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Cited by 38Estrogen and related hormone effectsBreast Cancer Treatment StudiesProstate Cancer Treatment and Research

Effect of Dehydroepiandrosterone and the Antiestrogen EM-800 on Growth of Human ZR-75-1 Breast Cancer Xenografts

Couillard, Steeve, Labrie, Claude, Bélanger, Alain, Candas, Bernard, Pouliot, Frédéric, Labrie, Fernand·1998·JNCI Journal of the National Cancer Institute
DOI 10.1093/jnci/90.10.772
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Abstract

Background: In the mammary gland, androgens are formed from the precursor steroid dehydroepiandrosterone (DHEA). Clinical evidence indicates that androgens have inhibitory effects on breast cancer. Estrogens, on the other hand, stimulate the development and growth of breast cancer. We studied the effect of DHEA alone or in combination with the newly described pure antiestrogen EM-800 on the growth of subcutaneous tumor xenografts formed by the human breast cancer cell line ZR-75-1 in ovariectomized nude mice. Methods: Immediately after ovariectomy, mice received daily subcutaneous injections of 0.5 µg estrone (E1) (an estrogenic hormone). EM-800 (15, 50, or 100 µg) was given orally once daily. DHEA was administered percutaneously twice daily (total dose of 0.3, 1.0, or 3.0 mg) to the dorsal skin either alone or in combination with a 15-µg daily oral dose of EM-800. Changes in tumor size in response to the treatments (in relation to measurements made on the first day of treatment) were assessed periodically. At the end of the experiments, tumors were dissected and weighed. Results: A 9.4-fold increase in tumor size in 9.5 months was observed in ovariectomized mice receiving E1alone. Administration of 15, 50, or 100 µg EM-800 in E1-supplemented mice led to inhibitions of 87.5%, 93.5%, and 94.0% in tumor size, respectively. DHEA, on the other hand, at doses of 0.3, 1.0, or 3.0 mg inhibited terminal tumor size by 50.4%, 76.8%, and 80.0%, respectively. Comparable inhibitions in tumor size were obtained with a daily 15-µg oral dose of EM-800 with or without different doses of percutaneous DHEA. Conclusions: DHEA and EM800 independently suppressed the growth of E1-stimulated ZR-75-1 xenograft tumors in nude mice. Administration of DHEA at the defined doses did not alter the inhibitory effect of EM800. [J Natl Cancer Inst 1998;90: 772-8] Estrogens are recognized to play a predominant role in the development and growth of breast cancer (1-8). On the other hand, clinical studies (9-13) have shown that androgens have an opposite effect and have been used to treat advanced breast cancer in both premenopausal and postmenopausal women. Androgen treatment has a success rate comparable to that achieved with the other endocrine therapies (9-13). These clinical studies are well supported by a series of observations showing that androgens exert a direct inhibitory effect on the proliferation of human breast cancer ZR-75-1 cells under both basal and estrogen-stimulated conditions in vitro (13- 21) as well as in vivo in nude mice (22). More recently, the benefits of combined treatment with fluoxymesterone and tamoxifen were observed in postmenopausal women with metastatic breast cancer (23), both in terms of the response rate and time to progression of disease. A series of data show that the therapeutic activity of androgens is not restricted to premenopausal patients and is not limited to an inhibitory effect on gonadotropin secretion. There is also genetic evidence in agreement with the protective role of androgens against breast cancer (24,25). Such a role of androgens as direct regulatory factors of breast cancer growth is well supported by the presence of androgen receptors in a large proportion of human breast cancers (26-29). In addition to the direct growthinhibitory effect of physiologic concentrations of androgens demonstrated on human breast cancer cell lines in vitro (14- 21) and in vivo (22), we have observed that dihydrotestosterone (DHT) exerts an inhibitory effect on the growth of 7,12dimethylbenz[a ]anthracene (DMBA)induced mammary tumors in ovariectomized rats supplemented with estrogens (30). The inhibitory effect of DHT was reversed by simultaneous treatment with the antiandrogen flutamide, thus further supporting an action of DHT via specific binding to the androgen receptor in these mammary tumors (30,31). The human adrenals secrete large amounts of the precursor steroids dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), both of which are converted into androgens in target intracrine tissues (32-38). Since these two androgens inhibit breast cancer (9-23,30,39), we have studied the possibility that DHEA could inhibit the growth of the human ZR-75-1 breast cancer cell line in vivo in nude mice. To avoid the inhibitory effects of DHEA on gonadotropin secretion and to be able to assess the direct effects of DHEA-derived steroids on breast cancer growth, we have used ovariectomized animals supplemented with estrone (E1). We have also studied the potential interaction of the inhibitory effect of the novel antiestrogen EM-800 with that of DHEA by combined administration of the two drugs. Human ZR-75-1 breast cancer cells were obtained from the American Type Culture Collection (Rockville, MD). They were routinely cultured as monolayers in RPMI-1640 medium supplemented with 2 mM L-glutamine, 1 mM sodium pyruvate, 100 IU penicillin, 100 fg streptomycin, and 10% fetal bovine serum, under a humidified atmosphere

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Research works printed but not linked: 5

  1. Cooperative Breast Cancer Group. Testoster- one propionate therapy of breast cancer. JAMA 1964;188:1069-72.
  2. Ingle JN, Twito DI, Schaid DJ, Cullinan SA, Krook JE, Mailliard JA, et al. Combination hormonal therapy with tamoxifen plus fluoxy- mesterone versus tamoxifen alone in post- menopausal women with metastatic breast can- cer. An updated analysis. Cancer 1991;67: 886-91.
  3. 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. Early Breast Cancer Trialists' Collaborative Group. Lancet 1992;339:71-85.
  4. Simard J, Labrie C, Belanger A, Gauthier S, Singh SM, Merand Y, et al. Characterization of the effects of the novel non-steroidal antiestro- gen 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 1997;73:104-12.
  5. Quadri SK, Kledzik GS, Meites J. Counterac- tion by prolactin of androgen-induced inhibi- tion of mammary tumor growth in rats. J Natl Cancer Inst 1974;52:875-8.

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Authors
Couillard, S., Labrie, C., Bélanger, A., Candas, B., Pouliot, F., & Labrie, F.
Affiliations
Centre hospitalier de l'Université Laval (CA)
ORCID
Venue
JNCI Journal of the National Cancer Institute
Publisher
Oxford University Press (OUP)
Published
1998-05-20
Volume
90
Issue
10
Pages
772-778
ISSN
  • 0027-8874 (ISSN-L)
  • 1460-2105
DOI
10.1093/jnci/90.10.772
OpenAlex
W2117132131
Cited by
38
References
67
Citations by year
2013: 1 · 2012: 3
FWCI
2.47
Type
journal article
Language
en
Open access
closed
Locations
  • JNCI Journal of the National Cancer Institute (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
Keywords
dehydroepiandrosterone, antiestrogens, breast cancer, ZR-75-1 cells, tumor xenografts, estrone, androgens, combination therapy, tumor growth inhibition
MeSH terms
Administration, Cutaneous, Administration, Oral, Animals, Benzopyrans, Breast Neoplasms, Dehydroepiandrosterone, Drug Administration Schedule, Estrogen Antagonists, Estrone, Female, Humans, Mammary Neoplasms, Experimental, Mice, Nude, Ovariectomy, Propionates, Time Factors, Transplantation, Heterologous, Tumor Cells, Cultured, Mice

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