Breast Cancer Research and Treatment

, Volume 30, Issue 1, pp 19–29 | Cite as

Regulation of aromatase expression in human tissues

  • Serdar E. Bulun
  • Evan R. Simpson
Article

Summary

Extraglandular conversion of C19 steroids to estrogens takes place primarily in the stromal cell compartments of adipose tissue and is catalyzed by aromatase cytochrome P450 (P450arom, the product of the CYP19 gene). CYP19 gene expression and aromatase activity in breast adipose stromal cells in culture are subject to complex hormonal regulation, which was recently found to be mediated in part by alternative use of tissue-specific promoters of the CYP19 gene. It has been proposed that increased local aromatase activity in breast adipose tissue may influence the growth of breast carcinomas. Using competitive RT-PCR, we quantified P450arom transcripts in breast adipose tissue from mastectomy specimens. In 10 out of 15 patients, the highest transcript levels were found in the quadrant where the tumor was located. We also found the highest proportions of adipose stromal cells vs. adipocytes in these quadrants. These findings suggest that regional differences in the relative proportions of the histologic components give rise to local elevated concentrations of estrogens. Although the initiating events are not known, once a neoplastic change has occurred, tumor growth may be promoted by these locally increased estrogen levels. We are currently investigating alternative promoter use for CYP19 gene transcription to explain this association. Our results underscore the importance of aromatase inhibitors as effective agents in treatment of hormone-responsive breast cancer, since aromatase inhibitors reduce local aromatase activity as well as blood estradiol levels.

Key words

adipose tissue alternative promoters aromatase regulation estrogen biosynthesis RT-PCR stromal cells tumor origins 

