The long-term goal of this project is the elucidation of the mechanisms whereby Ets upstream effectors anddownstream target genes contribute to progression to invasive breast cancer. Breast cancer is the secondleading cause of cancer mortality in women. Unfortunately, little is known about the most devastating phaseof its progression, metastasis. To metastasize, cells acquire ectopic motility and invasiveness as well as theability to proliferate in a new microenvironment. Metastasis is a multi-step process, including breaking loosefrom cell-cell contacts, migrating through stromal tissues, invading endothelial cell layer, re-establishing andmaintaining cell contacts at the metastatic site, remaining proliferative.Recently, a novel ETS factor, PDEF, was cloned and initially reported to be specific to prostateepithelium (prostate derived ets factor). Our work has demonstrated that PDEF is expressed in severaladditional epithelial tissues including breast and colon. We also show that PDEF protein loss is correlatedwith prostate, colon and breast cancer progression. To support the model that PDEF has a central role inmodulating metastatic potential, we have demonstrated that PDEF protein expression is lost in highlymetastatic cell lines and in invasive breast tumor tissues. Re-expression of Pdef into invasive cancer cellsinhibits cell growth, migration and invasion. Mouse Pdef is down-regulated in tumors in Neu transgenic mice.Pdef activates the tumor metastasis suppressor maspin while down-regulating the metastasis promoter uPA.The Drosophila PDEF homolog is a negative modulator of cell migration and invasion during development.Thus, our observations lead us to propose that PDEF, as a transcription factor, controls multiple aspects of themulti-step metastatic process and therefore, loss of PDEF expression is a key event in the development ofinvasive breast cancer.In this proposal, we employ a comprehensive strategy to elucidate PDEF function, integrating four in vitroand in vivo experimental systems. (1) Cell culture for studying cellular phenotypes associated with PDEFexpression levels and for identifying downstream effectors of PDEF functions. (2) Mouse knockout andtransgenic systems for analyzing the role of the Pdef gene in mammary development and cancer. (3) TheDrosophila system to investigate the function of Pdef in cell migration and invasion in vivo. (4) Human breasttumor samples for correlating expression of PDEF and its effectors with cancer progression.
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