Aromatase inhibitors and models for breast cancer

  • Angela Brodie
Part of the Milestones in Drug Therapy book series (MDT)


Two approaches that are used to ameliorate the growth effects of oestrogens on primary and metastastic breast cancers are the inhibition of oestrogen action by compounds interacting with oestrogen receptors (ERs; antioestrogens) and the inhibition of oestrogen synthesis by inhibitors of the enzyme, aromatase. Treatment with the antioestrogen, tamoxifen, has been an important therapeutic advance in breast cancer management for patients with ER-positive tumours. However, concerns exist about the long-term use of this antioestrogen. Although tamoxifen functions as an ER antagonist, it also exhibits weak or partial agonist properties. The antioestrogenic activity of tamoxifen is limited to its effects on breast tumour cells whereas in other regions of the body tamoxifen may actually function as an oestrogen agonist. This can lead to increased risk of hyperplasia of the endometrium and occasionally cancer and increased risk of strokes [1], [2]. These agonist effects of tamoxifen were realized from its inception [3]. Because of these concerns, we proposed selective inhibition of aromatase to reduce oestrogen production as a different strategy that is unlikely to be associated with oestrogenic effects. For this reason, aromatase inhibition could have greater antitumour efficacy than tamoxifen. The selective approach would not interfere with other cytochrome P450 enzymes involved in the synthesis of essential hormones such as cortisol and aldosterone.


Breast Cancer Aromatase Inhibitor Aromatase Activity Letrozole Treatment Aromatase Inhibitor Letrozole 
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  1. 1.
    Fornander T, Rutqvist LE, Cedermark B, Glass U, Matson A et al. (1989) Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancer. Lancet 1: 117–120PubMedCrossRefGoogle Scholar
  2. 2.
    Fornander T, Hellstrom AC, Moberger B (1993) Descriptive clinicopathologic study of 17 patients with endometrial cancer during or after adjuvant tamoxifen in early breast cancer. J Natl Cancer Inst 815: 1850–1855CrossRefGoogle Scholar
  3. 3.
    Jordan VC, Rowsby L, Dix CJ, Prestwich G (1978) Dose-related effects of non-steroidal antiestrogens and estrogens on the measurement of cytoplasmic estrogen receptors in the rat and mouse uterus. J Endocrinol 78: 71–78PubMedCrossRefGoogle Scholar
  4. 4.
    Schwarzel WC, Kruggel W, Brodie HJ (1973) Studies on the mechanism of estrogen biosynthesis. VII. The development of inhibitors of the enzyme system in the human placenta. Endocrinology 92: 866–880PubMedGoogle Scholar
  5. 5.
    Inkster SE, Brodie AMH (1989) Immunocytochemical studies of aromatase in early and full term human placental tissues: comparison with biochemical assays. Biol Reprod 41: 889–898PubMedCrossRefGoogle Scholar
  6. 6.
    Fournet-Dulguerov N, MacLusky NJ, Leranth CZ, Todd R, Mendelson CR, Simpson ER, Naftolin F (1987) Immunohistochemical localization of aromatase cytochrome PF-450 and estradiol dehydrogenase in the syncytiotrophoblast of the human placenta. J Clin Endocrinol Metab 65: 757–764PubMedCrossRefGoogle Scholar
  7. 7.
    Thompson EA Jr, Siiteri PK (1974) The involvement of human placental microsomal cytochrome P-450 in aromatization. J Biol Chem 249: 5373–5378PubMedGoogle Scholar
  8. 8.
    Brodie AMH, Schwarzel WC, Shaikh AA, Brodie HJ (1977) The effect of an aromatase inhibitor, 4-hydroxy-4-androstene-3,17-dione, on estrogen dependent processes in reproduction and breast cancer. Endocrinology 100: 1684–1694PubMedGoogle Scholar
  9. 9.
    Marsh DA, Brodie HJ, Garrett WM, Tsai-Morris CH, Brodie AMH (1985) Aromatase inhibitorssynthesis and biological activity of androstenedione derivatives. J Med Chem 28: 788–795PubMedCrossRefGoogle Scholar
  10. 10.
    Brodie AMH, Garrett WM, Hendrickson JR, Marcotte PA, Robinson CH (1981) Inactivation of aromatase activity in placental and ovarian microsomes by 4-hydroxyandrostene-3,17-dione and 4-acetoxyandrostene-3,17-dione. Steroids 38: 693–702PubMedCrossRefGoogle Scholar
  11. 11.
    Covey DF, Hood WF (1982) Aromatase enzyme catalysis is involved in the potent inhibition of estrogen biosynthesis caused by 4-acetoxy and 4-hydroxy-4-androstene-3,17-dione. Mol Pharmacol 21: 173–180PubMedGoogle Scholar
  12. 12.
    Covey DF, Hood WF, Parikh VD (1981) 10β-Propynyl-substituted steroids: mechanism-based enzyme-activated irreversible inhibitors of estrogen biosynthesis. J Biol Chem 256: 1076–1079PubMedGoogle Scholar
  13. 13.
    Marcotte PA, Robinson CH (1982) Synthesis and evaluation of 10β-substituted estrene-3,17-diones as inhibitors of human placental microsomal aromatase. Steroids 39: 325–344PubMedCrossRefGoogle Scholar
  14. 14.
    Metcalf BW, Wright CL, Burkhart JP, Johnston JO (1981) Substrate-induced inactivation of aromatase by allenic and acetylenic steroids. J Am Chem Soc 103: 3221–3222CrossRefGoogle Scholar
  15. 15.
    Bellino FL, Gilani SSH, Eng SS, Osawa Y, Duax WL (1976) Active-site inactivation of aromatase from human placental microsomes by brominated androgen derivatives. Biochemistry 15: 4730–4736PubMedCrossRefGoogle Scholar
  16. 16.
    Bruegemeier RW, Floyd EE, Counsell RE (1978) Synthesis and biochemical evaluation of inhibitors of estrogen biosynthesis. J Med Chem 21: 1007–1011CrossRefGoogle Scholar
  17. 17.
    Bruegemeier RW, Li PK, Snider CE, Darby MV, Katlic NE (1987) 7α-Substituted androstenediones as effective in vitro and in vivo inhibitors of aromatase. Steroids 50: 167–178CrossRefGoogle Scholar
  18. 18.
    Bruegemeier RW, Li PK, Chen HH, Moh PP, Katlic NE (1990) Biochemical pharmacology of new 7-substituted androstenediones as inhibitors of aromatase. J Steroid Biochem Mol Biol 37: 379–385CrossRefGoogle Scholar
  19. 19.
    Zaccheo T, Giudici D, Ornati G, Panzeri A, Di Salle E (1991) Comparison of the effects of the irreversible aromatase inhibitor exemestane with atamestane and MDL-18962 in rats with DMBAinduced mammary tumours. Eur J Cancer 27: 1145–1150PubMedCrossRefGoogle Scholar
  20. 20.
    Giudici D, Ornati G, Briatico G, Buzzetti F, Lombardi P, Salle ED (1988) 6-Methylenandrosta-1,4-diene-3,17-dione (FCE 24304): A new irreversible aromatase inhibitor. J Steroid Biochem Mol Biol 30: 391–394Google Scholar
  21. 21.
    Thompson EA Jr, Siiteri PK (1974) Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. J Biol Chem 249: 5364–5372PubMedGoogle Scholar
  22. 22.
    Siiteri PK, Thompson EA (1975) Studies of human placental aromatase. J Steriod Biochem 6: 317–322CrossRefGoogle Scholar
  23. 23.
    Cash R, Brough AJ, Cohen MNP, Satoh PS (1967) Aminoglutethimide (Elipten-CIBA) as an inhibitor of adrenal steroidogenesis. Mechanism of action and therapeutic trial. J Clin Endocrinol Metab 27: 1239–1248PubMedGoogle Scholar
  24. 24.
    Santen RJ, Santner S, Davis B, Velhuis J, Samojlik E, Ruby E (1978) Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. J Clin Endocrinol Metab 47: 1257–1265PubMedGoogle Scholar
  25. 25.
    Vytautas UI, Whipple CA, Salhanick HA (1977) Steroselective inhibition of cholesterol side chain cleavage by enantiomers of aminoglutethimide. Endocrinology 101: 89–92Google Scholar
  26. 26.