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References

  1. 1.
    Mendelson CR, Wright EE, Porter JC, Evans CT, Simpson ER: Preparation and characterization of polyclonal and monoclonal antibodies against human aromatase cytochrome P-450 (P-450arom), and their use in its purification. Arch Biochem Biophys 243:480–491, 1985Google Scholar
  2. 2.
    Kellis JT Jr, Vickery LE: Purification and characterization of human placental aromatase cytochrome P450. J Biol Chem 262:4413–4420, 1987Google Scholar
  3. 3.
    Ryan KJ: Biological aromatization of steroids. J Biol Chem 234:268–272, 1959Google Scholar
  4. 4.
    MacDonald PC, Siiteri PK: Study of estrogen production in women with hydatidiform mole. J Clin Endocrinol Metab 24:685–690, 1964Google Scholar
  5. 5.
    Bahn RS, Worsham A, Speeg KV, Ascoli M, Rabin D: Characterization of steroid production in cultured human choriocarcinoma cells. J Clin Endocrinol Metab 52:447–450, 1981Google Scholar
  6. 6.
    Siiteri PK: Review of studies on estrogen biosynthesis in the human. Cancer Res 42:3269S-3273S, 1982Google Scholar
  7. 7.
    McNatty KP, Baird DT, Bolton A, Chambers P, Corker CS, MacLean H: Concentrations of oestrogens and androgens in human ovarian venous plasma and follicular fluid throughout the menstrual cycle. J Endocrinol 71:77–85, 1976Google Scholar
  8. 8.
    Brodie A, Inkster S: Aromatase in the human testis. J Steroid Biochem Mol Biol 44:549–555, 1993Google Scholar
  9. 9.
    Fritz IB, Griswald MD, Louis BF, Dorrington JH: Similarity of responses of cultured Sertoli cells to cholera toxin and FSH. Mol Cell Endocrinol 5:289–294, 1976Google Scholar
  10. 10.
    Valladares LE, Payne AH: Acute stimulation of aromatization in Leydig cells by human chorionic gonadotropin in vitro. Proc Natl Acad Sci USA 76:4460–4463, 1979Google Scholar
  11. 11.
    Tsai-Morris CH, Aquilana DR, Dufau ML: Gonadotropic regulation of aromatase activity in the adult rat testis. Endocrinology 116:31–37, 1985Google Scholar
  12. 12.
    Nitta H, Bunick D, Hess RA, et al: Germ cells of the mouse testis express P450 aromatase. Endocrinology 132:1396–1401, 1993Google Scholar
  13. 13.
    Naftolin F, Ryan KJ, Petro Z: Aromatization of androstenedione. J Clin Endocrinol Metab. 33:368–370, 1970Google Scholar
  14. 14.
    Ackerman GE, Smith ME, Mendelson CR, MacDonald PC, Simpson ER: Aromatization of androstenedione by human adipose tissue stromal cells in monolayer culture. J Clin Endocrinol Metab 53:412–417, 1981Google Scholar
  15. 15.
    Forney JP, Milewich L, Chen GT, et al: Aromatization of androstenedione to estrone by human adipose tissuein vitro. Correlation with adipose tissue mass, age, and endometrial neoplasia. J Clin Endocrinol Metab 53:192–199, 1981Google Scholar
  16. 16.
    O'Neill JS, Elton RA, Miller WR: Aromatase activity in adipose tissue from breast quadrants: a link with tumor site. Brit Med J 296:741–743, 1988Google Scholar
  17. 17.
    Price T, Aitken J, Head J, Mahendroo MS, Means GD, Simpson ER: 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, 1992Google Scholar
  18. 18.
    Perel E, Wilkins D, Killinger DW: The conversion of androstenedione to estrone, estradiol to testosterone in breast tissue. J Steroid Biochem 13:89–94, 1980Google Scholar
  19. 19.
    Killinger DW, Perel E, Daniilescu D, Kharlip L, Blankenstein MA: Aromatase activity in the breast and other peripheral tissues and its therapeutic regulation. Steroids 50:523–536, 1987Google Scholar
  20. 20.
    Lipton A, Santen RJ, Santner SJ, et al: Prognostic value of breast cancer aromatase. Cancer 70:1951–1955, 1992Google Scholar
  21. 21.
    Grodin JM, Siiteri PK, MacDonald PC: Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 36:207–214, 1973Google Scholar
  22. 22.
    Hemsell DL, Grodin JM, Brenner PF, Siiteri PK, MacDonald PC: 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, 1974Google Scholar
  23. 23.
    Miller WR, O'Neill J: The importance of local synthesis of estrogen within the breast. Steroids 50:537–548, 1987Google Scholar
  24. 24.
    Bulun SE, Mahendroo MS, Price T, Aitken J, Simpson ER: A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts by competitive PCR. J Clin Endocrinol Metab 77: 1622–1628, 1993Google Scholar
  25. 25.
    James VHT, Reed MJ, Lai LC, et al: Regulation of estrogen concentrations in human breast tissues. J Clin Endocrinol Metab 595:227–235, 1990Google Scholar
  26. 26.
    Malet C, Vacca A, Kuttenn F, Mauvais-Jarvis PJ: 17β-estradiol dehydrogenase (E2DH) activity in T47D cells. J Steroid Biochem Mol Biol 39:769–775, 1991Google Scholar
  27. 27.
    Ballard-Barbash R, Schatzkin A, Carter CL, et al: Body fat distribution and breast cancer in the Framingham study. J Natl Cancer Inst 82:286–290, 1990Google Scholar
  28. 28.
    Sellers TA, Kushi LH, Potter JD, et al: Effect of family history, body-fat distribution, and reproductive factors on the risk of postmenopausal breast cancer. N Engl J Med 326:1323–1329, 1992Google Scholar
  29. 29.
    DeRidder CM, Bruning PF, Zonderland ML, et al: Body fat mass, body fat distribution, and plasma hormones in early puberty in females. J Clin Endocrinol Metab 70:888–893, 1990Google Scholar
