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Oestrogen producing enzymes and mammary carcinogenesis: a review

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Abstract

There is a large and compelling body of epidemiological and experimental evidence that oestrogens are instrumental in the aetiology of breast cancer. Their mechanisms of action are varied, including stimulation of cellular proliferation through receptor-mediated hormonal activity, increasing genetic mutation rates through cytochrome P450-mediated metabolic activation, and induction of aneuploidy. The local biosynthesis of oestrogens especially in postmenopausal women is believed to play a very important role in the pathogenesis and development of hormone dependent breast carcinoma and the over-expression of regulatory enzymes seems to be associated with the development of a more aggressive disease and associated with poor outcome and increased local and distant recurrences. In this article we highlight the role of CYP19 gene expression and aromatase activity in mammary carcinogenesis. Other oestrogen producing (17-β-hydroxysteroid dehydrogenase and steroid sulphatase) and catalyzing enzymes (3-β-hydroxysteroid dehydrogenase, Oestrogen sulfotransferase, CYP1A1, CYP1B1, and CYP3A4) are also discussed in some detail. Understanding the mechanisms that regulate these enzymes is crucial to the development of new endocrine therapies in post-menopausal females with hormone dependant breast cancer. Currently, third generation aromatase inhibitors has revolutionized the treatment of oestrogen dependant breast cancer. However, the important role of both STS and 17-β-HSD type 1 in local oestrogen production provides novel potential targets for endocrine therapy. Such endocrine therapy is currently being explored and the development of STS inhibitors, combined aromatase/steroid sulfatase inhibitors and 17-β-HSD type 1 inhibitors is underway with promising initial results.

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References

  1. Sasco AJ (2003) Breast cancer and the environment. Horm Res 60(Suppl 3):50

    PubMed  CAS  Google Scholar 

  2. Henderson IC, Canellos GP (1990) Cancer of the breast: the past decade. N Engl J Med 302:17–30

    Article  Google Scholar 

  3. Henderson HS, Ross RK, Bernstein L (1988) Oestrogens as a cause of human cancer: The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 48:246

    PubMed  CAS  Google Scholar 

  4. Page DL, Dupont WD, Rogers LW, Rados MS (1985) Atypical hyperplastic lesions of the female breast; a longterm follow-up study. Cancer 55:2698–2708

    PubMed  CAS  Google Scholar 

  5. Russo J, Hasan Lareef M, Balogh G, Guo S, Russo IH (2003) Oestrogen and its metabolites are carcinogenic agents in human breast epithelial cells. J Steroid Biochem Mol Biol 87(1):1–25

    PubMed  CAS  Google Scholar 

  6. Chen S (1998) Aromatase and breast cancer. Front Biosci 3:922–933

    Google Scholar 

  7. London SJ, Connolly JL, Schnitt SJ, Colditz GA (1992) A prospective study of benign breast disease and the risk of breast cancer. JAMA 267:941–944

    PubMed  CAS  Google Scholar 

  8. Shekhar PVM, Werdell J, Barsrur VS (1997) Environmental oestrogen stimulation of growth and oestrogen receptor function in preneoplastic and cancerous human breast cell lines. J Natl Cancer Inst 89:1774–1782

    PubMed  CAS  Google Scholar 

  9. Dao TL (1981) The role of the ovarian steroid hormones in mammary carcinogenesis. In: Pike MC, Siiteri PK, Welsch CW (eds) Hormones and breast cancer. (anbury repport no.8). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 281–295

    Google Scholar 

  10. Wadia PR, Vandenberg LN, Schaeberle CM, Rubin BS, Sonnenschein C, Soto AM (2007) Perinatal bisphenol A exposure increases oestrogen sensitivity of the mammary gland in diverse mouse strains. Environ Health Perspect 115(4):592–598

    Article  PubMed  CAS  Google Scholar 

  11. Muñoz-de-Toro M, Markey CM, Wadia PR, Luque EH, Rubin BS, Sonnenschein C, Soto AM (2005) Perinatal exposure to bisphenol-A alters peripubertal mammary gland development in mice. Endocrinology 146(9):4138–4147

    PubMed  Google Scholar 

  12. Murray TJ, Maffini MV, Ucci AA, Sonnenschein C, Soto AM (2007) Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reprod Toxicol 23(3):383–390

    PubMed  CAS  Google Scholar 

  13. Pietras RJ, Marquez DC, Chen HW, Tsai E, Weinberg O, Fishbein M (2005) Oestrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. Steroids 70:372–381

