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Published 26 April 2004. doi:10.1083/jcb.200309102
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 2, 263-273
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Article

Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture



Carolyn N. Wrobel1, Jayanta Debnath1,2, Eva Lin1, Sean Beausoleil1, Martine F. Roussel3, and Joan S. Brugge1

1 Department of Cell Biology, Harvard Medical School, Boston, MA 02115
2 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115
3 Department of Tumor Cell Biology and Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105

Address correspondence to Joan S. Brugge, Dept. of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115. Tel.: 617-432-3974. Fax: 617-432-3969. email: joan_brugge{at}hms.harvard.edu

Elevated coexpression of colony-stimulating factor receptor (CSF-1R) and its ligand, CSF-1, correlates with invasiveness and poor prognosis of a variety of epithelial tumors (Kacinski, B.M. 1995. Ann. Med. 27:79–85). Apart from recruitment of macrophages to the tumor site, the mechanisms by which CSF-1 may potentiate invasion are poorly understood. We show that autocrine CSF-1R activation induces hyperproliferation and a profound, progressive disruption of junctional integrity in acinar structures formed by human mammary epithelial cells in three-dimensional culture. Acini coexpressing receptor and ligand exhibit a dramatic relocalization of E-cadherin from the plasma membrane to punctate intracellular vesicles, accompanied by its loss from the Triton-insoluble fraction. Interfering with Src kinase activity, either by pharmacological inhibition or mutation of the Y561 docking site on CSF-1R, prevents E-cadherin translocation, suggesting that CSF-1R disrupts cell adhesion by uncoupling adherens junction complexes from the cytoskeleton and promoting cadherin internalization through a Src-dependent mechanism. These findings provide a mechanistic basis whereby CSF-1R could contribute to invasive progression in epithelial cancers.

Key Words: CSF-1 receptor; autocrine signaling; Src; cadherins; mammary neoplasms

The online version of this article contains supplemental material.

Abbreviations used in this paper: 3D, three dimensional; CSF-1R, colony-stimulating factor receptor; RTK, receptor tyrosine kinase.


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