This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart 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 Sun, Y. Articles by Salomon, D. S. Search for Related Content PubMed PubMed Citation Articles by Sun, Y. Articles by Salomon, D. S.

(American Journal of Pathology. 2005;167:585-597.)
© 2005 American Society for Investigative Pathology

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 and David S. Salomon^*

From the Tumor Growth Factor^* and Oncogenetics Sections, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, Maryland; the Laboratory of Animal Sciences Program, SAIC, Incorporated, Frederick, Maryland; and the Upper Austrian Research GmbH Linz, Linz, Austria

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.

This article has been cited by other articles:

				C. Bianco, L. Strizzi, M. Mancino, K. Watanabe, M. Gonzales, S. Hamada, A. Raafat, L. Sahlah, C. Chang, F. Sotgia, et al. Regulation of Cripto-1 Signaling and Biological Activity by Caveolin-1 in Mammary Epithelial Cells Am. J. Pathol., February 1, 2008; 172(2): 345 - 357. [Abstract] [Full Text] [PDF]

				K. Watanabe, C. Bianco, L. Strizzi, S. Hamada, M. Mancino, V. Bailly, W. Mo, D. Wen, K. Miatkowski, M. Gonzales, et al. Growth Factor Induction of Cripto-1 Shedding by Glycosylphosphatidylinositol-Phospholipase D and Enhancement of Endothelial Cell Migration J. Biol. Chem., October 26, 2007; 282(43): 31643 - 31655. [Abstract] [Full Text] [PDF]

				M. M. Shen Nodal signaling: developmental roles and regulation Development, March 15, 2007; 134(6): 1023 - 1034. [Abstract] [Full Text] [PDF]

				C. Bianco, L. Strizzi, M. Mancino, A. Rehman, S. Hamada, K. Watanabe, A. De Luca, B. Jones, G. Balogh, J. Russo, et al. Identification of Cripto-1 as a Novel Serologic Marker for Breast and Colon Cancer Clin. Cancer Res., September 1, 2006; 12(17): 5158 - 5164. [Abstract] [Full Text] [PDF]