    PubMed  CAS  Google Scholar 

  14. Garvin S, Nilsson UW, Dabrosin C (2005) Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells. Br J Cancer 93:1005–1010

    PubMed  CAS  Google Scholar 

  15. Maor S, Mayer D, Yarden RI, Lee AV, Sarfstein R, Werner H, Papa MZ (2006) Oestrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1. J Endocrinol 191(3):605–612

    PubMed  CAS  Google Scholar 

  16. Redeuilh G, Attia A, Mester J, Sabbah M (2002) Transcriptional activation by the oestrogen receptor alpha is modulated through inhibition of cyclin-dependent kinases. Oncogene 21:5773–5782

    PubMed  CAS  Google Scholar 

  17. Yue W, Wang JP, Hamilton CJ, Demers LM, Santen RJ (1998) In situ aromatization enhances breast tumor estradiol levels and cellular proliferation. Cancer Res 58:927–932

    PubMed  CAS  Google Scholar 

  18. Planas-Silva MD, Waltz PK (2007) Oestrogen promotes reversible epithelial-to mesenchymal-like transition and collective motility in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol 104(1–2):11–21

    PubMed  CAS  Google Scholar 

  19. Sasano H, Okamoto M, Mason JI, Simpson ER, Mendelson CR, Sasano N, Silverberg SG (1989) Immunolocalization of aromatase, 17-alpha-hydroxylase and side-chain-cleavage cytochromes P-450 in the human ovary. J Reprod Fertil 85:163–169

    Article  PubMed  CAS  Google Scholar 

  20. Sasano H (1994) Functional pathology of human ovarian steroidogenesis: normal cycling ovary and steroidproducing neoplasms. Endocr Pathol 5:81–89

    Article  Google Scholar 

  21. Labrie F, Luu-The V, Labrie C, Belanger A, Simard J, Lin SX, Pelletier G (2003) Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev 24:152–182

    PubMed  CAS  Google Scholar 

  22. Berrino F, Muti P, Micheli A, Bolelli G, Krogh V, Sciajno R, Pisani P, Panico S, Secreto G (1996) Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst 88:291–296

    PubMed  CAS  Google Scholar 

  23. Lipworth L, Adami HO, Trichopoulos D, Carlstrom K, Mantzoros C (1996) Serum steroid hormone levels, sex hormone-binding globulin, and body mass index in the etiology of postmenopausal breast cancer. Epidemiology 7:96–100

    PubMed  CAS  Google Scholar 

  24. Dorgan JF, Stanczyk FZ, Longcope C, Stephenson Jr HE, Chang L, Miller R, Franz C, Falk RT, Kahle L (1997) Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-androstene-3 beta, 17-β-diol to risk of breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 6:177–181

    PubMed  CAS  Google Scholar 

  25. Sasano H, Harada N (1998) Intratumoral aromatase in human breast, endometrial, and ovarian malignancies. Endocr Rev 19:593–607

    PubMed  CAS  Google Scholar 

  26. Miller WR (1991) Aromatase activity in breast tissue. J Steroid Biochem Mol Biol 39:783–790

    PubMed  CAS  Google Scholar 

  27. Schweikert HU, Milewich L, Wilson JD (1976) Aromatization of androstenedione by cultured human fibroblasts. J Clin Endocrinol Metab 43:785–795

    PubMed  CAS  Google Scholar 

  28. Longcope C, Pratt JH, Schneider SN, Fineberg SE (1978) Aromatization of androgens by muscle and adipose tissue in vivo. J Clin Endocrinol Metab 46:146–152

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  30. Santner SJ, Chen S, Zhou D, Korsunsky Z, Martel J, Santen RJ (1993) Effect of androstenedione on growth of untransfected and aromatase-transfected MCF-7 cells in culture. J Steroid Biochem Mol Biol 44:611–616

    PubMed  CAS  Google Scholar 

  31. Chetrite GS, Cortes-Prieto J, Philippe JC, Wright F, Pasqualini JR (2000) Comparison of oestrogen concentrations, oestrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Mol Biol 72:23–27

    PubMed  CAS  Google Scholar 

  32. Pasqualini JR, Chetrite G, Blacker C, Feinstein MC, Delalonde L, Talbi M, Maloche C (1996) Concentrations of oestrone, estradiol, and oestrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients, fr. Clin Endocr Metab 81:1460–1464

    CAS  Google Scholar 

  33. Pasqualini JR (2004) The selective oestrogen enzyme modulators in breast cancer: a review. Biochim Biophys Acta 1654:123–143

