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Effect of low dose tamoxifen on the insulin-like growth factor system in healthy women

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Abstract

The use of tamoxifen as a preventive agent may be limited by the increased risk of endometrial cancer and venous thromboembolic events observed in postmenopausal women. We have recently shown a comparable activity of lower doses of tamoxifen on several surrogate biomarkers of cardiovascular disease and breast cancer, including Insulin-like Growth Factor-I (IGF-I). To provide further insight into the effect of tamoxifen at low doses on the IGF system, we have correlated the drug serum levels attained after 2 months of either placebo (n=32), tamoxifen 20mg/day (n=26), 10mg/day (n=23) or 10mg/every other day (n=29) with the changes in IGF-I, Insulin-like Growth Factor-II (IGF-II), Insulin-like Growth Factor Binding Protein-1 (IGFBP-1), Insulin-like Growth Factor Binding Protein-3 (IGFBP-3), and IGF-I/IGFBP-3 ratio. Compared with placebo, tamoxifen induced a mean±standard error (SE) reduction of IGF-I of 16.9±7.8%, p≤0.05, a non-significant increase of 22.9±12.2% in IGF-II, an increase in IGFBP-1 of 49.3±22.7%, p≤0.05, and a non-significant change of IGFBP-3 (−4.0%±9.2). No significant concentration-response relationship was observed between serum tamoxifen concentrations and the biomarker changes except for the ratio of IGF-I/IGFBP-3, which decreased by 1.53±0.68% for any increase by 10ng/ml of serum tamoxifen concentration (p=0.02). Although low tamoxifen concentrations induce a comparable modulation of the IGF family relative to the conventional dose, the lower decrements in the IGF-I/IGFBP-3 ratio observed at low drug concentrations might be associated with a reduced preventive activity. Further studies on the search of the minimal active dose of tamoxifen are warranted.

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References

  1. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998

    Google Scholar 

  2. Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, Tidy A, Viggers J, Davey J: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352: 98-101, 1998

    Google Scholar 

  3. Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, Rotmensz N, Boyle P: Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women, Italian Tamoxifen Prevention Study. Lancet 352: 93-97, 1998

    Google Scholar 

  4. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351: 1451-1467, 1998

    Google Scholar 

  5. Rutqvist LE, Johansson H, Signomklao T, Johansson U, Fornander T, Wilking N: Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies, Stockholm Breast Cancer Study Group. J Natl Cancer Inst 87: 645-651, 1995

    Google Scholar 

  6. Decensi A, Bonanni B, Guerrieri-Gonzaga A, Gandini S, Robertson C, Johansson H, Travaglini R, Sandri MT, Tessadrelli A, Farante G, Salinaro F, Bettega D, Barreca A, Boyle P, Costa A, Veronesi U: Biologic activity of tamoxifen at low doses in healthy women. J Natl Cancer Inst 90: 1461-1467, 1998

    Google Scholar 

  7. Decensi A, Gandini S, Guerrieri-Gonzaga A, Johansson H, Manetti L, Bonanni B, Sandri MT, Barreca A, Costa A, Robertson C, Lien EA: Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction. J Clin Oncol 17: 2633-2638, 1999

    Google Scholar 

  8. Yu H, Rohan T: Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 92: 1472-1489, 2000

    Google Scholar 

  9. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M: Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351: 1393-1396, 1998

    Google Scholar 

  10. Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16: 3-34, 1995

    Google Scholar 

  11. Gill ZP, Perks CM, Newcomb PV, Holly JM: Insulin-like growth factor-binding prote in (IGFBP-3) predisposes breast cancer cells to programmed cell death in a non-IGF-dependent manner. J Biol Chem 272: 25602-25607, 1997

    Google Scholar 

  12. Oh Y, Muller HL, Pham H, Rosenfeld RG: Demonstration of receptors for insulin-like growth factor binding protein-3 on Hs578T human breast cancer cells. J Biol Chem 268: 26045-26048, 1993

    Google Scholar 

  13. Colletti RB, Roberts JD, Devlin JT, Copeland KC: Effect of tamoxifen on plasma insulin-like growth factor I in patients with breast cancer. Cancer Res 49: 1882-1884, 1989

    Google Scholar 

  14. Helle SI, Holly JM, Tally M, Hall K, Vander SJ, Lonning PE: Influence of treatment with tamoxifen and change in tumor burden on the IGF-system in breast cancer patients. Int J Cancer 69: 335-339, 1996

    Google Scholar 

  15. Lonning PE, Hall K, Aakvaag A, Lien EA: Influence of tamoxifen on plasma levels of insulin-like growth factor I and insulin-like growth factor binding protein I in breast cancer patients. Cancer Res 52: 4719-4723, 1992

    Google Scholar 

  16. Juul A, Flyvbjerg A, Frystyk J, Muller J, Skakkebaek NE: Serum concentrations of free and total insulin-like growth factor-I, IGF binding proteins-1 and-3 and IGFBP-3 protease activity in boys with normal or precocious puberty. Clin Endocrinol (Oxf) 44: 515-523, 1996

    Google Scholar 

  17. Daughaday WH, Mariz IK, Blethen SL: Inhibition of access of bound somatomed in to membrane receptor and immunobinding sites: a comparison of radioreceptor and radioimmunoassay of somatomedin in native and acid-ethanolextracted serum. J Clin Endocrinol Metab 51: 781-788, 1980

    Google Scholar 

  18. Juul A, Ma in K, Blum WF, Lindholm J, Ranke MB, Skakkebaek NE: The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients. Clin Endocrinol 41: 85-93, 1994

