This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Bocchinfuso, W. P. Articles by Korach, K. S. Search for Related Content PubMed PubMed Citation Articles by Bocchinfuso, W. P. Articles by Korach, K. S.

A Mouse Mammary Tumor Virus-Wnt-1 Transgene Induces Mammary Gland Hyperplasia and Tumorigenesis in Mice Lacking Estrogen Receptor-

Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709 [W. P. B., J. F. C., K. S. K.]; and Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892 [W. P. H., H. E. V.]

Estrogens have important functions in mammary gland development and carcinogenesis. To better define these roles, we have used two previously characterized lines of genetically altered mice: estrogen receptor- (ER) knockout (ERKO) mice, which lack the gene encoding ER, and mouse mammary virus tumor (MMTV)-Wnt-1 transgenic mice (Wnt-1 TG), which develop mammary hyperplasia and neoplasia due to ectopic production of the Wnt-1 secretory glycoprotein. We have crossed these lines to ascertain the effects of ER deficiency on mammary gland development and carcinogenesis in mice expressing the Wnt-1 transgene. Introduction of the Wnt-1 transgene into the ERKO background stimulates proliferation of alveolar-like epithelium, indicating that Wnt-1 protein can promote mitogenesis in the absence of an ER-mediated response. The hyperplastic glandular tissue remains confined to the nipple region, implying that the requirement for ER in ductal expansion is not overcome by ectopic Wnt-1. Tumors were detected in virgin ERKO females expressing the Wnt-1 transgene at an average age (48 weeks) that is twice that seen in virgin Wnt-1 TG mice (24 weeks) competent to produce ER. Prepubertal ovariectomy of Wnt-1 TG mice also extended tumor latency to 42 weeks. However, pregnancy did not appear to accelerate the appearance of tumors in Wnt-1 TG mice, and tumor growth rates were not measurably affected by late ovariectomy. Small hyperplastic mammary glands were observed in Wnt-1 TG males, regardless of ER gene status; the glands were similar in appearance to those found in ERKO/Wnt-1 TG females. Mammary tumors also occurred in Wnt-1 TG males; latency tended to be longer in the heterozygous ER and ERKO males (86 to 100 weeks) than in wild-type ER mice (ca. 75 weeks). We conclude that ectopic expression of the Wnt-1 proto-oncogene can induce mammary hyperplasia and tumorigenesis in the absence of ER in female and male mice. The delayed time of tumor appearance may depend on the number of cells at risk of secondary events in the hyperplastic glands, on the carcinogenesis-promoting effects of ER signaling, or on both.

This article has been cited by other articles:

				C. E. Glover, K. E. Gurley, K.-H. Kim, B. Storer, M. L. Fero, and C. J. Kemp Endocrine dysfunction in p27Kip1 deficient mice and susceptibility to Wnt-1 driven breast cancer Carcinogenesis, June 1, 2009; 30(6): 1058 - 1063. [Abstract] [Full Text] [PDF]

				Z. Wang, G. T. Wijewickrama, K.-w. Peng, B. M. Dietz, L. Yuan, R. B. van Breemen, J. L. Bolton, and G. R. J. Thatcher Estrogen Receptor {alpha} Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus J. Biol. Chem., March 27, 2009; 284(13): 8633 - 8642. [Abstract] [Full Text] [PDF]

				M.-L. Asselin-Labat, F. Vaillant, M. Shackleton, T. Bouras, G.J. Lindeman, and J.E. Visvader Delineating the Epithelial Hierarchy in the Mouse Mammary Gland Cold Spring Harb Symp Quant Biol, November 19, 2008; (2008) sqb.2008.73.020v2. [Abstract] [PDF]

				X.-Y. Wang, Y. Yin, H. Yuan, T. Sakamaki, H. Okano, and R. I. Glazer Musashi1 Modulates Mammary Progenitor Cell Expansion through Proliferin-Mediated Activation of the Wnt and Notch Pathways Mol. Cell. Biol., June 1, 2008; 28(11): 3589 - 3599. [Abstract] [Full Text] [PDF]

				Y. Huang, S. V. Fernandez, S. Goodwin, P. A. Russo, I. H. Russo, T. R. Sutter, and J. Russo Epithelial to Mesenchymal Transition in Human Breast Epithelial Cells Transformed by 17 -Estradiol Cancer Res., December 1, 2007; 67(23): 11147 - 11157. [Abstract] [Full Text] [PDF]

