Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Drug Insight: breast cancer prevention and tissue-targeted hormone replacement therapy

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 584–593 (2007)Cite this article

Abstract

The first-generation selective estrogen receptor modulator (SERM) tamoxifen has been the mainstream hormone therapy in breast cancer. Tamoxifen benefits all stages of the disease, but its use increases the risk of uterine cancer and thromboembolic events and it can only be administered for 5 years. Aromatase inhibitors are superior to tamoxifen at advanced stages of disease and as adjuvants; however, because they increase fractures, aromatase inhibitors are unlikely to be used to prevent disease. Raloxifene, a second-generation SERM, leads, like tamoxifen, to approximately 50% fewer cases of invasive breast cancer in high risk women, with a lower incidence of thromboembolic events. Several other SERMs are in development to improve tissue specificity, efficacy and tolerance. Raloxifene shows protection against vertebral fractures similar to bisphosphonates; however, no significant effect has been observed on nonvertebral fractures. Many SERMs are in development for prevention and treatment of osteoporosis. As breast cancer metastasizes early and advanced disease cannot be cured, prevention is essential. To avoid the concerns about the use of traditional hormone replacement therapy, dehydroepiandrosterone—a tissue-targeted precursor of sex steroid formation—offers hope of a physiological tissue-targeted hormone replacement that, combined with a SERM, would simultaneously prevent breast and uterine cancer.

Key Points

  • The selective estrogen receptor modulator (SERM) tamoxifen blocks estrogen action and prolongs survival in breast cancer

  • New SERMs have more potent activity in the mammary gland and at least one does not stimulate the uterus, reducing the risk of uterine cancer

  • The best hope of decreasing death from breast cancer is prevention of the disease, thereby avoiding micrometastases

  • Dehydroepiandrosterone (DHEA) is the precursor component of tissue-specific hormone replacement therapy (HRT) and avoids exposure of other tissues as found with traditional HRT

  • DHEA allows compensation for the loss of androgens at menopause exclusively in the tissues that need them

  • The addition of a highly specific SERM to DHEA might offer the best hope to prevent breast and uterine cancer and to replace traditional HRT, thereby meeting many other needs of women after the menopause

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Human steroidogenic and steroid-inactivating enzymes in peripheral intracrine tissues
Figure 2: Structure of selective estrogen receptor modulators in current use or in development for osteoporosis or breast cancer
Figure 3: Schematic representation of the role of ovarian and adrenal sources of sex steroids in postmenopausal women
Figure 4: Effect of age on DHEA and DHEA-S levels in women
Figure 5: Schematic representation of the effects expected from the combination of a specific estrogen receptor modulator (acolbifene) and DHEA

Similar content being viewed by others

References

  1. Jemal A et al. (2007) Cancer statistics, 2007. CA Cancer J Clin 57: 43–66

    Article  Google Scholar 

  2. Berry DA et al. (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353: 1784–1792

    Article  CAS  Google Scholar 

  3. Fisher B et al. (1996) Five versus more than five years of tamoxifen for breast cancer patients with negative lymph nodes and estrogen positive tumors. J Natl Cancer Inst 88: 1529–1542

    Article  CAS  Google Scholar 

  4. Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365: 1687–1717

  5. Women's Health Initiative (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 288: 321–333

  6. Beral V et al. (2005) Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 365: 1543–1551

    Article  Google Scholar 

  7. Archer DF et al. (1999) A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group. Obstet Gynecol 94: 498–503

    CAS  PubMed  Google Scholar 

  8. Labrie F et al. (2001) 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

    Article  CAS  Google Scholar 

  9. Vogel VG et al. (2006) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295: 2727–2741

    Article  CAS  Google Scholar 

  10. Barrett-Connor E et al. (2006) Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 355: 125–137

    Article  CAS  Google Scholar 

  11. Melnikow J et al. (2006) Chemoprevention: drug pricing and mortality: the case of tamoxifen. Cancer 107: 950–958

    Article  Google Scholar 

  12. Vogel VG et al. (2002) Re: tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 94: 1504

    Article  CAS  Google Scholar 

  13. Land SR et al. (2006) Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295: 2742–2751

    Article  CAS  Google Scholar 

  14. Paridaens R 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: 1391–1398

    Article  CAS  Google Scholar 

  15. Coombes RC et al. (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350: 1081–1092

    Article  CAS  Google Scholar 

  16. Poulin R and Labrie F (1986) Stimulation of cell proliferation and estrogenic response by adrenal C19-Δ5-steroids in the ZR-75-1 human breast cancer cell line. Cancer Res 46: 4933–4937

