Overexpression of human Cripto-1 in transgenic mice delays mammary gland development and differentiation and induces mammary tumorigenesis

Youping Sun, Luigi Strizzi, Ahmed Raafat, Morihisa Hirota, Caterina Bianco, Lionel Feigenbaum, Nicholas Kenney, Christian Wechselberger, Robert Callahan, David S. Salomon

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Abstract

Overexpression of Cripto-1 has been reported in several types of human cancers including breast cancer. To investigate the role of human Cripto-1 (CR-1) in mammary gland development and tumorigenesis, we developed transgenic mice that express the human CR-1 transgene under the regulation of the whey acidic protein (WAP) promoter in the FVB/N mouse background. The CR-1 transgene was detected in the mammary gland of 15-week-old virgin WAP-CR-1 female mice that eventually developed hyperplastic lesions. From mid-pregnancy to early lactation, mammary lobulo-alveolar structures in WAP-CR-1 mice were less differentiated and delayed in their development due to decreased cell proliferation as compared to FVB/N mice. Early involution, due to increased apoptosis, was observed in the mammary glands of WAP-CR-1 mice. Higher levels of phosphorylated AKT and MAPK were detected in mammary glands of multiparous WAP-CR-1 mice as compared to multiparous FVB/N mice suggesting increased cell proliferation and survival of the transgenic mammary gland. In addition, more than half (15 of 29) of the WAP-CR-1 multiparous female mice developed multifocal mammary tumors of mixed histological subtypes. These results demonstrate that overexpression of CR-1 during pregnancy and lactation can lead to alterations in mammary gland development and to production of mammary tumors in multiparous mice.

Original languageEnglish
Pages (from-to)585-597
Number of pages13
JournalAmerican Journal of Pathology
Volume167
Issue number2
DOIs
Publication statusPublished - 2005 Aug

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Sun, Y., Strizzi, L., Raafat, A., Hirota, M., Bianco, C., Feigenbaum, L., Kenney, N., Wechselberger, C., Callahan, R., & Salomon, D. S. (2005). Overexpression of human Cripto-1 in transgenic mice delays mammary gland development and differentiation and induces mammary tumorigenesis. American Journal of Pathology, 167(2), 585-597. https://doi.org/10.1016/S0002-9440(10)63000-3