  30. 30.
    Bulun SE, Simpson ER: Competitive RT-CR analysis indicates levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with age. J Clin Endocrinol Metab 78:428–432, 1994Google Scholar
  31. 31.
    Evans CT, Corbin CJ, Saunders CT, Merrill JC, Simpson ER, Mendelson CR: Regulation of estrogen biosynthesis in human adipose stromal cells: effects of dibutyryl cyclic AMP, epidermal growth factor, and phorbol esters on the synthesis of aromatase cytochrome P-450. J Biol Chem 262:6914–6920, 1987Google Scholar
  32. 32.
    Simpson ER, Merrill JC, Hollub AJ, Graham-Lorence S, Mendelson CR: Regulation of estrogen biosynthesis by human adipose cells. Endocr Rev 10:136–148, 1989Google Scholar
  33. 33.
    Simpson ER, Ackerman GE, Smith ME, Mendelson CR: Estrogen formation in stromal cells of adipose tissue of women: induction by glucocorticosteroids. Proc Natl Acad Sci USA 78:5690–5694, 1981Google Scholar
  34. 34.
    Mendelson CR, Cleland WH, Smith ME, Simpson ER: Regulation of aromatase activity of stromal cells derived from human adipose tissue. Endocrinology 111:1077–1085, 1982Google Scholar
  35. 35.
    Mendelson CR, Corbin CJ, Smith ME, Smith J, Simpson ER: Growth factors suppress, and phorbol esters potentiate the action of dibutyryl cyclic AMP to stimulate aromatase activity of human adipose stromal cells. Endocrinology 118:968–973, 1986Google Scholar
  36. 36.
    Steinkampf MP, Mendelson CR, Simpson ER: Regulation by FSH of the synthesis of aromatase cytochrome P-450 (P-450arom) in human granulosa cells. Mol Endocrinol 1:465–471, 1987Google Scholar
  37. 37.
    Chen S, Besman MJ, Sparkes RS, et al: Human aromatase: cDNA cloning, southern blot analysis, and assignment to the gene to chromosome 15. DNA 7: 27–38, 1988Google Scholar
  38. 38.
    Mahendroo MS, Mendelson CR, Simpson ER: Tissue-specific and hormonally-controlled alternative promoters regulate aromatase cytochrome P450 gene expression in human adipose tissue. J Biol Chem 268:19463–19470, 1993Google Scholar
  39. 39.
    Means GD, Kilgore MW, Mahendroo MS, Mendelson CR, Simpson ER: Tissue-specific promoters regulate aromatase cytochrome P450 gene expression in human ovary and fetal tissues. Mol Endocrinol 5:2005–2013, 1991Google Scholar
  40. 40.
    Ozawa T, Tanaka M, Ikebe S, Ohno K, Kondo T, Mizuno Y: Quantitative determination of deleted mitochondrial DNA relative to normal DNA in Parkinsonian striatum by a kinetic PCR analysis. Biochem Biophys Res Commun 172:483–489, 1990Google Scholar
  41. 41.
    Chelly J, Kaplan J, Maire P, Gautron S, Kahn A: Transcription of the dystrophin gene in human muscle and non-muscle tissues. Nature 333:858–860, 1988Google Scholar
  42. 42.
    Bulun SE, Mahendroo MS, Simpson ER: Polymerase chain reaction amplification fails to detect aromatase cytochrome P450 transcripts in normal human endometrium or decidua. J Clin Endocrinol Metab 76:1458–1463, 1993Google Scholar
  43. 43.
    Miller WR: Aromatase activity in breast tissue. J Steroid Biochem Mol Biol 39:783–790, 1991Google Scholar
  44. 44.
    Dickson RB, Lippman ME: Estrogenic regulation of growth and polypeptide growth factor secretion in human breast carcinoma. Endocr Rev 8:29–43, 1987Google Scholar
  45. 45.
    VanDerBurg B, deGroot RP, Isbrucker L, et al: Oestrogen directly stimulates growth factor signal transduction pathways in human breast cancer cells. J Steroid Biochem Mol Biol 40:215–221, 1991Google Scholar
  46. 46.
    Bradlow HL: The re-assessment of the role of breast tumor aromatization. Cancer Res 42:3382S-3386S, 1982Google Scholar
  47. 47.
    Koos RD, Banks PK, Inkster SE, Yue W, Brodie AMH: Detection of aromatase and keratinocyte growth factor expression in breast tumors using reverse transcription-polymerase chain reaction. J Steroid Biochem Mol Biol 45:217–225, 1993Google Scholar
  48. 48.
    Esteban JM, Warsi Z, Haniu M: Detection of intratumoral aromatase in breast carcinomas. Am J Pathol 140:337–343, 1992Google Scholar
  49. 49.
    Santen RJ, Manni A, Harvey H, Redmond C: Endocrine treatment of breast cancer in women. Endocr Rev 11:221–265, 1990Google Scholar
  50. 50.
    Clarke R, Dickson RB, Lippman ME: Hormonal aspects of breast cancer: Growth factors, drugs, and stromal interactions. Crit Rev Oncol Hematol 12:1–23, 1992Google Scholar
  51. 51.
    Bezwoda WR, Mansoor N, Dansey R: Correlation of breast tumor aromatase activity and response to aromatase inhibition with aminoglutethimide. Oncology 44:345–350, 1987Google Scholar
  52. 52.
    Brodie A: Aromatase and its inhibitors — an overview. J Steroid Biochem Mol Biol 40:255–261, 1991Google Scholar
  53. 53.
    Mahendroo MS, Means GD, Mendelson CR, Simpson ER: Tissue-specific expression of human P450arom: the promoter responsible for expression in adipose is different from that utilized in placenta. J Biol Chem 266:11276–11281, 1991Google Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • Serdar E. Bulun
    • 1
  • Evan R. Simpson
    • 1
  1. 1.Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Departments of Obstetrics/Gynecology and BiochemistryUniversity of Texas Southwestern Medical Center at DallasDallasUSA

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