Caveolin-1 deficiency (-/-) conveys premalignant alterations in mammary epithelia, with abnormal lumen formation, growth factor independence, and cell invasiveness

Federica Sotgia, Terence M. Williams, William Schubert, Freddy Medina, Carlo Minetti, Richard G. Pestell, Michael P. Lisanti

Research output: Contribution to journalArticlepeer-review

Abstract

During breast cancer development, the luminal space of the mammary acinar unit fills with proliferating epithelial ceils 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 caveolta-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 ldnase cascade. In addition, Cav-1-null mammary epithelial cells deprived of exogenous extracellular matrix underwent a spontaneous epitheal-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-β/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 die 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.

Original languageEnglish
Pages (from-to)292-309
Number of pages18
JournalAmerican Journal of Pathology
Volume168
Issue number1
DOIs
Publication statusPublished - Jan 2006

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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