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Pathologic progression of mammary carcinomas in a C3(1)/SV40 T/t-antigen transgenic rat model of human triple-negative and Her2-positive breast cancer

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Abstract

The C3(1) component of the rat prostate steroid binding protein has been used to target expression of the SV40 T/t-antigen to the mammary epithelium of mice resulting in pre-neoplastic lesions that progress to invasive and metastatic cancer with molecular features of human basal-type breast cancer. However, there are major differences in the histologic architecture of the stromal and epithelial elements between the mouse and human mammary glands. The rat mammary gland is more enriched with epithelial and stromal components than the mouse and more closely resembles the cellular composition of the human gland. Additionally, existing rat models of mammary cancer are typically estrogen receptor positive and hormone responsive, unlike most genetically engineered mouse mammary cancer models. In an attempt to develop a mammary cancer model that might more closely resemble the pathology of human breast cancer, we generated a novel C3(1)/SV40 T/t-antigen transgenic rat model that developed progressive mammary lesions leading to highly invasive adenocarcinomas. However, aggressive tumor development prevented the establishment of transgenic lines. Characterization of the tumors revealed that they were primarily estrogen receptor and progesterone receptor negative, and either her2/neu positive or negative, resembling human triple-negative or Her2 positive breast cancer. Tumors expressed the basal marker K14, as well as the luminal marker K18, and were negative for smooth muscle actin. The triple negative phenotype has not been previously reported in a rat mammary cancer model. Further development of a C3(1)SV40 T/t-antigen based model could establish valuable transgenic rat lines that develop basal-type mammary tumors.

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Acknowledgments

This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. We are grateful to Ron Lubet (NCI) and Clinton Grubbs (University of Alabama-Birmingham) for their assistance in providing control samples for immunohistochemistry, and Donna Bucher at PHL (NCI-Frederick) for technical assistance. We would like to thank Jerry Ward (Global Vet Pathology) for helpful discussions.

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Author notes

  1. M. J. Hoenerhoff

    Present address: Investigative Pathology Group, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Drive, Research Triangle Park, NC, 27709, USA

  2. M. A. Shibata

    Present address: Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, Osaka, Japan

Authors and Affiliations

  1. Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Building 37, Room 4054, Bethesda, MD, 20892, USA

    M. J. Hoenerhoff & J. E. Green

  2. Carcinogenesis and Chemoprevention Program, Hormel Institute, University of Minnesota, Austin, MN, 55912, USA

    A. Bode

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  1. M. J. Hoenerhoff
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  4. J. E. Green
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Correspondence to J. E. Green.

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M. J. Hoenerhoff, and M. A. Shibata contributed equally to this work.

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Hoenerhoff, M.J., Shibata, M.A., Bode, A. et al. Pathologic progression of mammary carcinomas in a C3(1)/SV40 T/t-antigen transgenic rat model of human triple-negative and Her2-positive breast cancer. Transgenic Res 20, 247–259 (2011). https://doi.org/10.1007/s11248-010-9406-5

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