				A. Kuorelahti, S. Rulli, I. Huhtaniemi, and M. Poutanen Human Chorionic Gonadotropin (hCG) Up-Regulates wnt5b and wnt7b in the Mammary Gland, and hCG{beta} Transgenic Female Mice Present with Mammary Gland Tumors Exhibiting Characteristics of the Wnt/{beta}-Catenin Pathway Activation Endocrinology, August 1, 2007; 148(8): 3694 - 3703. [Abstract] [Full Text] [PDF]

				C. M. Silva and M. A. Shupnik Integration of Steroid and Growth Factor Pathways in Breast Cancer: Focus on Signal Transducers and Activators of Transcription and Their Potential Role in Resistance Mol. Endocrinol., July 1, 2007; 21(7): 1499 - 1512. [Abstract] [Full Text] [PDF]

				E. Labbe, L. Lock, A. Letamendia, A. E. Gorska, R. Gryfe, S. Gallinger, H. L. Moses, and L. Attisano Transcriptional Cooperation between the Transforming Growth Factor-{beta} and Wnt Pathways in Mammary and Intestinal Tumorigenesis Cancer Res., January 1, 2007; 67(1): 75 - 84. [Abstract] [Full Text] [PDF]

				J. Russo, S. V. Fernandez, P. A. Russo, R. Fernbaugh, F. S. Sheriff, H. M. Lareef, J. Garber, and I. H. Russo 17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells FASEB J, August 1, 2006; 20(10): 1622 - 1634. [Abstract] [Full Text] [PDF]

				L. Blavier, A. Lazaryev, F. Dorey, G. M. Shackleford, and Y. A. DeClerck Matrix metalloproteinases play an active role in wnt1-induced mammary tumorigenesis. Cancer Res., March 1, 2006; 66(5): 2691 - 2699. [Abstract] [Full Text] [PDF]

				S. J. Han, F. J. DeMayo, J. Xu, S. Y. Tsai, M.-J. Tsai, and B. W. O'Malley Steroid Receptor Coactivator (SRC)-1 and SRC-3 Differentially Modulate Tissue-Specific Activation Functions of the Progesterone Receptor Mol. Endocrinol., January 1, 2006; 20(1): 45 - 55. [Abstract] [Full Text] [PDF]

				D. J. Mulholland, S. Dedhar, G. A. Coetzee, and C. C. Nelson Interaction of Nuclear Receptors with the Wnt/{beta}-Catenin/Tcf Signaling Axis: Wnt You Like to Know? Endocr. Rev., December 1, 2005; 26(7): 898 - 915. [Abstract] [Full Text] [PDF]

				S.-Q. Kuang, L. Liao, S. Wang, D. Medina, B. W. O'Malley, and J. Xu Mice Lacking the Amplified in Breast Cancer 1/Steroid Receptor Coactivator-3 Are Resistant to Chemical Carcinogen-Induced Mammary Tumorigenesis Cancer Res., September 1, 2005; 65(17): 7993 - 8002. [Abstract] [Full Text] [PDF]

				M. S. Frech, E. D. Halama, M. T. Tilli, B. Singh, E. J. Gunther, L. A. Chodosh, J. A. Flaws, and P. A. Furth Deregulated Estrogen Receptor {alpha} Expression in Mammary Epithelial Cells of Transgenic Mice Results in the Development of Ductal Carcinoma In situ Cancer Res., February 1, 2005; 65(3): 681 - 685. [Abstract] [Full Text] [PDF]

				W. Yue, J.-P. Wang, Y. Li, W. P. Bocchinfuso, K. S. Korach, P. D. Devanesan, E. Rogan, E. Cavalieri, and R. J. Santen Tamoxifen versus Aromatase Inhibitors for Breast Cancer Prevention Clin. Cancer Res., January 15, 2005; 11(2): 925s - 930s. [Abstract] [Full Text] [PDF]

				M. H. Herynk and S. A. W. Fuqua Estrogen Receptor Mutations in Human Disease Endocr. Rev., December 1, 2004; 25(6): 869 - 898. [Abstract] [Full Text] [PDF]

				H. Zhang, S.-Q. Kuang, L. Liao, S. Zhou, and J. Xu Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor {gamma} and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice Cancer Res., October 1, 2004; 64(19): 7169 - 7177. [Abstract] [Full Text] [PDF]

				R. R. Driskell, X. Liu, M. Luo, M. Filali, W. Zhou, D. Abbott, N. Cheng, C. Moothart, C. D. Sigmund, and J. F. Engelhardt Wnt-responsive element controls Lef-1 promoter expression during submucosal gland morphogenesis Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L752 - L763. [Abstract] [Full Text] [PDF]

				S.-Q. Kuang, L. Liao, H. Zhang, A. V. Lee, B. W. O'Malley, and J. Xu AIB1/SRC-3 Deficiency Affects Insulin-Like Growth Factor I Signaling Pathway and Suppresses v-Ha-ras-induced Breast Cancer Initiation and Progression in Mice Cancer Res., March 1, 2004; 64(5): 1875 - 1885. [Abstract] [Full Text] [PDF]