    PubMed  CAS  Google Scholar 

  34. Reed MJ, Owen AM, Lai LC, Coldham NG, Ghilchik MW, Shaikh NA, James VHT (1989) In situ ooestrone synthesis in normal breast and breast tumour tissues: effect of treatment with 4-hydroxyandrostenedione. Int J Cancer 44:233–237

    PubMed  CAS  Google Scholar 

  35. Reed MJ, Purohit A, Howarth NM, Potter BVL (1994) Steroid sulphatase inhibitors: a new endocrine therapy. Drugs Future 19:673–680

    Google Scholar 

  36. Miyoshi Y, Ando A, Shiba E, Taguchi T, Tamaki Y, Noguchi S (2001) Involvement of up-regulation of 17-β-hydroxysteroid dehydrogenase type I in maintenance of high intra-tumoural high estradiol levels in postmenopausal breast cancers. Int J Cancer 94:685–689

    PubMed  CAS  Google Scholar 

  37. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, Nebert DW (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1–42

    PubMed  CAS  Google Scholar 

  38. Chen SA, Besman MJ, Sparkes RS, Zollman S, Klisak I, Mohandas T, Hall PF, Shively JE (1988) Human aromatase: cDNA cloning, Southern blot analysis, and assignment of the gene to chromosome 15. DNA 7:27–38

    PubMed  CAS  Google Scholar 

  39. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, Amarneh B, Ito Y, Fisher CR, Michael MD, Mendelson CR, Bulun SE (1994) Aromatase cytochrome P450, the enzyme responsible for oestrogen biosynthesis. Endocr Rev 15:342–355

    PubMed  CAS  Google Scholar 

  40. Sebastian S, Bulun SE (2001) A highly complex organization of the regulatory region of the human CYP 19 (Aromatase) gene revealed by the Human Genome Project. J Clin Endocrinol Metab 86:4600–4602

    PubMed  CAS  Google Scholar 

  41. Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K, Speed C, Jones M (2002) Aromatase–a brief overview. Annu Rev Physiol 64:93–127

    PubMed  CAS  Google Scholar 

  42. Simpson ER (2003) Sources of oestrogen and their importance. J Steroid Biochem Mol Biol 86:225–230

    PubMed  CAS  Google Scholar 

  43. Nelson LR, Bulun SE (2001) Oestrogen production and action. J Am Acad Dermatol 45:116–124

    Google Scholar 

  44. Simpson ER, Davis SR (2001) Minireview: aromatase and the regulation of oestrogen biosynthesis- some new perspectives. Endocrinology 142:4589–4594

    PubMed  CAS  Google Scholar 

  45. Sebastian S, Takayama K, Shozu M. Bulun SE (2002) Cloning and characterization of a novel endothelial promoter of the human CYP19 (aromatase P450) gene that is upregulated in breast cancer tissue, Mol. Endocrinol 16:2243–2254

    CAS  Google Scholar 

  46. Harada N (1993) A unique aromatase (P-450arom) mRNA formed by alternative use of tissue-specific exons 1 in human skin fibroblasts. Biochem Biophys Res Commun 189:1001–1007

    Google Scholar 

  47. Zhou C, Zhou D, Esteban J, Murai J, Siiteri PK, Wilczynski S, Chen S (1996) Aromatase gene expression and its exon I usage in human breast tumors. Detection of aromatase messenger RNA by reverse transcription-polymerase chain reaction (RT-PCR). J Steroid Biochem Mol Biol 59:163–171

    PubMed  CAS  Google Scholar 

  48. Bulun SE, Noble LS, Takayama K, Michael MD, Agarwal V, Fisher C, Zhao Y, Hinshelwood MM, Ito Y, Simpson ER (1997) Endocrine disorders associated with inappropriately high.aromatase expression. J Steroid Biochem Mol Biol 61:133–139

    PubMed  CAS  Google Scholar 

  49. Simpson ER, Michael MD, Agarwal VR, Hinshelwood MM, Bulun SE, Zhao Y (1997) Cytochromes P450 11: expression of the CYP19 (aromatase) gene: an unusual case of alternative promoter usage. FASEB J 11:29–36

    PubMed  CAS  Google Scholar 

  50. Harada N, Utsumi T, Takagi Y (1993) Tissue-specific expression of the human aromatase cytochrome P-450 gene by alternative use of multiple exons 1 and promoters, and switching of tissuespecific exons 1 in carcinogenesis. Proc Natl Acad Sci USA 90:11312–11316

