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The C3(1)/SV40 T-antigen transgenic mouse model of mammary cancer: ductal epithelial cell targeting with multistage progression to carcinoma

Oncogene volume 19, pages 1020–1027 (2000)Cite this article

Abstract

The 5′ flanking region of the C3(1) component of the rat prostate steroid binding protein (PSBP) has been used to successfully target the expression of the SV40 large T-antigen (Tag) to the epithelium of both the mammary and prostate glands resulting in models of mammary and prostate cancers which histologically resemble the human diseases. Atypia of the mammary ductal epithelium develops at about 8 weeks of age, progressing to mammary intraepithelial neoplasia (resembling human ductal carcinoma in situ [DCIS]) at about 12 weeks of age with the development of invasive carcinomas at about 16 weeks of age in 100% of female mice. The carcinomas share features to what has been classified in human breast cancer as infiltrating ductal carcinomas. All FVB/N female mice carrying the transgene develop mammary cancer with about a 15% incidence of lung metastases. Approximately 10% of older male mice develop anaplastic mammary carcinomas. Unlike many other transgenic models in which hormones and pregnancy are used to induce a mammary phenotype, C3(1)/Tag mice develop mammary tumors in the mammary epithelium of virgin animals without hormone supplementation or pregnancy. Although mammary tumor development appears hormone-responsive at early stages, invasive carcinomas are hormone-independent, which corresponds to the loss of estrogen receptor-α expression during tumor progression. Molecular and biologic factors related to mammary tumor progression can be studied in this model since lesions evolve over a predictable time course. Genomic alterations have been identified during tumor progression, including an amplification of the distal portion of chromosome 6 containing ki-ras and loss of heterozygosity (LOH) in other chromosomal regions. We have demonstrated that stage specific alterations in the expression of genes which are critical regulators of the cell cycle and apoptosis are functionally important in vivo. C3(1)/Tag mice appear useful for testing particular therapies since growth of the mammary tumors can be reduced using chemopreventive agents, cytokines, and an anti-angiogenesis agent.

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Acknowledgements

This project has been funded in part with Federal funds from the National Cancer Institute, NIH, under contract no. NO1-CO-56000.

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Author notes

  1. Masa-Aki Shibata

    Present address: 1st Department of Anatomy and Biology, Osaka Medical College, Osaka, Japan

Authors and Affiliations

  1. Transgenic Oncogenesis Group, Laboratory of Cell Regulation and Carcinogenesis, Building 41, Room C629, NCI, Bethesda, 20892, Maryland, MD, USA

    Jeffrey E Green, Masa-Aki Shibata, Katsuhide Yoshidome, Min-ling Liu, Eiko Shibata, Stanislaw Kaczmarczyk, Weili Wang, Zi-yao Liu, Alfonso Calvo & Christine Couldrey

  2. Biology Department, Boise State University, Boise, 83725, Idaho, ID, USA

    Cheryl Jorcyk

  3. Pathology/Histopathology Laboratory, SAIC, Frederick, 21712, Maryland, MD, USA

    Miriam R Anver

  4. Laboratory of Experimental Immunology, NCI, Frederick, 21712, Maryland, MD, USA

    Jon Wigginton & Robert Wiltrout

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Green, J., Shibata, MA., Yoshidome, K. et al. The C3(1)/SV40 T-antigen transgenic mouse model of mammary cancer: ductal epithelial cell targeting with multistage progression to carcinoma. Oncogene 19, 1020–1027 (2000). https://doi.org/10.1038/sj.onc.1203280

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