The long-term goal of this project is the elucidation of the mechanisms whereby Ets upstream effectors and downstream target genes contribute to progression to invasive breast cancer. Breast cancer is the second leading cause of cancer mortality in women. Unfortunately, little is known about the most devastating phase of its progression, metastasis. To metastasize, cells acquire ectopic motility and invasiveness as well as the ability to proliferate in a new microenvironment. Metastasis is a multi-step process, including breaking loose from cell-cell contacts, migrating through stromal tissues, invading endothelial cell layer, re-establishing and maintaining cell contacts at the metastatic site, remaining proliferative. Recently, a novel ETS factor, PDEF, was cloned and initially reported to be specific to prostate epithelium (prostate derived ets factor). Our work has demonstrated that PDEF is expressed in several additional epithelial tissues including breast and colon. We also show that PDEF protein loss is correlated with prostate, colon and breast cancer progression. To support the model that PDEF has a central role in modulating metastatic potential, we have demonstrated that PDEF protein expression is lost in highly metastatic cell lines and in invasive breast tumor tissues. Re-expression of Pdef into invasive cancer cells inhibits 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 the multi-step metastatic process and therefore, loss of PDEF expression is a key event in the development of invasive breast cancer. In this proposal, we employ a comprehensive strategy to elucidate PDEF function, integrating four in vitro and in vivo experimental systems. (1) Cell culture for studying cellular phenotypes associated with PDEF expression levels and for identifying downstream effectors of PDEF functions. (2) Mouse knockout and transgenic systems for analyzing the role of the Pdef gene in mammary development and cancer. (3) The Drosophila system to investigate the function of Pdef in cell migration and invasion in vivo. (4) Human breast tumor samples for correlating expression of PDEF and its effectors with cancer progression.
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