    CAS  PubMed  Google Scholar 

  17. Howell A et al. (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365: 60–62

    Article  CAS  Google Scholar 

  18. Howell A et al. (2004) Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol 22: 1605–1613

    Article  CAS  Google Scholar 

  19. Howell A et al. (2002) Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progression after prior endocrine treatment. J Clin Oncol 20: 3396–3403

    Article  CAS  Google Scholar 

  20. Johnston SR (2005) Endocrinology and hormone therapy in breast cancer: selective oestrogen receptor modulators and downregulators for breast cancer—have they lost their way? Breast Cancer Res 7: 119–130

    Article  CAS  Google Scholar 

  21. Roy J et al. (2003) 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

    Article  CAS  Google Scholar 

  22. Gutman M et al. (2002) 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

    Article  CAS  Google Scholar 

  23. Gutman M et al. (2003) Effect of treatment sequence with radiotherapy and the antiestrogen EM 800 on the growth of ZR 75 1 human mammary carcinoma in nude mice. Int J Cancer 103: 268–276

    Article  CAS  Google Scholar 

  24. Simard J et al. (1997) Blockade of the stimulatory effect of estrogens, OH-tamoxifen, OH-toremifene, droloxifene and raloxifene on alkaline phosphatase activity by the antiestrogen EM-800 in human endometrial adenocarcinoma Ishikawa cells. Cancer Res 57: 3494–3497

    CAS  PubMed  Google Scholar 

  25. Labrie F et al. (2004) Activity and safety of the orally active pure antiestrogen EM-800 (SCH 57050) in tamoxifen-resistant breast cancer. J Clin Oncol 22: 864–871

    Article  CAS  Google Scholar 

  26. Duvernoy CS et al. (2005) Vascular events in the multiple outcomes of raloxifene evaluation (MORE) trial: incidence, patient characteristics and effect of raloxifene. Menopause 12: 444–452

    Article  Google Scholar 

  27. Labrie F et al. (2005) Is DHEA a hormone? Starling Review. J Endocrinol 187: 169–196

    Article  CAS  Google Scholar 

  28. Labrie F et al. (2006) Androgen glucuronides, instead of testosterone as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol 99: 182–188

    Article  CAS  Google Scholar 

  29. Wierman ME et al. (2006) Androgen therapy in women: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 91: 3697–3710

    Article  CAS  Google Scholar 

  30. Gammon MD and Thompson WD (1991) Polycystic ovaries and the risk of breast cancer. Am J Epidemiol 134: 818–824

    Article  CAS  Google Scholar 

  31. Dimitrakakis C et al. (2003) A physiologic role for testosterone in limiting estrogenic stimulation of the breast. Menopause 10: 292–298

    Article  Google Scholar 

  32. Labrie F et al. (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

    Article  CAS  Google Scholar 

  33. Ulrich P (1939) Testosterone (male hormone) and its possible role in the treatment of some breast cancers [French]. Acta - Unio Internationalis Contra Cancrum 4: 377–379

    Google Scholar 

  34. Sturgeon SR et al. (2004) Serum levels of sex hormones and breast cancer risk in premenopausal women: a case-control study (USA). Cancer Causes Control 15: 45–53

    Article  Google Scholar 

  35. Key T et al. (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94: 606–616

    Article  CAS  Google Scholar 

  36. Beattie MS et al. (2006) Endogenous sex hormones, breast cancer risk, and tamoxifen response: an ancillary study in the NSABP Breast Cancer Prevention Trial (P-1). J Natl Cancer Inst 98: 110–115

