The importance of the a6b4 integrin to the progression of breast and other carcinomas is underscored by an increasingly convincing literature. Given that the involvement of a6b4 in progression has important implications for clinical management of carcinomas, especially with regard to the reported relationship of this integrin to growth factor receptors that have been implicated in progression and for which clinical trials are in progress, it is imperative to understand its involvement rigorously. The three specific aims that are proposed have been designed to address the most compelling and timely issues related to the function of a6b4 in breast cancer. In the first aim, mouse models of mammary tumor progression will be established in which the expression of a6b4 is abrogated by genetic approaches. The establishment of such models is long overdue and they will provide critical data and reagents.
The second aim will examine the hypothesis that a6b4-mediated stimulation of the mTOR/4E-BP pathway results in an increase in the cap-dependent translation of proteins essential for breast cancer. An important component of this aim is the use of polysome mRNA for microarray analysis to identify proteins that are regulated by a6b4.
This aim, which is supported by strong initial data, represents a new dimension for the role of this integrin and cancer and the proposed studies will generate a wealth of novel information that will be useful not only for our work but that of many other labs.
The final aim will address the hypothesis that the ability of a6b4 to activate key signaling pathways that are important for progression derives, in part, from its ability to regulate the expression and function of specific tyrosine kinase and G protein coupled receptors. Specifically, the possibility that a6b4 regulates expression of the Met tyrosine kinase in breast carcinoma cells and that Met, which has been implicated in breast cancer progression, actually mediates some a6b4 signaling will be studied. Also, the hypothesis will be addressed that two key signaling functions of a6b4 - its ability to regulate the intracellular cAMP concentration and activate the RhoA GTPase - are actually mediated indirectly through the ability of a6b4 to regulate the expression and function of a specific G-coupled receptor CXCR4 that has been shown to be necessary for the metastasis of breast tumors.
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