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A Novel Pure SERM Achieves Complete Regression of the Majority of Human Breast Cancer Tumors in Nude Mice

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Abstract

Background. The objective was to determine if EM-652, a novel selective estrogen receptor modulator (SERM) having highly potent and pure antiestrogenic activity in the mammary gland could cause complete regression of the majority of human breast cancer xenografts in nude mice.

Methods. Human breast cancer ZR-75-1 xenografts were used as model in nude mice.

Results. EM-652 not only prevented estrogen-induced tumor growth but it reduced tumor size to 20% of the pretreatment value. Complete disappearance of the tumors was observed in 65% (106/163) of tumors. No tumor progressed. Most importantly, 93% of the tumors which had become undetectable under EM-652 treatment did not reappear when exposed to estrogen challenge for 12 weeks, thus achieving an overall 61% cure rate.

Conclusions. The present data demonstrate that EM-652 is strongly cytotoxic or tumorocidal and not only cytostatic or tumorostatic in estrogen-sensitive breast cancer, thus changing the paradigm of a tumorostatic role of estrogen blockade established with tamoxifen. These findings support the use of such a compound for more efficient breast cancer prevention and therapy.

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References

  1. Schwartzman RA, Cidlowski JA: Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr Rev 14: 133–151, 1993

    Google Scholar 

  2. Cameron DA, Ritchie AA, Miller WR: The relative importance of proliferation and cell death in breast cancer growth and response to tamoxifen. Eur J Cancer 37: 1545–1553, 2001

    Google Scholar 

  3. Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC: Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 48: 812–815, 1988

    Google Scholar 

  4. Gottardis MM, Jordan VC: Development of tamoxifenstimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48: 5183–5187, 1988

    Google Scholar 

  5. Bardon S, Vignon F, Montcourrier P, Rochefort H: Steroid receptor-mediated cytotoxicity of an antiestrogen and an antiprogestin in breast cancer cells. Cancer Res 47: 1441–1448, 1987

    Google Scholar 

  6. Kyprianou N, English HF, Davidson NE, Isaacs JT: Programmed cell death during regression of the MCF-7 human breast cancer following estrogen ablation. Cancer Res 51: 162–166, 1991

    Google Scholar 

  7. Warri AM, Huovinen RL, Laine AM, Martikainen PM, Harkonen PL: Apoptosis in toremifene-induced growth inhibition of human breast cancer cells in vivo and in vitro. J Natl Cancer Inst 85: 1412–1418, 1993

    Google Scholar 

  8. Cameron AD, Ritchie AA, Langdon S, Anderson TJ, Miller WR: Tamoxifen-induced apoptosis in ZR-75-1 breast cancer xenografts antedates tumor regression. Breast Cancer Res Treat 45: 99–107, 1997

    Google Scholar 

  9. Diel P, Smolnikar K, Michna H: The pure antiestrogen ICI 182780 is more effective in the induction of apoptosis and down regulation of BCL-2 than tamoxifen in MCF-7 cells. Breast Cancer Res Treat 58: 87–97, 1999

    Google Scholar 

  10. Haeryfar SM, Nagy E, Baral E, Krepart G, Lotocki R, Berczi I: Antiestrogens affect both pathways of killer cell-mediated oncolysis. Anticancer Res 20: 1849–1854, 2000

    Google Scholar 

  11. Dowsett M, Bundred NJ, Decensi A, Sainsbury RC, Lu Y, Hills MJ, Cohen FJ, Veronesi P, O'Brien ME, Scott T, Muchmore DB: Effect of raloxifene on breast cancer cell Ki67 and apoptosis: a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients. Cancer Epidemiol Biomarkers Prev 10: 961–966, 2001

    Google Scholar 

  12. Perry RR, Kang Y, Greaves B: Effects of tamoxifen on growth and apoptosis of estrogen-dependent and-independent human breast cancer cells. Ann Surg Oncol 2: 238–245, 1995

    Google Scholar 

  13. Imai A, Tamaya T: GnRH receptor and apoptotic signaling. Vitam Horm 59: 1–33, 2000

    Google Scholar 

  14. Green S, Walter P, Kumar V, Krust V, Bornert JM, Argos P, Chambon P: Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 320: 134–139, 1986

    Google Scholar 

  15. Gronemeyer H, Benhamou B, Berry M, Bocquel MT, Gofflo D, Garcia T, Lerouge T, Metzger D, Meyer ME, Tora L, Vergezac A, Chambon P: Mechanisms of antihormone action. J Steroid Biochem Mol Biol, 41: 217–221, 1992

    Google Scholar 

  16. Clarke R, Leonessa F, Welch JN, Skaar TC: Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev 53: 25–71, 2001

    Google Scholar 

  17. Gottardis M, Jiang S, Jeng M, Jordan V: Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res 49: 4090–4093, 1989

    Google Scholar 

  18. Osborne CK, Coronado Heinsohn EB, Hilsenbeck SG, McCue BL, Wakeling AE, McClelland RA, Manning DL, Nicholson RI: Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 87: 746–750, 1995

    Google Scholar 

  19. Couillard S, Labrie C, Bélanger A, Candas B, Pouliot F, Labrie F: Effect of dehydroepiandrosterone and the antiestrogen EM-800 on the growth of human ZR-75-1 breast cancer xenografts. J Natl Cancer Inst 90: 772–778, 1998

    Google Scholar 

  20. Labrie C, Martel C, Dufour JM, Lévesque C, Mérand Y, Labrie F: Novel compounds inhibit estrogen formation and action. Cancer Res 52: 610–615, 1992