    Article  CAS  Google Scholar 

  37. Onland-Moret NC et al. (2003) Urinary endogenous sex hormone levels and the risk of postmenopausal breast cancer. Br J Cancer 88: 1394–1399

    Article  CAS  Google Scholar 

  38. Tworoger SS et al. (2006) The association of plasma DHEA and DHEA sulfate with breast cancer risk in predominantly premenopausal women. Cancer Epidemiol Biomarkers Prevent 15: 967–971

    Article  CAS  Google Scholar 

  39. Tamimi RM et al. (2006) Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med 166: 1483–1489

    Article  CAS  Google Scholar 

  40. Vermeulen A et al. (1986) Aromatase, 17β-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. J Steroid Biochem 25: 799–802

    Article  CAS  Google Scholar 

  41. Bone Health and Osteoporosis: A Report of the Surgeon General [http://www.surgeongeneral.gov/library/bonehealth/] (accessed March 27 2007)

  42. Fisher B et al. (1998) 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

    Article  CAS  Google Scholar 

  43. Delmas PD et al. (2002) Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 87: 3609–3617

    Article  CAS  Google Scholar 

  44. Ettinger B et al. (2004) Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 19: 745–751

    Article  CAS  Google Scholar 

  45. Michalska D et al. (2006) The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 91: 870–877

    Article  CAS  Google Scholar 

  46. Martel C et al. (1998) Predominant androgenic component in the stimulatory effect of dehydroepiandrosterone on bone mineral density in the rat. J Endocrinol 157: 433–442

    Article  CAS  Google Scholar 

  47. Labrie F et al. (1997) Effect of 12-month DHEA replacement therapy on bone, vagina, and endometrium in postmenopausal women. J Clin Endocrinol Metab 82: 3498–3505

    Article  CAS  Google Scholar 

  48. Diamond P et al. (1996) Metabolic effects of 12-month percutaneous dehydroepiandrosterone replacement therapy in postmenopausal women. J Endocrinol Suppl 150: S43–S50

    Article  CAS  Google Scholar 

  49. Villareal DT and Holloszy JO (2004) Effect of DHEA on abdominal fat and insulin action on elderly women and men: a randomized controlled trial. JAMA 292: 2243–2248

    Article  CAS  Google Scholar 

  50. Morales AJ et al. (1998) The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol 49: 421–432

    Article  CAS  Google Scholar 

  51. Jankowski CM et al. (2006) Effects of dehydroepiandrosterone replacement therapy on bone mineral density in older adults: a randomized, controlled trial. J Clin Endocrinol Metab 91: 2986–2993

    Article  CAS  Google Scholar 

  52. Nair KS et al. (2006) DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 355: 1647–1659

    Article  CAS  Google Scholar 

  53. Weigelt B et al. (2003) Gene expression profiles of primary breast tumors maintained in distant metastases. Proc Natl Acad Sci USA 100: 15901–15905

    Article  CAS  Google Scholar 

  54. Labrie F et al. (2003) The combination of a novel SERM with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health? Endocrinology 144: 4700–4706

    Article  CAS  Google Scholar 

  55. Stomati M et al. (2000) Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol 14: 342–36355

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Molecular Endocrinology and Oncology Research Center, Laval University Hospital Research Center (CRCHUL), 2705 Laurier Boulevard, Quebec City, Quebec G1V 4G2, Canada fernand.labrie@crchul.ulaval.ca

Authors and Affiliations

  1. F Labrie is a Professor of Physiology at Laval University and physician in the department of medicine at Le Centre Hospitalier de l'Université Laval (CHUL), Québec City, Canada. He is scientific director of the CHUL Research Center (CRCHUL) and head of the Molecular Endocrinology and Oncology Research Center.,

    Fernand Labrie

Authors
  1. Fernand Labrie
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

F Labrie is President of Endorecherche, Quebec City, QC, Canada, the company developing acolbifene and dehydroepiandrosterone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Labrie, F. Drug Insight: breast cancer prevention and tissue-targeted hormone replacement therapy. Nat Rev Endocrinol 3, 584–593 (2007). https://doi.org/10.1038/ncpendmet0559

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0559

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing