CAV-1 in Jak/STAT Signaling, Lactation, & Breast Cancer

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DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand the role of caveolin-1 in i) Jak/STAT signaling, ii) lactation, and iii) the pathogenesis of breast cancer. Caveolae function as "message centers" for regulating signal transduction. Caveolin-1 (Cav-1) is the principal structural protein of caveolae membranes that are found in most cells. We mapped human CAV-1 to a suspected tumor suppressor locus (7q31.1/D7S522). In addition, the Cav-1 gene is mutated (P132L) in up to 16% of human breast cancers. The aim of this proposal is to test the hypothesis that Cav-1 expression is important for regulating lactation via modulation of Jak/STAT signaling and that loss of Cav-1 contributes to the oncogenicity of breast cancer cells. To test this hypothesis, we will use a variety of complementary in vivo approaches, such as i) a Cav-1 null mouse model and ii) the development of transgenic mice that express dominant-negative Cav-1 (PI32L) found in human breast cancers. The three Specific Aims of the project are: 1) To determine the role of Cav-1 in negatively regulating Jak/STAT signaling. We will examine the effects of Cav-1 on the activation of Jak/STAT signaling in cultured mammary epithelial cells that are responsive to prolactin. Our preliminary results indicate that Cav-1 negatively regulates Jak/STAT5a signaling by inhibiting Jak-mediated phosphorylation of STAT5a; 2) To examine the role of Cav-1 in lactation and epithelial cell hyperplasia. Signaling from the hormone prolactin vial the Jak/STAT pathway controls normal mammary gland development. Thus, if Cav-1 were a negative regulator of Jak/STAT signaling, we would predict that a loss of Cav-1 expression leads to premature lactation. Indeed, our preliminary results show that Cav-1 null mice exhibit premature lactation, as well as hyper-activation of the Jak/STAT5a signaling cascade; and 3) To determine if transgenic expression of Cav-1 (P132L) predisposes towards mammary tumor development. For this purpose, we will generate Cav-1 (P132L) mice that transgenically express this form of Cav-1 in the mammary gland. Our preliminary results indicate that Cav-1 (P132L) acts in a dominant-negative fashion in cultured cells. In addition, our preliminary results with Cav-1 null mice show early development of wide-spread mammary epithelial hyperplasia. We predict that this phenotype will be accelerated Cav-1 (P132L) transgenic mice. We will cross Cav-1 (P132L) transgenic mice with other well-established models of mammary tumorigenesis, such as MMTVErbB2 and MMTV-polyoma middle T mice. It is expected that these studies will contribute fundamental knowledge towards understanding the role of Cav-1 in Jak/STAT signaling and mammary tumorigenesis in vivo.