				V. Novaro, D. C. Radisky, N. E. R. Castro, A. Weisz, and M. J. Bissell Malignant Mammary Cells Acquire Independence from Extracellular Context for Regulation of Estrogen Receptor {alpha} Clin. Cancer Res., January 1, 2004; 10(1): 402S - 409S. [Abstract] [Full Text] [PDF]

				S. Yeh, Y.-C. Hu, P.-H. Wang, C. Xie, Q. Xu, M.-Y. Tsai, Z. Dong, R.-S. Wang, T.-H. Lee, and C. Chang Abnormal Mammary Gland Development and Growth Retardation in Female Mice and MCF7 Breast Cancer Cells Lacking Androgen Receptor J. Exp. Med., December 15, 2003; 198(12): 1899 - 1908. [Abstract] [Full Text] [PDF]

				X. Yang, S. M. Edgerton, S. D. Kosanke, T. L. Mason, K. M. Alvarez, N. Liu, R. T. Chatterton, B. Liu, Q. Wang, A. Kim, et al. Hormonal and Dietary Modulation of Mammary Carcinogenesis in Mouse Mammary Tumor Virus-c-erbB-2 Transgenic Mice Cancer Res., May 15, 2003; 63(10): 2425 - 2433. [Abstract] [Full Text] [PDF]

				Y.-C. Hu, C.-R. Shyr, W. Che, X.-M. Mu, E. Kim, and C. Chang Suppression of Estrogen Receptor-mediated Transcription and Cell Growth by Interaction with TR2 Orphan Receptor J. Biol. Chem., September 6, 2002; 277(37): 33571 - 33579. [Abstract] [Full Text] [PDF]

				S. C. Hewitt, W. P. Bocchinfuso, J. Zhai, C. Harrell, L. Koonce, J. Clark, P. Myers, and K. S. Korach Lack of Ductal Development in the Absence of Functional Estrogen Receptor {alpha} Delays Mammary Tumor Formation Induced by Transgenic Expression of ErbB2/neu Cancer Res., May 1, 2002; 62(10): 2798 - 2805. [Abstract] [Full Text] [PDF]

				P. Devanesan, R. J. Santen, W. P. Bocchinfuso, K. S. Korach, E. G. Rogan, and E. Cavalieri Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor-{alpha} knock-out (ERKO)/Wnt-1 mice: implications for initiation of mammary tumors Carcinogenesis, September 1, 2001; 22(9): 1573 - 1576. [Abstract] [Full Text] [PDF]

				P. E. Blackshear Genetically Engineered Rodent Models of Mammary Gland Carcinogenesis: An Overview Toxicol Pathol, January 1, 2001; 29(1): 105 - 116. [Abstract] [PDF]

				K. Yoshidome, M.-A. Shibata, C. Couldrey, K. S. Korach, and J. E. Green Estrogen Promotes Mammary Tumor Development in C3(1)/SV40 Large T-Antigen Transgenic Mice: Paradoxical Loss of Estrogen Receptor{{alpha}} Expression during Tumor Progression Cancer Res., December 1, 2000; 60(24): 6901 - 6910. [Abstract] [Full Text]

				W. P. Bocchinfuso, J. K. Lindzey, S. C. Hewitt, J. A. Clark, P. H. Myers, R. Cooper, and K. S. Korach Induction of Mammary Gland Development in Estrogen Receptor-{alpha} Knockout Mice Endocrinology, August 1, 2000; 141(8): 2982 - 2994. [Abstract] [Full Text] [PDF]

				C. Brisken, A. Heineman, T. Chavarria, B. Elenbaas, J. Tan, S. K. Dey, J. A. McMahon, A. P. McMahon, and R. A. Weinberg Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling Genes & Dev., March 15, 2000; 14(6): 650 - 654. [Abstract] [Full Text]

				J. G. Liehr Is Estradiol a Genotoxic Mutagenic Carcinogen? Endocr. Rev., February 1, 2000; 21(1): 40 - 54. [Abstract] [Full Text]

				K. S. Korach Estrogen Receptor Knock-Out Mice: Molecular and Endocrine Phenotypes Reproductive Sciences, January 1, 2000; 7(1_suppl): S16 - S17. [Abstract] [PDF]

				J. F. Couse and K. S. Korach Estrogen Receptor Null Mice: What Have We Learned and Where Will They Lead Us? Endocr. Rev., June 1, 1999; 20(3): 358 - 417. [Abstract] [Full Text]