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© The Rockefeller University Press, 0021-9525/1997//1025 $5.00
The Journal of Cell Biology, Volume 139, Number 4, , 1997 1025-1032

Article

Precocious Mammary Gland Development in P-Cadherin–deficient Mice



Glenn L. Radice*,{ddagger},§, M. Celeste Ferreira-Cornwell§, Stephen D. Robinson*, Helen Rayburn*, Lewis A. Chodosh||, Masatoshi Takeichi{ddagger}, and Richard O. Hynes*

* Howard Hughes Medical Institute, Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; {ddagger} Department of Biophysics, Faculty of Science, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto, 60601, Japan; § Departments of Obstetrics and Gynecology; and || Molecular and Cellular Engineering, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

To investigate the functions of P-cadherin in vivo, we have mutated the gene encoding this cell adhesion receptor in mice. In contrast to E- and N-cadherin– deficient mice, mice homozygous for the P-cadherin mutation are viable. Although P-cadherin is expressed at high levels in the placenta, P-cadherin–null females are fertile. P-cadherin expression is localized to the myoepithelial cells surrounding the lumenal epithelial cells of the mammary gland. The role of the myoepithelium as a contractile tissue necessary for milk secretion is clear, but its function in the nonpregnant animal is unknown. The ability of the P-cadherin mutant female to nurse and maintain her litter indicates that the contractile function of the myoepithelium is not dependent on the cell adhesion molecule P-cadherin. The virgin P-cadherin–null females display precocious differentiation of the mammary gland. The alveolar-like buds in virgins resemble the glands of an early pregnant animal morphologically and biochemically (i.e., milk protein synthesis). The P-cadherin mutant mice develop hyperplasia and dysplasia of the mammary epithelium with age. In addition, abnormal lymphocyte infiltration was observed in the mammary glands of the mutant animals. These results indicate that P-cadherin–mediated adhesion and/or signals derived from cell–cell interactions are important determinants in negative growth control in the mammary gland. Furthermore, the loss of P-cadherin from the myoepithelium has uncovered a novel function for this tissue in maintaining the undifferentiated state of the underlying secretory epithelium.

1. Abbreviations used in this paper: APC, adenomatous polyposis coli; ECM, extracellular matrix; ES, embryonic stem; HGF/SF, hepatocyte growth factor/scatter factor; HSV, Herpes simplex virus; PCD-1, P-cadherin antibody.

Special thanks to members of the Takeichi and Hynes labs for making this project possible. We thank Dr. Charles Daniel for the polyclonal casein antibody. We thank Nohelia Canales, Jose Carlos de Lima and Keisha Jones for technical assistance.


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