolz G, Brodie A: Expression of aromatase protein and messanger ribonucleic acid in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers. Endocrinol 137: 3061–3068, 1996

    Article  CAS  Google Scholar 

  21. Santner SJ, Pauley RJ, Tait L, Kaseta J, Santen RJ: Aromatase activity and expression in breast cancer and benign breast tissue stromal cells. J Clin Endocrinol Metab 82: 200–208, 1997

    Article  PubMed  CAS  Google Scholar 

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Santen, R., Martel, J., Hoagland, M. et al. Demonstration of aromatase activity and its regulation in breast tumor and benign breast fibroblasts. Breast Cancer Res Treat 49 (Suppl 1), S93–S99 (1998).

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