© 2005 Oxford University Press
ARTICLE |
Medroxyprogesterone Acetate Elevation of Nm23-H1 Metastasis Suppressor Expression in Hormone Receptor–Negative Breast Cancer
Affiliations of authors: Women's Cancers Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD (DP, DOH, TO, CEH, MS, PSS); Laboratory Animal Sciences Program, SAIC, Frederick, MD (JJ); Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD (WDF); Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD (MH); Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, Bethesda, MD (SH, DB); Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD (SMS); Surgical Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD (MJM)
Correspondence to: Patricia S.Steeg, PhD, National Institutes of Health, Bldg. 10, Rm. 2A33, Bethesda MD 20892 (e-mail: steegp{at}mail.nih.gov).
Background: Reestablishment of metastasis suppressor gene expression may constitute a therapeutic strategy for high-risk breast cancer patients. We previously showed that medroxyprogesterone acetate (MPA), a progestin that has been tested as treatment for advanced breast cancer, elevates expression of the Nm23-H1 metastasis suppressor gene in hormone receptor–negative metastatic human breast carcinoma cell lines in vitro via a glucocorticoid receptor–based mechanism. Here, we tested whether MPA treatment inhibits metastatic colonization of a hormone receptor–negative breast cancer cell line in vivo. Methods: We tested the soft-agar colony-forming efficiency of untransfected MDA-MB-231T human breast carcinoma cells and MDA-MB-231T cells transfected with antisense Nm23-H1 in the presence and absence of MPA. Pharmacokinetic studies were used to establish dose and injection schedules that led to MPA serum levels in mice similar to those achievable in humans. For in vivo studies, nude mice were injected intravenously with MDA-MB-231T cells. After 4 weeks, mice were randomized to control or MPA arms. Endpoints included incidence, number, and size of gross pulmonary metastases; Nm23-H1 protein expression in gross metastases; and side effects. All statistical tests were two-sided. Results: MPA reduced colony formation of MDA-MB-231T cells by 40%–50% but had no effect on colony formation of Nm23-H1 antisense transfectants. Metastases developed in 100% (95% confidence interval [CI] = 78% to 100% and 77% to 100%, respectively) of control mice injected with MDA-MB-231T cells. In two independent experiments, only 73% (95% CI = 45% to 92%) and 64% (95% CI = 35% to 87%) of mice injected with 2 mg of MPA developed metastases. Mice injected with 2 mg of MPA showed reductions in the mean numbers, per mouse, of all metastases and of large (>3 mm) metastases (P = .04 and .013, respectively). Nm23-H1 was expressed at high levels in 43% of pulmonary metastases in MPA-treated mice but only 13% of metastases in untreated mice. Mice receiving at least 1-mg doses of MPA gained more weight than control-treated mice but exhibited no bone density alterations or abnormal mammary fat pad histology. Conclusion: Our preclinical results show that MPA appears to elevate Nm23-H1 metastasis suppressor gene expression, thereby reducing metastatic colonization. The data suggest a new use for an old agent in a molecularly defined subset of breast cancer patients.
CiteULike 
Connotea 
Del.icio.us What's this?
Correspondence about this Article
- Re: Medroxyprogesterone Acetate and Metastases: Of Mice and (Wo)Men
- Ann F. Chambers
J Natl Cancer Inst 2005 97: 1225.[Extract] [Full Text] [PDF]
Editorial about this Article
- Medroxyprogesterone Acetate and Metastases: Of Mice and (wo)Men
- V. Craig Jordan
J Natl Cancer Inst 2005 97: 619-621.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
|
|
 |
|
  G. C. Hughes, S. Thomas, C. Li, M.-K. Kaja, and E. A. Clark Cutting Edge: Progesterone Regulates IFN-{alpha} Production by Plasmacytoid Dendritic Cells J. Immunol., February 15, 2008; 180(4): 2029 - 2033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Horak, A. Mendoza, E. Vega-Valle, M. Albaugh, C. Graff-Cherry, W. G. McDermott, E. Hua, M. J. Merino, S. M. Steinberg, C. Khanna, et al. Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor EDG2 Cancer Res., December 15, 2007; 67(24): 11751 - 11759. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kaul, M. Murakami, T. Choudhuri, and E. S. Robertson Epstein-Barr Virus Latent Nuclear Antigens Can Induce Metastasis in a Nude Mouse Model J. Virol., October 1, 2007; 81(19): 10352 - 10361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Horak, J. H. Lee, A. G. Elkahloun, M. Boissan, S. Dumont, T. K. Maga, S. Arnaud-Dabernat, D. Palmieri, W. G. Stetler-Stevenson, M.-L. Lacombe, et al. Nm23-H1 Suppresses Tumor Cell Motility by Down-regulating the Lysophosphatidic Acid Receptor EDG2 Cancer Res., August 1, 2007; 67(15): 7238 - 7246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Rinker-Schaeffer, J. P. O'Keefe, D. R. Welch, and D. Theodorescu Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application. Clin. Cancer Res., July 1, 2006; 12(13): 3882 - 3889. [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Loprinzi, R. Levitt, D. Barton, J. A. Sloan, S. R. Dakhil, D. A. Nikcevich, J. D. Bearden III, J. A. Mailliard, L. K. Tschetter, T. R. Fitch, et al. Phase III Comparison of Depomedroxyprogesterone Acetate to Venlafaxine for Managing Hot Flashes: North Central Cancer Treatment Group Trial N99C7 J. Clin. Oncol., March 20, 2006; 24(9): 1409 - 1414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. Chambers Re: Medroxyprogesterone Acetate and Metastases: Of Mice and (Wo)Men J Natl Cancer Inst, August 17, 2005; 97(16): 1225 - 1225. [Full Text] [PDF]
|
|
|
|
|
|
V. C. Jordan RESPONSE: Re: Medroxyprogesterone Acetate and Metastases: Of Mice and (Wo)Men J Natl Cancer Inst, August 17, 2005; 97(16): 1225 - 1226. [Full Text] [PDF]
|
|
|
|
|
|
V. C. Jordan Medroxyprogesterone Acetate and Metastases: Of Mice and (wo)Men J Natl Cancer Inst, May 4, 2005; 97(9): 619 - 621. [Full Text] [PDF]
|
|