Caveolin-1 mutations ( @entity22156 and null) and the pathogenesis of @entity0 : caveolin-1 ( XXXX ) behaves in a dominant-negative manner and caveolin-1 (-/-) null @entity19 show mammary epithelial cell @entity1373 .

@entity1 @entity0 @entity5 @entity19 @entity1373 @entity5689 @entity22156 @entity3895
Caveolin-1 ( @entity3895 -1) is the principal structural protein of caveolae membranes that are found in most cells types, including mammary epithelial cells. Recently, we mapped the @entity1 @entity5689 gene to a suspected @entity5 suppressor locus (7q31.1/D7S522) that is deleted in a variety of @entity1 @entity5 , as well as @entity5 . In addition, the @entity5689 gene is mutated ( @entity22156 ) in up to approximately 16% of @entity1 @entity0 . The mechanism by which deletion or mutation of the @entity3895 -1 gene contributes to mammary tumorigenesis remains unknown. To understand the role of the @entity3895 -1 ( @entity22156 ) mutation in the pathogenesis of @entity1 @entity0 , we generated the same mutation in wild-type (WT) @entity3895 -1 and studied its behavior in cultured cells. Interestingly, the @entity22156 mutation leads to formation of misfolded @entity3895 -1 oligomers that are retained within the Golgi complex and are not targeted to caveolae or the plasma membrane. To examine whether the @entity3895 -1 ( @entity22156 ) mutant behaves in a dominant-negative manner, we next co-transfected cells with @entity3895 -1 ( @entity22156 ) and WT @entity3895 -1, and evaluated their caveolar targeting. Our results indicate that @entity3895 -1 ( @entity22156 ) behaves in a dominant-negative manner, causing the mislocalization and intracellular retention of WT @entity3895 -1. Virtually identical results were obtained when @entity3895 -1 ( @entity22156 ) was stably expressed at physiological levels in a nontransformed @entity1 mammary epithelial cell line (hTERT-HME1). These data provide a molecular explanation for why only a single mutated @entity5689 allele is found in @entity1 with @entity0 . Thus, we next investigated if functional inactivation of @entity3895 -1 gene expression leads to mammary tumorigenesis in vivo. For this purpose, we performed mammary gland analysis on @entity3895 -1-deficient @entity19 (-/-) that harbor a targeted disruption of the @entity3895 -1 gene (a null mutation). Interestingly, we show that inactivation of @entity3895 -1 gene expression leads to mammary epithelial cell @entity1373 , even in 6-week-old virgin female @entity19 . These data clearly implicate loss of functional @entity3895 -1 in the pathogenesis of mammary epithelial cell @entity1373 , and suggest that @entity3895 -1-null @entity19 represent a novel animal model to study premalignant mammary disease.
