Expression of an activated Notch4(int-3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro.
The protein encoded by the Notch4 gene is a member of the Notch/lin-12 family of transmembrane receptor proteins, which have been shown to control cell fate determination and cell differentiation in a wide variety of organisms. Expression of Notch4(int-3), a truncated form of Notch4 having most of its extracellular domain deleted, as a transgene in mice induces the formation of poorly differentiated mammary carcinomas. To establish whether Notch4(int-3) has the capacity of subverting normal epithelial architecture, we assessed the effect of Notch4(int-3) expression on the in vitro morphogenetic properties of TAC-2 mammary epithelial cells. When grown in three-dimensional collagen gels in the presence of hydrocortisone, both wild-type and LacZ-transfected TAC-2 cells formed alveolar-like structures composed of polarized epithelial cells surrounding a central lumen. In contrast, TAC-2 cells programmed to express Notch4(int-3) formed compact cell aggregates devoid of tissue-specific organization. In addition, when grown on the surface of a collagen gel, Notch4(int-3)-expressing TAC-2 cells invaded the underlying matrix, whereas TAC-2 LacZ cells remained strictly confined to the gel surface. Expression of Notch4(int-3) in TAC-2 cells also disrupted contact-inhibition of cell proliferation, resulting in cell multilayering. Our results suggest that the ability of Notch4(int-3) to subvert normal epithelial morphogenesis and to promote invasion of the extracellular matrix contributes significantly to its tumorigenic potential.
Soriano
J V
JV
Institute of Histology and Embryology, Department of Morphology, University of Geneva Medical Center, Geneva, Switzerland.
Uyttendaele
H
H
Kitajewski
J
J
Montesano
R
R
D000818:Animals; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch
C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch