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  • Review Article
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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

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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

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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

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Competing interests

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

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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

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

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