    Brodie AMH, Longcope C (1980) Inhibition of peripheral aromatization by aromatase inhibitors, 4-hydroxy-and 4-acetoxy-androstene-3,17-dione. Endocrinology 106: 19–21PubMedCrossRefGoogle Scholar
  27. 27.
    Brodie AMH, Garrett WM, Hendrickson JR, Tsai-Morris CH (1982) Effects of 4-hydroxyandrostenedione and other compounds in the DMBA breast carcinoma model. Cancer Res 42: 3360s–3364sPubMedGoogle Scholar
  28. 28.
    Goss PE, Coombes RL, Powles TJ, Dowsett M, Brodie AMH (1986) Treatment of advanced postmenopausal breast cancer with aromatase inhibitor, 4-hydroxyandrostenedione-phase 2 report. Cancer Res 46: 4823–4826PubMedGoogle Scholar
  29. 29.
    Coombes CR, Goss P, Dowsett M, Gazet JC, Brodie A (1984) 4-Hydroxyandostenedione in treatment of postmenopausal patients with advanced breast cancer. Lancet 2: 1237–1239PubMedCrossRefGoogle Scholar
  30. 30.
    Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D et al. (2003) Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol 14: 1391–1398PubMedCrossRefGoogle Scholar
  31. 31.
    Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Klijn IG et al. (2003) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98: 1802–1810PubMedCrossRefGoogle Scholar
  32. 32.
    Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A et al. (2003) Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21: 2101–2109PubMedCrossRefGoogle Scholar
  33. 33.
    Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A et al. (2000) Anastrazole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 18: 3758–3767PubMedGoogle Scholar
  34. 34.
    Coombes RC, Hall E, Gibson LJA (2004) Randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Eng J Med 350: 1081–1092CrossRefGoogle Scholar
  35. 35.
    Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ et al. (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. New Engl J Med 349: 1793–1802PubMedCrossRefGoogle Scholar
  36. 36.
    Brodie AMH, Marsh DA, Wu JT, Brodie HJ (1979) Aromatase inhibitors and their use in controlling estrogen dependent processes. J Steroid Biochem 11: 107–112PubMedCrossRefGoogle Scholar
  37. 37.
    Brodie AMH, Wu JT, Marsh DA, Brodie HJ (1978) Aromatase inhibitors III. Studies on the antifertility effects of 4-acetoxy-4-androstene-3,17-dione. Biol Reprod 18: 365–370PubMedCrossRefGoogle Scholar
  38. 38.
    Fisher CR, Graves KH, Parlow AF, Simpson ER (1998) Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the CYP19 gene. Proc Natl Acad Sci USA 95: 6965–6970PubMedCrossRefGoogle Scholar
  39. 39.
    Couse JF, Korach KS (1999) Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 20: 358–417PubMedCrossRefGoogle Scholar
  40. 40.
    Tekmal R, Ramachandra N, Gubba S, Durgam VR, Manitone J, Toda K et al. (1996) Overexpression of int-5/aromatase in mammary glands of transgenic mice results in the induction of hyperplasia and nuclear abnormalities. Cancer Res 56: 3180–3185PubMedGoogle Scholar
  41. 41.
    Gill K, Keshava N, Manitone J, Tekmal RR (2001) Overexpression of aromatase in transgenic male mice results in the induction of gynecomastia and other biochemical changes in mammary glands. J Steroid Biochem Mol Biol 77: 13–18PubMedCrossRefGoogle Scholar
  42. 42.
    Fowler KA, Gill K, Kirma N, Dillehay DL, Tekmal RR (2000) Overexpression of aromatase leads to development of testicular leydig cell tumors: an in vivo model for hormone-mediated testicular cancer. Am J Pathol 156: 347–353PubMedGoogle Scholar
  43. 43.
    Keshava N, Fang C, Bhalla KN, Tekmal RR (1995) Environmental mutagen (DMBA) acts synergistically in int-5/aromatase transgenic mice that have mammary estrogen activity. Mutat Res 379: S151Google Scholar
  44. 44.
    Brodie AMH, Marsh DA, Brodie HJ (1979) Aromatase inhibitors IV. Regression of estrogendependent mammary tumors in the rat with 4-acetoxy-4-androstene-3,17-dione. J Steroid Biochem 10: 423–429PubMedCrossRefGoogle Scholar
  45. 45.