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  52. Purohit A, Ghilchik MW, Duncan LJ, Wang DY, Singh A, Walker MM, Reed MJ (1995) Aromatase activity and interleukin 6 production by normal and malignant breast tissues. J Clin Endocrinol Metab 80:3052–3058

    PubMed  CAS  Google Scholar 

  53. Singh A, Purohit A, Duncan LJ, Mokbel K, Ghilchik MW, Reed MJ (1997) Control of aromatase in breast tumours: the role of the immune system. J Steroid Biochem Mol Biol 61:185–192

    PubMed  CAS  Google Scholar 

  54. Reed MJ, Coldham NG, Patel SR, Ghilchik MW, James VHT (1992) Interleukin-1 and interleukin-6 in breast cyst fluid: their role in regulating aromatase activity in breast cancer cells. J Endocrinol 132:R5–R8

    PubMed  Google Scholar 

  55. Reed MJ, Purohit A (1993) Sulphatase inhibitors: the rationale for the development of a new endocrine therapy. Rev Endocr Relat Cancer 45:51–62

    Google Scholar 

  56. Miller WR, Mullen P (1993) Factors influencing aromatase activity in the breast. J Steroid Biochem Mol Biol 44:597–604

    PubMed  CAS  Google Scholar 

  57. Zhao Y, Nichols JE, Bulnn SE, Mendelson CR, Simpson ER (1995) Aromatase P450 gene expression in human adipose tissue. J Biol Chem 270:16449–16457

    PubMed  CAS  Google Scholar 

  58. Singh A, Purohit A, Wang DY, Duncan LJ, Ghilchik MW, Reed MJ (1995) IL-6sR: release from MCF-7 breast cancer cells and role in regulating peripheral oestrogen synthesis. J Endocrinol 147:R9–R12

    PubMed  CAS  Google Scholar 

  59. Macdiarmid F, Wang DY, Duncan LJ, Purohit A, Ghilchik MW, Reed MJ (1994) Stimulation of aromatase activity in breast fibroblasts by tumour necrosis factor α Molec. Cell Endocr 106:17–21

    CAS  Google Scholar 

  60. Meng L, Zhou J, Hironobu S, Suzuki T, Zeitoun K, Bulun S (2001) TNFalpha and IL-11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively downregulating C/EBPalpha and PPARgamma: mechanism of desmoplastic reaction. Cancer Res 61:2250–2255

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  62. Zhao Y, Agarwal VR, Mendelsohn CR, Simpson ER (1997) Transcriptional regulation of CYP19 (aromatase) gene expression in adipose stromal cells in primary culture. J Steroid Biochem Mol Biol 61(3–6):203–210

    PubMed  CAS  Google Scholar 

  63. Singh A, Purohit A, Ghilchik MW, Reed MJ (1999) The regulation of aromatase activity in breast fibroblasts: the role of interleukin-6 and prostaglandin E2. Endocr Relat Cancer 6:139–147

    PubMed  CAS  Google Scholar 

  64. Miller WR, O’Neill JS (1987) The importance of local synthesis of oestrogen within the breast. Steroids 50:537–547

    PubMed  CAS  Google Scholar 

  65. Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER (1993) A link between breast cancer and local oestrogen 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

    PubMed  CAS  Google Scholar 

  66. Utsumi T, Harada N, Maruta M, Takagi Y (1996) Presence of alternatively spliced transcripts of aromatase gene in human breast cancer. J Clin Endocrinol Metab 81:2344–2349

    PubMed  CAS  Google Scholar 

  67. James VHT, McNeill JM, Lai LC, Newton CJ, Ghilchik MW, Reed MJ (1987) Aromatase activity in normal breast and breast tumor tissues: in vivo and in vitro studies. Steroids 50:269–279

    PubMed  CAS  Google Scholar 

  68. Zhou D, Pompon D, Chen S (1990) Stable expression of human aromatase cDNA in mammalian cells – a useful system for aromatase inhibitor screening. Cancer Res 50:6949–6954

    PubMed  CAS  Google Scholar 

  69. Yue W, Zhou D, Chen S, Brodie A (1994) A new nude mouse model for post.menopausal breast cancer using MCF-7 cells transfected with the htmmn aromatase gene. Cancer Res 54:5092–5095

