Real-time imaging reveals that noninvasive mammary epithelial acini can contain motile cells.
To determine how extracellular signal-regulated kinases (ERK) 1/2 promote mammary tumorigenesis, we examined the real-time behavior of cells in an organotypic culture of the mammary glandular epithelium. Inducible activation of ERK1/2 in mature acini elicits cell motility and disrupts epithelial architecture in a manner that is reminiscent of ductal carcinoma in situ; however, motile cells do not invade through the basement membrane and branching morphogenesis does not take place. ERK1/2-induced motility causes cells to move both within the cell monolayer that contacts the basement membrane surrounding the acinus and through the luminal space of the acinus. E-cadherin expression is reduced after ERK1/2 activation, but motility does not involve an epithelial-mesenchymal transition. Cell motility and the disruption of epithelial architecture require a Rho kinase- and myosin light chain kinase-dependent increase in the phosphorylation of myosin light chain 2. Our results identify a new mechanism for the disruption of architecture in epithelial acini and suggest that ERK1/2 can promote noninvasive motility in preinvasive mammary tumors.
Pearson
Gray W
GW
Molecular and Cell Biology Laboratory, Salk Institute, La Jolla, CA 92037, USA.
Hunter
Tony
T
D001940:Breast / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D024722:Cardiac Myosins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology; D009924:Organ Culture Techniques; D010766:Phosphorylation; D054460:rho-Associated Kinases / Q000378:metabolism
D015820:Cadherins; D018994:Myosin Light Chains; C107184:myosin light chain 2; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D048052:Mitogen-Activated Protein Kinase 3; D024722:Cardiac Myosins