    Brodie AMH, Garrett W, Hendrickson JM, Marsh DA, Brodie HJ (1982) The effect of 1,4,6-androstatriene-3,17-dione (ATD) on DMBA-induced mammary tumors in the rat and its mechanism of action in vivo. Biochem Pharmacol 31: 2017–2023PubMedCrossRefGoogle Scholar
  46. 46.
    Jordan VC (1987) Lab models of breast cancer to aid the elucidation of antiestrogenation. J Lab Clin Med 106: 267–277Google Scholar
  47. 47.
    Jordan VC (1982) Lab models of hormone-dependent cancer. In: Furr BJA (ed.): Clinics in oncology. WB Saunders Co, London, 21–40Google Scholar
  48. 48.
    Huggins C, Briziarelli G, Sutton H (1959) Rapid induction of mammary carcinoma in the rat and the influence of hormones on tumors. J Exp Med 109: 25–42PubMedCrossRefGoogle Scholar
  49. 49.
    DeSombre ER, Arbogast LY (1974) Effect of the antiestrogen C1628 on the growth of rat mammary tumors. Cancer Res 34: 1971–1976PubMedGoogle Scholar
  50. 50.
    Thompson EA, Hemsell D, McDonald PC, Siiteri PK (1974) Inhibition of aromatization by steroidal drugs. J Biol Chem 5: 315Google Scholar
  51. 51.
    Uzgiris VI, Graves P, Salhanick HA (1977) Liquid modification of corpus luteum mitochondrial cytochrome P-450 spectra and cholesterol monooxygenation: an assay of enzyme-specific inhibitors. Endocrinology 101: 89–92PubMedGoogle Scholar
  52. 52.
    Sherman BM, Chapler FK, Crickard K, Wycoff D (1979) Endocrine consequences of continuous antiestrogen therapy with tamoxifen in premenopausal women. J Clin Invest 64: 398–404PubMedCrossRefGoogle Scholar
  53. 53.
    Samojilik E, Veldhuis JD, Wells SA, Santen RJ (1980) Preservation of androgen secretion during estrogen suppression with aminoglutethimide in the treatment of metastatic breast carcinoma. J Clin Invest 65: 602–612CrossRefGoogle Scholar
  54. 54.
    Wing LY, Garrett WM, Brodie MH (1985) The effect of aromatase inhibitors, aminogluthimide and 4-hydroxyandrostenedione on cyclic rats with DMBA-induced mammary tumors. Cancer Res 45: 2425–2428PubMedGoogle Scholar
  55. 55.
    Hemsell DL, Gordon J, Breuner PF, Siiteri PK, MacDonald PC (1974) Plasma precursors of estrogen. II. Correlation of extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab 38: 476–479PubMedGoogle Scholar
  56. 56.
    Thorsen T, Tangen M, Stoa KF (1982) Concentrations of endogeneous estradiol as related to estradiol receptor sites in breast tumor cytosol. Eur J Cancer Clin Oncol 18: 333–337PubMedCrossRefGoogle Scholar
  57. 57.
    van Landeghem AAJ, Portman J, Nabauurs M (1985) Endogeneous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res 45: 2900–2906PubMedGoogle Scholar
  58. 58.
    Blankenstein MA, Maitimu-Smeele I, Donker GH, Daroszewski J, Milewicz A, Thijssen JHH (1992) On the significance of in situ production of oestrogens in human breast cancer tissue. J Steroid Biochem Mol Biol 41: 891–896PubMedCrossRefGoogle Scholar
  59. 59.
    Perel E, Blackstein ME, Killinger DW (1982) Aromatase in human breast carcinoma. Cancer Res (suppl.) 42: 3369s–3372sPubMedGoogle Scholar
  60. 60.
    James VHT, McNeill JM, Lai L, Newton CJ, Ghilchik MW, Reed MJ (1987) Aromatase activity in normal breast and breast tumor tissue: in vivo and in vitro studies. Steroids 50: 269–279PubMedCrossRefGoogle Scholar
  61. 61.
    Killinger DW, Perel E, Daniilescu D, Kharlip L, Blackstein ME (1987) Aromatase activity in the breast and other peripheral tissues and its therapeutic regulation. Steroids 50: 523–535PubMedCrossRefGoogle Scholar
  62. 62.