    PubMed  CAS  Google Scholar 

  70. Macaulay VM, Nicholls J E, GledhiU J, Rowlands MG, Dowsett M, Ashworth A (1994) Biological effects of stable overexpression of aromatase in human hormone-dependent breast cancer ceils. Br J Cancer 69:77–83

    PubMed  CAS  Google Scholar 

  71. Salhab M, Reed MJ, Al Sarakbi W, Jiang WG, Mokbel K (2006) The role of aromatase and 17-β-hydroxysteroid dehydrogenase type 1 mRNA expression in predicting the clinical outcome of human breast cancer. Breast Cancer Res Treat 99(2):155–162

    PubMed  CAS  Google Scholar 

  72. Miller WR, Anderson TJ, Lack WJL (1990) Relationship between tumor aromatase activity, tumor characteristics and response to therapy, fr. Steroid Biochem Mol Biol 37:1055–1059

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  74. Zhang Z, Yamashita H, Toyama T, Hara Y, Omoto Y, Sugiura H, Kobayashi S, Harada N, Iwase H (2002) Semi quantitative immunohistochemical analysis of aromatase expression in ductal carcinoma in situ of the breast. Breast Cancer Res Treat 74:47–53

    PubMed  CAS  Google Scholar 

  75. Brodie A, Lu Q, Nakamura J (1997) Aromatase in the normal breast and breast cancer. J Steroid Biochem Mol Biol 61:281–286

    PubMed  CAS  Google Scholar 

  76. The ATAC (Arimidex Tamoxifen alone or in Combination) Trialists’ Group (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359:2131–2139

    Google Scholar 

  77. Cunnick GH, Mokbel K (2001) Aromatase inhibitors. Curr Med Res Opin 17:217–222

    PubMed  CAS  Google Scholar 

  78. Mokbel K (2002) The evolving role of aromatase inhibitors in breast cancer. Int J Clin Oncol 7:279–283

    PubMed  CAS  Google Scholar 

  79. Mokbel R, Karat I, Mokbel K (2006) Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update. Int Semin Surg Oncol 3:31

    PubMed  Google Scholar 

  80. Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardly A, Price KN, Goldhirsch A: Breast International Group (BIG) 1–98 (2005) Collaborative Group. A comparison of letrozole, tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353(26):2747–2757

    Google Scholar 

  81. Luu-The V, Labrie C, Zhao HF, Couet J, Lachance Y, Simard J, Leblanc G, Cote J, Berube D, Gagne R, Labrie F (1989) Characterization of cDNAs for human estradiol 17-β-dehydrogenase and assignment of the gene to chromosome 17: evidence of two mRNA species with distinct 50-termini in human placenta. Mol Endocrinol 3:1301–1309

    Article  PubMed  CAS  Google Scholar 

  82. Miettinen MM, Mustonen MVJ, Poutanen MH, Isomaa VV, Vihko RK (1996) Human 17b-hydroxysteroid dehydrogenase type 1 and type 2 isozymes have opposite activities in 690 cultured cells and characteristic celland tissue-specific expression. Biochem J 314:839–845

    PubMed  CAS  Google Scholar 

  83. Gunnarsson C, Ahnstrom M, Kirschner K, Olsson B, Nordenskjold B, Rutqvist LE, Skoog L, Stal O (2003) Amplification of HSD17B1 and ERBB2 in primary breast cancer. Oncogene 22:34–40

    PubMed  CAS  Google Scholar 

  84. Takeyama J, Sasano H, Suzuki T, Iinuma K, Nagura H, Andersson S (1998) 17-Betahydroxysteroid dehydrogenase types 1 and 2 in human placenta: an immunohistochemical study with correlation to placental development. J Clin Endocrinol Metab 83:3710–3715

    PubMed  CAS  Google Scholar 

  85. Takeyama J, Suzuki T, Hirasawa G, Muramatsu Y, Nagura H, Iinuma K, Nakamura J, Kimura KI, Yoshihama M, Harada N, Andersson S, Sasano H (2000) 17-Beta-hydroxysteroid dehydrogenase type 1 and 2 expression in the human fetus. J Clin Endocrinol Metab 85:410–416

    PubMed  CAS  Google Scholar 

  86. Adams EF, Rafferty B, White MC (1991) Interleukin-6 is secreted by breast fibroblasts and stimulates 17-beta oxidoreductase activity in MCF-7 breast cancer cells: possible paracrine regulation of 17-beta oestradiol levels. Int J Cancer 49:118–121

