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Originally published online as doi:10.2353/ajpath.2008.070696 on January 17, 2008

Published online before print January 17, 2008
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(American Journal of Pathology. 2008;172:345-357.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070696

Regulation of Cripto-1 Signaling and Biological Activity by Caveolin-1 in Mammary Epithelial Cells

Caterina Bianco*, Luigi Strizzi*, Mario Mancino*, Kazuhide Watanabe*, Monica Gonzales*, Shin Hamada*, Ahmed Raafat{dagger}, Lawson Sahlah{dagger}, Cindy Chang{ddagger}, Federica Sotgia§, Nicola Normanno||, Michael Lisanti§ and David S. Salomon*

From the Tumor Growth Factor*and Oncogenetics{dagger}Sections, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; the New Jersey Dental School,{ddagger}University of Medicine and Dentistry of New Jersey, Newark, New Jersey; the Department of Cancer Biology,§Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and the Cell Biology and Preclinical Models Unit,||ITN-Fondazione Pascale, Naples, Italy

Human and mouse Cripto-1 (CR-1/Cr-1) proteins play an important role in mammary gland development and tumorigenesis. In this study, we examined the relationship between Cripto-1 and caveolin-1 (Cav-1), a membrane protein that acts as a tumor suppressor in the mammary gland. Cripto-1 was found to interact with Cav-1 in COS7 cells and mammary epithelial cells. Using EpH4 mouse mammary epithelial cells expressing Cr-1 (EpH4 Cr-1) or Cr-1 and Cav-1 (EpH4 Cr-1/Cav-1), we demonstrate that Cav-1 expression markedly reduced the ability of Cr-1 to enhance migration, invasion, and formation of branching structures in EpH4 Cr-1/Cav-1 cells as compared to EpH4 Cr-1 cells. Furthermore, coexpression of Cav-1 together with Cr-1 in EpH4 Cr-1/Cav-1 cells inhibited Cr-1-mediated activation of c-src and mitogen-activated protein kinase signaling pathways. Conversely, primary mammary epithelial cells isolated from Cav-1 null–/–/mouse mammary tumor virus-CR-1 transgenic animals showed enhanced motility and activation of mitogen-activated protein kinase and c-src as compared to Cav-1+/–/CR-1 mammary cells. Finally, mammary tumors derived from mouse mammary tumor virus-CR-1 mice showed a dramatic reduction of Cav-1 expression as compared to mammary tissue from normal FVB/N mice, suggesting that in vivo Cav-1 is down-regulated during the process of CR-1-mediated mammary tumorigenesis.






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