Skip to main content
SpringerLink
Log in

p53 expression in breast and endometrium during estrogen and tamoxifen treatment of surgically postmenopausal cynomolgus macaques

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Estrogens are important for both normal cell growth and malignant proliferation in the mammary gland as well as in the endometrium. Tamoxifen is a non‐steroidal anti‐estrogen widely used in breast cancer treatment. In recent years reports have been made of an increased risk of endometrial carcinoma during tamoxifen treatment. We used surgically menopausal cynomolgus macaques to study proliferation and p53 expression during hormonal replacement therapy (HRT) and tamoxifen treatment. Animals were treated continuously for 35 months with either conjugated equine estrogens (CEE; n = 20); medroxyprogesterone acetate (MPA; n =17); the combination of CEE + MPA (n = 13) or tamoxifen (n = 17) for 35 months. We found an increased expression of p53 in normal breast and endometrial tissue linked to CEE but not tamoxifen treatment. In the breast alveoli there was an association between proliferation measured by morphometry and p53 expression in all groups. However, in the endometrium CEE induced significantly more p53 positivity than tamoxifen, 9/20 vs. 3/17 in glands and 9/19 vs. 0/17 in stroma, respectively. If indeed long‐term treatment with tamoxifen as in the present study could inactivate the tumor‐suppressive function of p53, endometrial cells might thereby become more susceptible to genetic lesions associated with carcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Henderson BE, Ross R, Bernstein L: Estrogen as a cause of human cancer: The Richard and Hilnda Rosenthal Foundation Award Lecture. Cancer Res 48: 246–251, 1988

    Google Scholar 

  2. Henderson BE, Ross RK, Pike MC, Casagrande JT: Endogenous hormones as a major factor in human cancer. Cancer Res 42: 3232–3239, 1982

    Google Scholar 

  3. Grady D, Rubin SM, Petitti DB, Black D, Ettinger B, Ernster VL, Cummings SR:Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Int Med 117: 1016–1037, 1992

    Google Scholar 

  4. Colditz GA, Hankinson SE, Hunter DJ, Willet WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Spezier FE: The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl JMed 332: 1589–1593, 1995

    Google Scholar 

  5. Going JJ, Anderson TJ, Battersby MacIntyre CC: Proliferative and secretory activity in human breast during natural and artificial menstrual cycle. Am J Pathol 130: 193–204, 1988

    Google Scholar 

  6. King RJB: A discussion of the roles of oestrogen and progestin in human mammary carcinogenesis. J Steroid Biochem Molec Biol 39: 811–818, 1991

    Google Scholar 

  7. Spicer DV, Pike MC: Sex steroids and breast cancer prevention. J Nat Cancer Inst Monogr No. 16: 139–147, 1994

    Google Scholar 

  8. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31 000 recurrences and 24 000 deaths among 75 000 women. Lancet 339: 1–15, 71–85, 1992

    Google Scholar 

  9. Lönning PE, Lien EA: Mechanisms of action of endocrine treatment in breast cancer. Clin Rev Oncol Hematol 21: 158–193, 1995

    Google Scholar 

  10. Watts CKW, Brady A, Sarcevic B, deFazio A, Musgrove FA, Sutherland RL: Antiestrogen inhibition of cell cycle progression in breast cancer cells is associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol 9: 1804–1813, 1996

    Google Scholar 

  11. Love RR, Wiebe DA, Newcomb PA, Cameron L, Leventhal H, Jordan VC, Feyzi J, De Mets DL: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 115: 860–864, 1991

    Google Scholar 

  12. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, Carbone PP, DeMets DC: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 236: 852–856, 1992

    Google Scholar 

  13. Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfversvärd C, Skoog L, Somell A, Theve T, Wilking N: Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet i: 117–120, 1989

  14. Robinson DC, Bloss JD, Schiano MA: A retrospective study of tamoxifen and endometrial cancer in breast cancer patients. Gynecol Oncol 59: 186–190, 1995

    Google Scholar 

  15. Sidransky D, Hollstein M: Clinical implications of the p53 gene. Ann Rev Med 47: 285–301, 1996

    Google Scholar 

  16. Lane DP: p53, guardian of the genome. Nature 358: 15–16, 1992

    Google Scholar 

  17. Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 253: 49–53, 1991

    Google Scholar 

  18. Ito K, Watanabe K, Nasim S, Sasano H, Sato S, Yajima A, Silverberg SG, Garrett CT: Prognostic significance of p53 overexpression in endometrial cancer. Cancer Res 54: 4667–4670, 1994

    Google Scholar 

  19. Wynford-Thomas D: p53 in tumor pathology: Can we trust immunohistochemistry? J Pathol 166: 329–330, 1992

    Google Scholar 

  20. Boccuzzi A, Terzolo M, Leonardo E, Cappia S, Tappero G, Paccotti P, Angeli A: High frequency of p53 expression in colorectal adenomatous polyps. Anticancer Res 15: 1407–1410, 1995

    Google Scholar 

  21. Brenner RM, Slayden OD: Cyclic changes in the primate oviduct and endometrium. In: Knobil E, Neill JD (eds), The Physiology of Reproduction, 2nd edition. Raven Press, Ltd., New York, 1994, pp 541–569