    PubMed  CAS  Google Scholar 

  87. Duncan LJ, Coldham NG, Reed MJ (1994) The interaction of cytokines in regulating oestradiol 17-beta-hydroxysteroid dehydrogenase activity in MCF-7 cells. J Steroid Biochem Mol Biol 49:63–68

    PubMed  CAS  Google Scholar 

  88. Singh A, Blench I, Morris HR, Savoy L-A, Reed MJ (1992) Synergistic interaction of growth factors and albumin in regulating oestrogen synthesis in breast cancer cells. Mol Cell Endocrinol 85:165–173

    PubMed  CAS  Google Scholar 

  89. Miller WR, Hawkins RA, Forrest APM (1982) Significance of aromatase activity in human breast cancer. Cancer Res 42:3365–3368

    Google Scholar 

  90. Perel E, Wilkins D, Killinger DW (1980) The conversion of androstenedione to oestrone, estradiol and testosterone in breast tissue. J Steroid Biochem 13:89–94

    PubMed  CAS  Google Scholar 

  91. Suzuki T, Moriya T, Ariga N, Kaneko C, Kanazawa M, Sasano H (2000) 17-Beta-hydroxysteroid dehydrogenase type 1 and type 2 in human breast carcinoma: a correlation to clinicopathological parameters. Br J Cancer 82:518–523

    PubMed  CAS  Google Scholar 

  92. Husen B, Huhtinen K, Saloniemi T, Messinger J, Thole HH, Poutanen M (2006) Human hydroxysteroid (17-beta) dehydrogenase 1 expression enhances oestrogen sensitivity of MCF-7 breast cancer cell xenografts. Endocrinology 147(11):5333–5339

    PubMed  CAS  Google Scholar 

  93. Sasano H, Frost AR, Saitoh R, Harada N, Poutanen M, Vihko R, Buhm SE, Silverberg SG, Nagura H (1996) Aromatase and 17-beta-hydroxysteroid dehydrogenase type 1 in human breast carcinoma. J Clin Endocrinol Metab 11:4042–4046

    Google Scholar 

  94. Suzuki T, Nakata T, Miki Y, Kaneko C, Moriya T, Ishida T, Akinaga S, Hirakawa H, Kimura M, Sasano H (2003) Oestrogen sulfotransferase and steroid sulfatase in human breast carcinoma. Cancer Res 63:2762–2770

    PubMed  CAS  Google Scholar 

  95. Ariga N, Moriya T, Suzuki T, Kimura M, Ohuchi N, Satomi S, Sasano H (2000) 17-Beta-hydroxysteroid dehydrogenase type 1 and type 2 in ductal carcinoma in situ and intraductal proliferative lesions of the human breast. Anticancer Res 20:1101–1108

    PubMed  CAS  Google Scholar 

  96. Oduwole OO, Li Y, Isomaa VV, Mantyniemi A, Pulkka AE, Soini Y, Vihko PT (2004) 17-Beta-hydroxysteroid dehydrogenase type 1 is an independent prognostic marker in breast cancer. Cancer Res 64:7604–7609

    PubMed  CAS  Google Scholar 

  97. Zhang Z, Yamashita H, Toyama T, Omoto Y, Sugiura H, Hara Y, Wu X, Kobayashi S, Iwase H (2003) Quantitative determination, by real-time reverse transcription polymerase chain reaction, of aromatase mRNA in invasive ductal carcinoma of the breast. Breast Cancer Res 5:250–256

    Google Scholar 

  98. Gunnarsson C, Olsson BM, Stal O (2001) Southeast Sweden Breast Cancer GroupAbnormal expression of 17-beta-hydroxysteroid dehydrogenases in breast cancer predicts late recurrence. Cancer Res 61:8448–8451

    PubMed  CAS  Google Scholar 

  99. Gunnarsson C, Jerevall PL, Hammar K, Olsson B, Nordenskjöld B, Jansson A, Stål O (2007) Amplification of HSD17B1 has prognostic significance in postmenopausal breast cancer. Breast Cancer Res Treat [Epub ahead of print]

  100. Feigelson SH, McKean-Cowdin R, Coetzee GA, Stram DO, Kolonel LN, Henderson BE (2001) Building a multigenic model of breast cancer susceptibility: CYP 17 and HSD 17-beta 1 are two important candidates. Cancer Res 61:785–789

    PubMed  CAS  Google Scholar 

  101. Fischer DS, Allan GM, Bubert C, Vicker N, Smith A, Tutill HJ, Purohit A, Wood L, Packham G, Mahon MF, Reed MJ, Potter BV (2005) E-ring modified steroids as novel potent inhibitors of 17-beta-hydroxysteroid dehydrogenase type 1. J Med Chem 48:5749–5770