    Miller WR, Hawkins RA, Forrest APM (1982) Significance of aromatase activity in human breast cancer. Cancer Res 42(suppl.): 3365s–3368sPubMedGoogle Scholar
  63. 63.
    Peice T, Aitken J, Head J, Mahendroo M, Means G, Simpson E (1992) Determination of aromatase cytochrome P-450 messenger ribonucleic acid in human breast tissue by competitive polymerase chain reaction amplification. J Clin Endocrinol Metab 174: 1247–1252Google Scholar
  64. 64.
    Koos RD, Banks PK, Inkster SE, Yue W, Brodie AMH (1993) Detection of aromatase and keratinocyte growth factor expression in breast tumors using reverse transcription-polymerase chain reaction. J Steroid Biochem Mol Biol 45: 217–225PubMedCrossRefGoogle Scholar
  65. 65.
    Lu Q, Nakamura J, Savinov A, Yue W, Weisz J, Dabbs DJ et al. (1996) Expression of aromatase protein and mRNA in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancer. Endocrinology 137: 3061–3068PubMedCrossRefGoogle Scholar
  66. 66.
    Lipton A, Santen RJ, Santen SJ, Harvey HA, Peil PD, White-Hershey D et al. (1987) Aromatase activity in primary and metastatic human breast cancer, Cancer 59: 779–783PubMedCrossRefGoogle Scholar
  67. 67.
    Brodie AMH, Lu Q, Long BJ, Fulton A, Chen T, MacPherson N et al. (2001) Aromatase and COX-2 expression in human breast cancers. J Steroid Biochem Mol Biol 1607: 1–7Google Scholar
  68. 68.
    Brueggemeier RW, Quinn AL, Parrett ML, Joarder FS, Harris RE, Robertson FM (1999) Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens. Cancer Lett 140: 27–35PubMedCrossRefGoogle Scholar
  69. 69.
    Simpson ER, Mehendroo MS, Means GD, Kilgore MW, Corbin CJ, Mendelson CR (1993) Tissuespecific promoters regulate cytochrome P-450 expression. J Steroid Biochem Mol Biol 44: 321–330PubMedCrossRefGoogle Scholar
  70. 70.
    Simpson ER, Ackerman GE, Smith ME, Mendelson CR (1981) Estrogen formation in stromal cells of adipose tissue of women: Induction of glucocorticosteroids. Proc Natl Acad Sci USA 78: 5690–5694PubMedCrossRefGoogle Scholar
  71. 71.
    Johnston JO, Wright CL, Schumaker RC (1989) Human trophoblast xenografts in athymic mice: a model for peripheral aromatization. J Steroid Biochem Mol Biol 33: 521–529Google Scholar
  72. 72.
    Franz C, Longcope C (1979) Androgen and estrogen metabolism in male Rhesus monkeys. Endocrinology 105: 869–874PubMedGoogle Scholar
  73. 73.
    Lonning PE, Geisler J, Bhatnagar A (2003) Development of aromatase inhibitors and their pharmacological profile. Am J Clin Oncol 4:S3–S8CrossRefGoogle Scholar
  74. 74.
    Yue W, Zhou D, Chen S, Brodie A (1994) A new nude mouse model for postmenopausal breast cancer using MCF-7 cells transfected with the human aromatase gene. Cancer Res 54: 5092–5095PubMedGoogle Scholar
  75. 75.
    Yue W, Wang J, Savinov A, Brodie A (1995) The effect of aromatase inhibitors on growth of mammary tumors in a nude mouse model. Cancer Res 55: 3073–3077PubMedGoogle Scholar
  76. 76.
    Mattern J, Bak M, Hahn EW, Volm M (1988) Human tumor xenografts as model for drug testing. Cancer Metas Rev 7: 263–284CrossRefGoogle Scholar
  77. 77.
    Osborne CK, Jarman M, McCague R, Coronado EB, Hilsenbeck SG, Wakeling AE (1994) The importance of tamoxifen metabolism in tamoxifen-stimulated breast tumor growth. Cancer Chemother Pharm 34: 89–95CrossRefGoogle Scholar
  78. 78.
