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  • Original Paper
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Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma

Oncogene volume 24, pages 4094–4105 (2005)Cite this article

Abstract

Human Cripto-1 (CR-1) is overexpressed in approximately 80% of human breast, colon and lung carcinomas. Mouse Cr-1 upregulation is also observed in a number of transgenic (Tg) mouse mammary tumors. To determine whether CR-1 can alter mammary gland development and/or may contribute to tumorigenesis in vivo, we have generated Tg mouse lines that express human CR-1 under the transcriptional control of the mouse mammary tumor virus (MMTV). Stable Tg MMTV/CR-1 FVB/N lines expressing different levels of CR-1 were analysed. Virgin female MMTV/CR-1 Tg mice exhibited enhanced ductal branching, dilated ducts, intraductal hyperplasia, hyperplastic alveolar nodules and condensation of the mammary stroma. Virgin aged MMTV/CR-1 Tg mice also possessed persistent end buds. In aged multiparous MMTV/CR-1 mice, the hyperplastic phenotype was most pronounced with multifocal hyperplasias. In the highest CR-1-expressing subline, G4, 38% (12/31) of the multiparous animals aged 12–20 months developed hyperplasias and approximately 33% (11/31) developed papillary adenocarcinomas. The long latency period suggests that additional genetic alterations are required to facilitate mammary tumor formation in conjunction with CR-1. This is the first in vivo study that shows hyperplasia and tumor growth in CR-1-overexpressing animals.

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Acknowledgements

We thank Dr Lionel Feigenbaum (SAIC Frederick) for generating the MMTV-CR-1 transgenic FVB/N mice and Amanda Kalmanowicz and Heidi Olesch from the Building 28 mouse facility at NIH for excellent animal care. We also thank Dr Humphrey Gardner of the Biogen Idec Department of Research Pathology for review of the MMTV/CR-1 histology slides. We gratefully acknowledge the generosity of Dr Yi Li (Baylor College of Medicine) for providing slides of the MMTV/Wnt-1 mammary tumors. This work was supported in part by funding from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to Nicola Normanno.

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Authors and Affiliations

  1. Tumor Growth Factor Section, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, MD, 20892, USA

    Christian Wechselberger, Luigi Strizzi, Nicholas Kenney, Morihisa Hirota, Youping Sun, Caterina Bianco, Nadia I Khan, Brenda Wallace-Jones & David S Salomon

  2. Department of Biological Science, Hampton University, Hampton, VA, 23668, USA

    Nicholas Kenney

  3. Department of Obstetrics and Gynecology, Medical Center Benjamin Franklin, Free University Berlin, 12200, Berlin, Germany

    Andreas Ebert

  4. Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA, 02142, USA

    Olivia Orozco, Heather Adkins & Michele Sanicola

  5. Division of Haematological Oncology and Department of Experimental Oncology, IT Fondazione Pascale, 80131, Naples, Italy

    Nicola Normanno

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  1. Christian Wechselberger
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Correspondence to David S Salomon.

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Wechselberger, C., Strizzi, L., Kenney, N. et al. Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma. Oncogene 24, 4094–4105 (2005). https://doi.org/10.1038/sj.onc.1208417

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