    PubMed  CAS  Google Scholar 

  102. Bond CS, Clements PR, Ashby SJ, Collyer CA, Harrop SJ, Hopwood JJ, Guss JM (1997) Structure of a human lysosomal sulfatase. Structure 5:277–289

    PubMed  CAS  Google Scholar 

  103. Ferrante P, Messali S, Meroni G, Ballabio A (2002) Molecular and biochemical characterisation of a novel sulphatase gene: aryl sulphatase G (ARSG). Eur J Hum Genet 10:813–818

    PubMed  CAS  Google Scholar 

  104. Yen PH, Marsh B, Allen E, Tsai SP, Ellison J, Connoly L, Neiswanger K, Shapiro LJ (1988) The human X-linked steroid sulfatase gene and a Y-encoded pseudogene: evidence for an inversion of the Y chromosome during primate evolution. Cell 55:1123–1135

    PubMed  CAS  Google Scholar 

  105. Reed MJ, Purohit A, Woo LW, Newman SP, Potter BV (2005) Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev 26(2):171–202

    PubMed  CAS  Google Scholar 

  106. Purohit A, Reed MJ (1992) Oestrogen sulphatase activity in hormone-dependent and hormone-independent breast cancer cells: modulation by steroidal and non760 steroidal therapeutic agents. Int J Cancer 50:901–905

    PubMed  CAS  Google Scholar 

  107. Newman SP, Purohit A, Ghilchik MW, Potter BVL, Reed MJ (2000) Regulation of steroid sulphatase expression and activity in breast cancer. J Steroid Biochem Mol Biol 75:259–264

    PubMed  CAS  Google Scholar 

  108. (a) Pasqualini JR, Maloche C, Maroni M, Chetrite G (1994) Effect of the progestagen Promegestone (R-5020) on mRNA of the ooestrone sulphatase in the MCF-7 human mammary cancer cells. Anticancer Res 14:1589–1594 (b) Reed MJ The role of aromatase in breast tumors. Breast Cancer Res Treat 30:7–17

    Google Scholar 

  109. Reed MJ, Purohit A, Woo LWL, Potter BVL (1996) The development of steroid sulphatase inhibitors. Endocr Rel Cancer 3:9–23

    CAS  Google Scholar 

  110. Reed MJ, Topping L, Coldham NG, Purohit A, Ghilchik MW, James VHT (1993) Control of aromatase activity in breast cancer cells: the role of cytokines and growth factors. J Steroid Biochem Mol Biol 44:589–596

    PubMed  CAS  Google Scholar 

  111. Reed MJ, Purohit A (1994) Inhibition of steroid sulphatases. In: Sandler M, Smith HJ (eds) Design of enzyme inhibitors as drugs, vol. 2. Oxford University Press, Oxford, pp 481–494

    Google Scholar 

  112. Basler E, Grompe M, Parenti G, Yates J, Ballabio A (1992) Identification of point mutations in the steroid sulfatase gene of three patients with X-linked ichthyosis. Am J Hum Genet 50:483–491

    PubMed  CAS  Google Scholar 

  113. Alperin ES, Shapiro LJ (1997) Characterization of point mutations in patients with Xlinked ichthyosis. Effects on the structure and function of the steroid sulfatase protein. J Biol Chem 272:20756–20763

    PubMed  CAS  Google Scholar 

  114. Poortman J, Andriesse R, Agema A, Douker GH, Schwarz F, Thijssen JHH (1980) Adrenal androgen secretion and metabolism in postmenopausal women. In: Genazzani AR, Thijssen JHH, Siiteri PK (eds) Adrenal androgens. Raven Press, New York, pp 219–240

    Google Scholar 

  115. Poulin R, Labrie F (1986) Stimulation of cell proliferation and oestrogenic response by adrenal C19- delta 5-steroids in the ZR-75–1 human breast cancer cell line. Cancer Res 46:4933–4937

    PubMed  CAS  Google Scholar 

  116. Maggiolini M, Donze O, Jeannin E, Ando S, Picard D (1999) Adrenal androgens stimulate the proliferation of breast cancer cells as direct activators of oestrogen receptor alpha. Cancer Res 59:4864–4869

    PubMed  CAS  Google Scholar 

  117. Morris KT, Toth-Fejel SE, Schmidt J, Fletcher WS, Pommier RF (2001) High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: a renewed role for adrenalectomy. Surgery 130:947–953