    Google Scholar 

  21. Wakeling AE: The future of new pure antiestrogens in clinical breast cancer. Breast Cancer Res Treat 25: 1–9, 1993

    Google Scholar 

  22. Gradishar WJ, Jordan VC: Clinical potential of new antiestrogens. J Clin Oncol 15: 840–852, 1997

    Google Scholar 

  23. Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, Giguere V: Cloning, chromosomal localization and functional analysis of the murine estrogen receptor β. Mol Endocrinol 11: 353–365, 1997

    Google Scholar 

  24. Tremblay A, Tremblay GB, Labrie C, Labrie F, Giguère V: EM-800, a novel antiestrogen, acts as a pure antagonist of the transcriptional functions of estrogen receptors α and β. Endocrinology 139: 111–118, 1998

    Google Scholar 

  25. Labrie F, Labrie C, Bélanger A, Simard J, Gauthier S, Luu-The V, Mérand Y, Giguère V, Candas B, Luo S, Martel C, Singh SM, Fournier M, Coquet A, Richard V, Charbonneau R, Charpenet G, Tremblay A, Tremblay G, Cusan L, Veilleux R, EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. J Steroid Biochem Mol Biol 69: 51–84, 1999

    Google Scholar 

  26. Martel C, Provencher L, Li X, St-Pierre A, Leblanc G, Gauthier S, Mérand Y, Labrie F: Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors. J Steroid Biochem Mol Biol 64: 199–205, 1998

    Google Scholar 

  27. Labrie F, Labrie C, Bélanger A, Simard J, Giguère V, Tremblay A, Tremblay G: EM-652 (SCH 57068), a pure SERM having complete antiestrogenic activity in the mammary gland and endometrium. J Steroid Biochem Mol Biol 79: 213–225, 2001

    Google Scholar 

  28. Gauthier S, Caron B, Cloutier J, Dory YL, Favre A, Larouche D, Mailhot J, Ouellet C, Schwerdtfeger A, Leblanc G, Martel C, Simard J, Mérand Y, Bélanger A, Labrie C, Labrie F: (S)-(+)-4-[7-(2,2-dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl 2,2-dimethylpropanoate (EM-800): a highly potent, specific, and orally active nonsteroidal antiestrogen. J Med Chem 40: 2117–2122, 1997

    Google Scholar 

  29. Gutman M, Couillard S, Roy J, Labrie F, Candas B, Labrie C: Comparison of the effects of EM-652 (SCH 57068), Tamoxifen, toremifene, droloxifene, idoxifene, GW-5638 and Raloxifene on the growth of human ZR-75-1 breast tumors in nude mice. Int J Cancer 99: 273–278, 2002

    Google Scholar 

  30. Morrow M, Jordan VC: Molecular mechanisms of resistance to tamoxifen therapy in breast cancer. Arch Surg 128: 1187–1191, 1993

    Google Scholar 

  31. Labrie F, Candas B, Gomez JL, Cusan L: Can combined androgen blockade provide long-term control or possible cure of localized prostate cancer? Urology 60: 115–119, 2002

    Google Scholar 

  32. Simard J, Labrie C, Bélanger A, Gauthier S, Singh SM, Mérand Y, Labrie F: Characterization of the effects of the novel non-steroidal antiestrogen EM-800 on basal and estrogen-induced proliferation of T-47D, ZR-75-1 and MCF-7 human breast cancer cells in vitro. Int J Cancer 73: 104–112, 1997

    Google Scholar 

  33. Couillard S, Gutman M, Labrie F, Candas B, Labrie C: Effect of the combined treatment with the pure antiestrogen EM-800 and radiotherapy on the growth of human ZR-75-1 breast cancer xenografts in nude mice. Cancer Res 59: 4857–4863, 1999

    Google Scholar 

  34. Gutman M, Couillard S, Labrie F, Candas B, Labrie C: Effects of the antiestrogen EM-800 (SCH 57050) and cyclophosphamide alone and in combination on growth of human ZR-75-1 breast cancer xenografts in nude mice. Cancer Res 59: 5176–5180, 1999

    Google Scholar 

  35. Dowsett M, Dixon JM, Horgan K, Salter J, Hills M, Harvey E: Antiproliferative effects of idoxifene in a placebo-controlled trial in primary human breast cancer. Clin Cancer Res 6: 2260–2267, 2000

    Google Scholar 

  36. Couillard S, Gutman M, Labrie C, Bélanger A, Candas B, Labrie F: Comparison of the effects of the antiestrogens EM-800 and Tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice. Cancer Res 58: 60–64, 1998

    Google Scholar 

  37. Simard J, Sanchez R, Poirier D, Gauthier S, Singh SM, Mérand Y, Bélanger A, Labrie C, Labrie F: Blockade of the stimulatory effect of estrogens, OH-Tamoxifen, OHToremifene, Droloxifene and Raloxifene on alkaline phosphatase activity by the antiestrogen EM-800 in human endometrial adenocarcinoma Ishikawa cells. Cancer Res 57: 3494–3497, 1997

    Google Scholar 

  38. Martel C, Picard S, Richard V, Bélanger A, Labrie C, Labrie F: Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat. J Steroid Biochem Mol Biol 74: 45–56, 2000

    Google Scholar 

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Authors and Affiliations

  1. Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL), Laval University, Quebec City, Que., Canada

    Jenny Roy, Steeve Couillard, Mathieu Gutman & Fernand Labrie

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  1. Jenny Roy
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  2. Steeve Couillard
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  3. Mathieu Gutman
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  4. Fernand Labrie
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Roy, J., Couillard, S., Gutman, M. et al. A Novel Pure SERM Achieves Complete Regression of the Majority of Human Breast Cancer Tumors in Nude Mice. Breast Cancer Res Treat 81, 223–229 (2003). https://doi.org/10.1023/A:1026118602273

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