    Google Scholar 

  22. Kaiserman-Abramof IR, Padykula HA: Ultrastructural epithelial zonation of the primate endometrium (rhesus monkey). Am J Anat 184: 13–30, 1989

    Google Scholar 

  23. Tsubura A, Hatano T, Hayama S, Morii S: Immunophenotypic difference of keratin expression in normal mammary glandular cells from five different species. Acta Anat 140: 287–293, 1991

    Google Scholar 

  24. Cline JM, Soderqvist G, von Schoultz E, Skoog L, von Schoultz B: Effects of hormonal replacement therapy on the mammary gland of surgically cynomolgus macaques. Am J Obstet Gynecol 174: 93–100, 1996

    Google Scholar 

  25. Adams MR, Register TC, Golden DL, Wagner JD, Williams JK: Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery arteriosclerosis. Arteriosclerosis Thrombosis & Vascular Biology 17: 217–221, 1997

    Google Scholar 

  26. Pike MC, Spicer DV, Dahmoush L, Press MF: Estrogens, progestogens, normal breast cell proliferation and breast cancer risk. Epidemiol Rev 15: 17–35, 1993

    Google Scholar 

  27. Rajan PB, Scott DJ, Perry RH, Griffith CDM: p53 protein expression in ductal carcinoma in situ (DCIS) of the breast. Breast Cancer Res Treat 42: 283–290, 1997

    Google Scholar 

  28. Moriki T, Takahashi T, Kataoka H, Hiroi M, Yamane T, Hara H: Proliferation marker MIB-1 correlates well with proliferative activity evaluated by BrdU in breast cancer: An immunohistochemical study including correlation with PCNA, p53, cerbB-2 and estrogen receptor status. Pathol Int 46: 953–961, 1996

    Google Scholar 

  29. Wilking N, Isaksson E, von Schoultz E: Tamoxifen secondary tumours: An update. Drug Safety 16: 104–117, 1997

    Google Scholar 

  30. Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fischer DE, Housman DE, Jacks T: p53 status and the efficacy of cancer therapy in vivo. Science 266: 807–810, 1994

    Google Scholar 

  31. O'Connor PM, Jackman J, Jondle D, Bhatra K, Magrath I, Kahk KW: Role of the p53 tumor suppressor gene in cell cycle arrest and radiosensitivity of Burkitt's lymphoma cell lines. Cancer Res 53: 4776–4780, 1993

    Google Scholar 

  32. Greenblatt MS, Bennett WP, Hollstein M, Harris CC: Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855–4878, 1994

    Google Scholar 

  33. Poller DN, Hutchings CE, Galea M, Bell JA, Nicholson RA, Elston CW, Blamey RW, Ellis IO: p53 protein expression in human breast carcinoma: relationship to expression of epidermal growth factor receptor, c-erbB-2 protein overexpression, and oestrogen receptor. Br J Cancer 66: 583–588, 1992

    Google Scholar 

  34. Schmitt FC, Leal C, Lopes C: p53 protein expression and nuclear DNA content in breast intraductal proliferation. J Pathol 176: 233–241, 1995

    Google Scholar 

  35. Koutselini H, Malliri A, Field JK, Spandidos DA: p53 expression in cytologic specimens from benign and malignant breast lesions. Anticancer Res 11: 1415–1420, 1991

    Google Scholar 

  36. Gudas JM, Oka M, Diella F, Trepel J, Cowan KH: Expression of wild-type p53 during the cell cycle in normal human mammary epithelial cells. Cell Growth Diff 5: 295–304, 1994

    Google Scholar 

  37. Jiko K, Sasano H, Ito K, Ozawa N, Sato S, Yajima A: Immunohistochemical and in situ hybridization analysis of p53 in human endometrial carcinoma of the uterus. Anticancer Res 13: 305–310, 1993

    Google Scholar 

  38. Guillot C, Falette N, Courtois S, Voeltzel T, Garcia E, Ozturk M, Puisieux A: Alteration of p53 damage response by tamoxifen treatment. Clin Cancer Res 2: 1439–1444, 1996

    Google Scholar 

  39. Hemminki K, Rajaniemi H, Lindahl B, Moberger B: Tamoxifen-induced DNA adducts in endometrial samples from breast cancer patients. Cancer Res 56: 4374–4377, 1996

    Google Scholar 

  40. Wogan GN: Review of the toxicology of tamoxifen. Semin Oncol 24: (1 Suppl 1): S1–87

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden

    E. Isaksson & E. von Schoultz

  2. Department of Comparative Medicine, Bowman Gray School ofMedicine, Wake Forest University, Winston‐Salem, NC, USA

    J.M. Cline

  3. Department of Pathology and Cytology, Karolinska Hospital, Stockholm, Sweden

    L. Skoog

  4. Department of Obstetrics and Gynecology, KarolinskaHospital, Stockholm, Sweden

    G. Söderqvist & B. von Schoultz

Authors
  1. E. Isaksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J.M. Cline
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Skoog
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Söderqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. Wilking
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. von Schoultz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. von Schoultz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Isaksson, E., Cline, J., Skoog, L. et al. p53 expression in breast and endometrium during estrogen and tamoxifen treatment of surgically postmenopausal cynomolgus macaques. Breast Cancer Res Treat 53, 61–67 (1999). https://doi.org/10.1023/A:1006172025349

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006172025349

Search

Navigation