    Kinoshita Y, Chen S (2003) Induction of aromatase expression in breast cancer cells through nongenomic action of ERa. Cancer Res 63: 3546–3555PubMedGoogle Scholar
  79. 79.
    Lu Q, Yue W, Wang J, Liu Y, Long BJ, Brodie A (1998) The effect of aromatase inhibitors and antiestrogens in the nude mouse model. Breast Cancer Res Treat 50: 63–71PubMedCrossRefGoogle Scholar
  80. 80.
    Long BJ, Jelovac D, Handratta V, Thiantanawat A, MacPherson N, Ragaz J, Brodie AM (2004) Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in breast cancer model. J Natl Cancer Inst 96: 456–465PubMedCrossRefGoogle Scholar
  81. 81.
    Zhou D, Pompon D, Chen S (1990) Stable expression of human aromatase complementary DNA in mammalian cells: a useful system for aromatase inhibitor screening, Cancer Res 50: 6949–6954PubMedGoogle Scholar
  82. 82.
    Rebar RW, Morandini IC, Erickson GF, Petze JE (1981) The hormonal basic of reproductive defects in athymic mice: diminished gonadotropin concentration in prepubertal females. Endocrinology 108: 120–126PubMedGoogle Scholar
  83. 83.
    Long BJ, Jelovac D, Thiantanawat A, Brodie AM (2002) The effect of second-line antiestrogen therapy on breast tumor growth after first-line treatment with the aromatase inhibitor letrozole: long-term studies using the intratumoral aromatase postmenopausal breast cancer model. Clin Cancer Res 8: 2378–2388PubMedGoogle Scholar
  84. 84.
    Lu Q, Liu Y, Long BJ, Grigoryev D, Gimbel M, Brodie A (1999) The effect of combining aromatase inhibitors with antiestrogens on tumor growth in a nude mouse model for breast cancer. Breast Cancer Res Treat 57: 183–192PubMedCrossRefGoogle Scholar
  85. 85.
    Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA et al. (1999) Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clin Cancer Res 5: 2338–2343PubMedGoogle Scholar
  86. 86.
    Jelovac D, Macedo L, Handratta V, Long BJ, Goloubeva OG, Brodie AMH (2004) Preclinical studies evaluating the anti-tumor effects of exemestane alone or combined with tamoxifen in a postmenopausal breast cancer model. Clin Cancer Res 10: 7375–7381PubMedCrossRefGoogle Scholar
  87. 87.
    Jelovac D, Sabnis G, Long BJ, Goloubeva OG, Brodie AMH (2005) Activation of MAPK in xenografts and cells during prolonged treatment with aromatase inhibitor letrozole. Cancer Res 65: 5380–5389PubMedCrossRefGoogle Scholar
  88. 88.
    Brodie A, Jelovac D, Long B, Macedo, L, Goloubeva O (2005) Model systems: mechanisms involved in the loss of sensitivity to letrozole. J Steroid Biochem Mol Biol 95: 41–48PubMedCrossRefGoogle Scholar
  89. 89.
    Sabnis GJ, Jelovac D, Long B, Brodie A (2005) The role of growth factor receptor pathways in human breast cancer cells adapted to long term estrogen deprivation. Cancer Res 65: 3903–3910PubMedCrossRefGoogle Scholar
  90. 90.
    Yue W, Wang JR, Conaway MR, Li Y, Santen RS (2003) Adaptive hypersensitivity following longterm estrogen deprivation: Involvement of multiple signal pathways. J Steroid Biochem Mol Biol 86: 265–274PubMedCrossRefGoogle Scholar
  91. 91.
    Shou J, Massarweh S, Osborne CK, Wakeling AE, Au S, Weiss H, Schiff P (2004) Mechanisms of tamoxifen resistances Increased estrogen receptor-HEP2/neu cross-talk in EP/HEP2-positive breast cancer. J Natl Cancer Inst 96: 926–935PubMedGoogle Scholar
  92. 92.
    Jelovac D, Macedo L, Goloubeva OG, Handratta V, Brodie AMH (2005) Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. Cancer Res 65: 5439–5444PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2008

Authors and Affiliations

  • Angela Brodie
    • 1
  1. 1.Department of Pharmacology & Experimental TherapeuticsUniversity of Maryland, School of MedicineBaltimoreUSA

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