Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture.
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.
Wrobel
Carolyn N
CN
Dept. of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
Debnath
Jayanta
J
Lin
Eva
E
Beausoleil
Sean
S
Roussel
Martine F
MF
Brugge
Joan S
JS
D019898:Autocrine Communication / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D048429:Cell Size; D003599:Cytoskeleton / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D042361:Mammary Glands, Human / Q000033:anatomy & histology* / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D004815:Epidermal Growth Factor; D016173:Macrophage Colony-Stimulating Factor; D019859:Proto-Oncogene Proteins c-met; D016186:Receptor, Macrophage Colony-Stimulating Factor; D019061:src-Family Kinases