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© The Rockefeller University Press, 0021-9525/1998//557 $5.00
The Journal of Cell Biology, Volume 142, Number 2, , 1998 557-571

Articles

E-Cadherin–dependent Growth Suppression is Mediated by the Cyclin-dependent Kinase Inhibitor p27KIP1



Brad St. Croix*, Capucine Sheehan*, Janusz W. Rak*, Vivi Ann Flørenes*, Joyce M. Slingerland*,{ddagger}, and Robert S. Kerbel*

* Division of Cancer Biology Research, Sunnybrook Health Science Center; and {ddagger} Department of Medicine and Department of Medical Biophysics, University of Toronto, Toronto-Sunnybrook Regional Cancer Center, Toronto, Ontario, Canada M4N 3M5

Recent studies have demonstrated the importance of E-cadherin, a homophilic cell–cell adhesion molecule, in contact inhibition of growth of normal epithelial cells. Many tumor cells also maintain strong intercellular adhesion, and are growth-inhibited by cell– cell contact, especially when grown in three-dimensional culture. To determine if E-cadherin could mediate contact-dependent growth inhibition of nonadherent EMT/6 mouse mammary carcinoma cells that lack E-cadherin, we transfected these cells with an exogenous E-cadherin expression vector. E-cadherin expression in EMT/6 cells resulted in tighter adhesion of multicellular spheroids and a reduced proliferative fraction in three-dimensional culture. In addition to increased cell–cell adhesion, E-cadherin expression also resulted in dephosphorylation of the retinoblastoma protein, an increase in the level of the cyclin-dependent kinase inhibitor p27kip1 and a late reduction in cyclin D1 protein. Tightly adherent spheroids also showed increased levels of p27 bound to the cyclin E-cdk2 complex, and a reduction in cyclin E-cdk2 activity. Exposure to E-cadherin–neutralizing antibodies in three-dimensional culture simultaneously prevented adhesion and stimulated proliferation of E-cadherin transfectants as well as a panel of human colon, breast, and lung carcinoma cell lines that express functional E-cadherin. To test the importance of p27 in E-cadherin–dependent growth inhibition, we engineered E-cadherin–positive cells to express inducible p27. By forcing expression of p27 levels similar to those observed in aggregated cells, the stimulatory effect of E-cadherin–neutralizing antibodies on proliferation could be inhibited. This study demonstrates that E-cadherin, classically described as an invasion suppressor, is also a major growth suppressor, and its ability to inhibit proliferation involves upregulation of the cyclin-dependent kinase inhibitor p27.

Key Words: E-cadherin • p27 • kip1 • cyclin D • epidermal growth factor receptor

Abbreviations used in this paper: cdk, cyclin-dependent kinase; CKI, cyclin-dependent kinase inhibitors; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; HA, hyaluronic acid; PI3K, phosphatidylinositol-3-kinase; RTK, receptor tyrosine kinase.

The present address of B. St. Croix is The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231.

Address all correspondence to Dr. R.S. Kerbel, Division of Cancer Biology Research, Sunnybrook Health Science Center, S-218, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. Tel.: 416-480-5711. Fax: 416-480-5703. E-mail: kerbel{at}srcl.sunnybrook.utoronto.ca


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