This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Medina, D. Articles by Brown, P. Search for Related Content PubMed PubMed Citation Articles by Medina, D. Articles by Brown, P. Related Collections Preclinical Intervention Preclinical Intervention: In Vivo (Animals): Drugs, Nutritional Interventions, Mechanisms

Tamoxifen Inhibition of Estrogen Receptor-–Negative Mouse Mammary Tumorigenesis

¹ Baylor College of Medicine, Houston, Texas and ² University of California, Santa Cruz, California

Requests for reprints: Daniel Medina, Baylor College of Medicine, One Baylor Plaza, MS 112A, Houston, TX 77030. Phone: 713-798-4483; Fax: 713-790-0545; E-mail: dmedina{at}bcm.tmc.edu.

Tamoxifen reduces the relative risk of breast cancer developing from specific premalignant lesions. Many breast cancers that arise after tamoxifen treatment are estrogen receptor- (ER-)–negative, although premalignant lesions such as atypical ductal hyperplasia are highly ER-–positive. The p53 null mouse mammary epithelial transplant model is characterized by ER-–positive premalignant lesions that give rise to both ER-–positive and ER-–negative tumors. Given this progression from ER-–positive to ER-–negative lesions, we tested the ability of tamoxifen to block or delay mammary tumorigenesis in several versions of this model. In groups 1 and 2, p53 null normal mammary epithelial transplants were maintained in virgin mice. In groups 3 to 5, the p53 null and mammary transplants were maintained in mice continuously exposed to high levels of progesterone. In groups 6 and 7, transplants of the premalignant outgrowth line PN8a were maintained in virgin mice. Tamoxifen blocked estrogen signaling in these mice as evidenced by decreases in progesterone-induced lateral branching and epithelial proliferation in the mammary epithelium. Tamoxifen did not alter the elevated levels of progesterone in the blood while significantly reducing the circulating level of prolactin. Tamoxifen reduced tumor incidence in p53 null normal mammary epithelial transplants maintained in virgin mice from 55% to 5% and in progesterone-stimulated mice from 81% to 21%. The majority of the resultant tumors were ER-–negative. Tamoxifen also significantly delayed tumorigenesis in the ER-–positive high premalignant line PN8a from 100% to 75%. These results show that tamoxifen delays the emergence of ER-–negative tumors if given early in premalignant progression.

This article has been cited by other articles:

				T. A. Rose-Hellekant, A. J. Skildum, O. Zhdankin, A. L. Greene, R. R. Regal, K. D. Kundel, and D. W. Kundel Short-term Prophylactic Tamoxifen Reduces the Incidence of Antiestrogen-Resistant/Estrogen Receptor-Positive/Progesterone Receptor-Negative Mammary Tumors Cancer Prevention Research, May 1, 2009; 2(5): 496 - 502. [Abstract] [Full Text] [PDF]

				D. Medina, F. Kittrell, J. Hill, Y. Zhang, S. G. Hilsenbeck, R. Bissonette, and P. H. Brown Prevention of Tumorigenesis in p53-Null Mammary Epithelium by Rexinoid Bexarotene, Tyrosine Kinase Inhibitor Gefitinib, and Celecoxib Cancer Prevention Research, February 1, 2009; 2(2): 168 - 174. [Abstract] [Full Text] [PDF]

				M. Zhang, F. Behbod, R. L. Atkinson, M. D. Landis, F. Kittrell, D. Edwards, D. Medina, A. Tsimelzon, S. Hilsenbeck, J. E. Green, et al. Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer Cancer Res., June 15, 2008; 68(12): 4674 - 4682. [Abstract] [Full Text] [PDF]

				Y. Feng, D. Manka, K.-U. Wagner, and S. A. Khan Estrogen receptor-{alpha} expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice PNAS, September 11, 2007; 104(37): 14718 - 14723. [Abstract] [Full Text] [PDF]

				S. N. Sundar, V. Kerekatte, C. N. Equinozio, V. B. Doan, L. F. Bjeldanes, and G. L. Firestone Indole-3-Carbinol Selectively Uncouples Expression and Activity of Estrogen Receptor Subtypes in Human Breast Cancer Cells Mol. Endocrinol., December 1, 2006; 20(12): 3070 - 3082. [Abstract] [Full Text] [PDF]

				R. D. Cardiff, M. R. Anver, G. P. Boivin, M. W. Bosenberg, R. R. Maronpot, A. A. Molinolo, A. Y. Nikitin, J. E. Rehg, G. V. Thomas, R. G. Russell, et al. Precancer in Mice: Animal Models Used to Understand, Prevent, and Treat Human Precancers Toxicol Pathol, October 1, 2006; 34(6): 699 - 707. [Abstract] [Full Text] [PDF]

				K. Liby, M. Rendi, N. Suh, D. B. Royce, R. Risingsong, C. R. Williams, W. Lamph, F. Labrie, S. Krajewski, X. Xu, et al. The Combination of the Rexinoid, LG100268, and a Selective Estrogen Receptor Modulator, Either Arzoxifene or Acolbifene, Synergizes in the Prevention and Treatment of Mammary Tumors in an Estrogen Receptor-Negative Model of Breast Cancer. Clin. Cancer Res., October 1, 2006; 12(19): 5902 - 5909. [Abstract] [Full Text] [PDF]

				L. M. Arendt, T. A. Rose-Hellekant, E. P. Sandgren, and L. A. Schuler Prolactin Potentiates Transforming Growth Factor {alpha} Induction of Mammary Neoplasia in Transgenic Mice Am. J. Pathol., April 1, 2006; 168(4): 1365 - 1374. [Abstract] [Full Text] [PDF]