    Google Scholar 

  19. Lien EA, Ueland PM, Solheim E, Kvinnsland S: Determination of tamoxifen and four metabolites in serum by lowdispersion liquid chromatography. Clin Chem 33: 1608-1614, 1987

    Google Scholar 

  20. SAS for Windows. VERSION 6.11: 1995

  21. Yee D, Chavea JB, Ruan W, Kleinberg DL: Inibition of normal mammary gland development and breast cancer growth by insulin-like growth factor binding protein-1 (abstract). Proc ASCO 19: 209a, 2000

    Google Scholar 

  22. Toniolo P, Bruning PF, Akhmedkhanov A, Bonfrer JMG, Koenig KL, Lukanova A, Shore RE, Zeleniuch-Jacquotte A: Serum insulin-like growth factor-I and breast cancer. Int J Cancer 88: 828-832, 2000

    Google Scholar 

  23. Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE: Plasma insulin-like growth factor (IGF) I, IGF binding protein 3, and mammographic density. Cancer Res 60: 3744-3748, 2000

    Google Scholar 

  24. Boyd NF, Byng JW, Jong RA, Fishell EK, Little LE, Miller AB, Lockwood GA, Tritchler DL, Yaffe MJ: Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 87: 670-675, 1995

    Google Scholar 

  25. Kaklamani VG, Linos A, Kaklamani E, Markaki I, Koumantaki Y, Mantzoros CS: Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults. J Clin Oncol 17: 3291-3298, 1999

    Google Scholar 

  26. Torrisi R, Parodi S, Fontana V, Pensa F, Casella C, Barreca A, De Palo G, Costa A, Decensi A: Effect of fenretinide on plasma IGF-I and IGFBP-3 in early breast cancer patients. Int J Cancer 76: 787-790, 1998

    Google Scholar 

  27. Johnston SR, Haynes BP, Sacks NP, McKinna JA, Griggs LJ, Jarman M, Baum M, Smith IE, Dowsett M: Effect of oestrogen receptor status and time on the intra-tumoural accumulation of tamoxifen and N-desmethyltamoxifen following short-term therapy in human primary breast cancer. Breast Cancer Res Treat 28: 241-250, 1993

    Google Scholar 

  28. Lien EA, Solheim E, Ueland PM: Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res 51: 4837-4844, 1991

    Google Scholar 

  29. Reddel RR, Sutherland RL: N-desmethyltamoxifen inhibits growth of MCF 7 human mammary carcinoma cells in vitro. Eur J Cancer Clin Oncol 19: 1179-1181, 1983

    Google Scholar 

  30. Sutherland RL, Watts CK, Hall RE, Ruenitz PC: Mechanisms of growth inhibition by nonsteroidal antioestrogens in human breast cancer cells. J Steroid Biochem 27: 891-897, 1987

    Google Scholar 

  31. Wakeling AE: Comparative studies on the effects of steroidal and nonsteroidal oestrogen antagonists on the proliferation of human breast cancer cells. J Steroid Biochem 34: 183-188, 1989

    Google Scholar 

  32. Reed MJ, Christodoulides A, Koistinen R, Seppala M, Teale JD, Ghilchik MW: The effect of endocrine therapy with medroxyprogesterone acetate, 4-hydroxyandrostenedione or tamoxifen on plasma concentrations of insulin-like growth factor (IGF)-I, IGF-II and IGFBP-1 in women with advanced breast cancer. Int J Cancer 52: 208-212, 1992

    Google Scholar 

  33. Ellis MJ, Jenkins S, Hanfelt J, Redington ME, Taylor M, Leek R, Siddle K, Harris A: Insulin-like growth factors in human breast cancer. Breast Cancer Res Treat 52: 175-184, 1998

    Google Scholar 

  34. Favoni RE, de Cupis A, Bruno S, Yee D, Ferrera A, Pirani P, Costa A, Decensi A: Modulation of the insulin-like growth factor-I system by N-(4-hydroxyphenyl)-retinamide in human breast cancer cell lines. Br J Cancer 77: 2138-2147, 1998

    Google Scholar 

  35. Werner H, LeRoith D: The role of the insulin-like growth factor system in human cancer. Adv Cancer Res 68: 183-223, 1996

    Google Scholar 

  36. Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H, Rinaldi S, Zeleniuch-Jacquotte A, Shore RE, Riboli E: Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 92: 1592-1600, 2000

    Google Scholar 

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Authors and Affiliations

  1. Divisions of Chemoprevention, European Institute of Oncology, Milan, Italy

    Bernardo Bonanni, Aliana Guerrieri-Gonzaga, Rosalba Torrisi, Massimiliano Cazzaniga, Serena Mora & Andrea Decensi

  2. Laboratory Medicine, European Institute of Oncology, Milan, Italy

    Harriet Johansson & Maria Teresa Sandri

  3. Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy

    Sara Gandini & Chris Robertson

  4. Department of Clinical Biology, Haukeland University Hospital, Bergen, Norway

    Ernst Asbjorn Lien

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  1. Bernardo Bonanni
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  2. Harriet Johansson
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  3. Sara Gandini
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  4. Aliana Guerrieri-Gonzaga
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  5. Rosalba Torrisi
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  6. Maria Teresa Sandri
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  7. Massimiliano Cazzaniga
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  9. Chris Robertson
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  10. Ernst Asbjorn Lien
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  11. Andrea Decensi
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Bonanni, B., Johansson, H., Gandini, S. et al. Effect of low dose tamoxifen on the insulin-like growth factor system in healthy women. Breast Cancer Res Treat 69, 21–27 (2001). https://doi.org/10.1023/A:1012241505717

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