    PubMed  CAS  Google Scholar 

  118. Utsumi T, Yoshimura N, Takeuchi S, Maruta M, Maeda K, Harada N (2000) Elevated steroid sulfatase expression in breast cancer. J Steroid Biochem Mol Biol 73:141–145

    PubMed  CAS  Google Scholar 

  119. Evans TR, Rowlands MG, Law M, Coombes RC (1994) Intratumoral ooestrone sulphatase activity as a prognostic marker in human breast carcinoma. Br J Cancer 69:555–561

    PubMed  CAS  Google Scholar 

  120. Utsumi T, Yoshimura N, Takeuchi S, Ando J, Maruta M, Maeda K, Harada N (1999) Steroid sulfatase expression is an independent predictor of recurrence in human breast cancer. Cancer Res 59:377–381

    PubMed  CAS  Google Scholar 

  121. Al Sarakbi W, Mokbel R, Salhab M, Jiang WG, Reed MJ, Mokbel K (2006) The role of STS and OATP-B mRNA expression in predicting the clinical outcome in human breast cancer. Anticancer Res 26(6C):4985–4990

    PubMed  CAS  Google Scholar 

  122. Nakata T, Takashima S, Shiotsu Y, Murakata C, Ishida H, Akinaga S, Li PK, Sasano H, Suzuki T, Saeki T (2003) Role of steroid sulfatase in local formation of oestrogen in post-menopausal breast cancer patients. J Steroid Biochem Mol Biol 86:455–460

    PubMed  CAS  Google Scholar 

  123. Selcer KW, Hegde PV, Li PK (1997) Inhibition of oestrone sulfatase and proliferation of human breast cancer cells by nonsteroidal (p-O-sulfamoyl)-N-alkanoyl tyramines. Cancer Res 57:702–707

    PubMed  CAS  Google Scholar 

  124. Purohit A, Woo LWL, Potter BVL et al (2000) In vivo inhibition of oestrone sulfatase activity and growth of nitrosomethylurea-induced mammary tumors by 667 COUMATE. Cancer Res 60:3394–3396

    PubMed  CAS  Google Scholar 

  125. Fischer DS, Chander SK, Woo LWL et al (2003) Novel D-ring modified steroid derivatives as potent, non-oestrogenic steroid sulfatase inhibitors with in vivo activity. J Steroid Biochem Mol Biol 84:343–349

    PubMed  CAS  Google Scholar 

  126. Foster PA, Newman SP, Chander SK et al (2006) In vivo efficacy of STX213, a second-generation steroid sulfatase inhibitor, for hormone-dependent breast cancer therapy. Clin Cancer Res 12:5543–5549

    PubMed  CAS  Google Scholar 

  127. Ho YT, Purohit A, Vicker N et al (2003) Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates. Biochem Biophys Res Commun 305:909 –914

    PubMed  CAS  Google Scholar 

  128. Stanway SJ, Purohit A, Woo LWL et al (2006) Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor. Clin Cancer Res 12:1585–1592

    PubMed  CAS  Google Scholar 

  129. Woo LW, Bubert C, Sutcliffe OB, Smith A, Chander SK, Mahon MF, Purohit A, Reed MJ, Potter BV (2007) Dual Aromatase-Steroid Sulfatase Inhibitors. J Med Chem [Epub ahead of print]

  130. Wood PM, Woo LW, Humphreys A, Chander SK, Purohit A, Reed MJ, Potter BV (2005) A letrozole-based dual aromatase-sulphatase inhibitor with in vivo activity. J Steroid Biochem Mol Biol 94(1–3):123–130

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. St. George’s Hospital, Blackshaw Road, Tooting, London, UK

    Ashok Subramanian & Kefah Mokbel

  2. Institute of Cancer Genetics and Pharmacogenetics, Brunel University, Uxbridge, Middlesex, UK

    Mohamed Salhab & Kefah Mokbel

  3. The London Breast Institute, The Princess Grace Hospitals, 42-52 Nottingham Place, London, W1M 3FD, UK

    Kefah Mokbel

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  1. Ashok Subramanian
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  3. Kefah Mokbel
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Correspondence to Kefah Mokbel.

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Subramanian, A., Salhab, M. & Mokbel, K. Oestrogen producing enzymes and mammary carcinogenesis: a review. Breast Cancer Res Treat 111, 191–202 (2008). https://doi.org/10.1007/s10549-007-9788-0

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