Caveolin-1 deficiency (-/-) conveys premalignant alterations in mammary epithelia, with abnormal lumen formation, growth factor independence, and cell invasiveness.
During breast cancer development, the luminal space of the mammary acinar unit fills with proliferating epithelial cells that exhibit growth factor-independence, cell attachment defects, and a more invasive fibroblastic phenotype. Here, we used primary cultures of mammary epithelial cells derived from genetically engineered mice to identify caveolin-1 (Cav-1) as a critical factor for maintaining the normal architecture of the mammary acinar unit. Isolated cultures of normal mammary epithelial cells retained the capacity to generate mammary acini within extracellular matrix. However, those from Cav-1 (-/-) mice exhibited defects in three-dimensional acinar architecture, including disrupted lumen formation and epidermal growth factor-independent growth due to hyperactivation of the p42/44 mitogen-activated protein kinase cascade. In addition, Cav-1-null mammary epithelial cells deprived of exogenous extracellular matrix underwent a spontaneous epithelial-mesenchymal transition, with reorganization of the actin cytoskeleton, and E-cadherin redistribution. Mechanistically, these phenotypic changes appear to be caused by increases in matrix metalloproteinase-2/9 secretion and transforming growth factor-beta/Smad-2 hyperactivation. Finally, loss of Cav-1 potentiated the ability of growth factors (hepatocyte growth factor and basic fibroblast growth factor) to induce mammary acini branching, indicative of a more invasive fibroblastic phenotype. Thus, a Cav-1 deficiency profoundly affects mammary epithelia by modulating the activation state of important signaling cascades. Primary cultures of Cav-1-deficient mammary epithelia will provide a valuable new model to study the spatial/temporal progression of mammary cell transformation.
Sotgia
Federica
F
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Williams
Terence M
TM
Schubert
William
W
Medina
Freddy
F
Minetti
Carlo
C
Pestell
Richard G
RG
Lisanti
Michael P
MP
D000818:Animals; D015153:Blotting, Western; D051242:Caveolin 1 / Q000172:deficiency*; D002471:Cell Transformation, Neoplastic / Q000648:ultrastructure*; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D006133:Growth Substances / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009361:Neoplasm Invasiveness / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D051242:Caveolin 1; D006133:Growth Substances; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9