The purpose of this study was to understand the characteristics of PDEF protein expression in breast and prostate cancer progression. A polyclonal antibody specific to PDEF was raised and reacted with tissue microarrays consisting of benign breast, in situ ductal, invasive ductal and invasive lobular breast carcinomas. The antibody was also reacted with tissue microarrays including benign prostate, prostate intra-epithelial neoplasias and prostate carcinomas. Increased expression of PDEF was identified in 18%, 50%, 46% and 51% of benign breast tissues, intraductal, invasive ductal and invasive lobular carcinomas, respectively. Importantly, in matched samples of benign breast versus tumor, 90% showed higher expression of PDEF in the tumor tissue. Moreover, in invasive breast carcinomas, increased PDEF expression tended to correlate with Her2/neu over expression. Increased expression of PDEF was also found in 27%, 33% and 40% of benign prostate tissues, PIN samples and prostate adenocarcinomas, respectively. Again, in matching samples of cancer versus benign and cancer versus PIN, 68% and 70% respectively showed increased expression in the malignant tissue. Moreover, PDEF was found to be more highly expressed in tumors with intermediate or high Gleason score compared to low grade tumors (P<0.01). Additionally, R1881 treatment induced PDEF expression in the LNCaP prostate tumor cell line, suggesting regulation of PDEF by androgens in vivo. Together, these results for the first time show frequent increased expression of PDEF protein in breast and prostate tumors and support a role for PDEF in breast and prostate cancer progression.

Gliomas take a number of different genetic routes in the progression to glioblastoma multiforme, a highly invasive variant that is mostly unresponsive to current therapies. Gliomas express elevated levels of matrix metalloproteinases (MMPs), which have been implicated in the control of proliferation and invasion as well as neovascularization. Progressive loss of LGI1 expression has been associated with the development of high grade gliomas. We have shown previously that the forced re-expression of LGI1 in different glioma cells inhibits proliferation, invasiveness, and anchorage-independent growth in cells null for its expression. Here, using Affymetrix gene chip analysis, we show that reexpression of LGI1 in T98G cells results in the downregulation of several MMP genes, in particular MMP1 and MMP3. LGI1 expression also results in the inhibition of ERK1/2 phosphorylation but not p38 phosphorylation. Inhibition of the MAPK pathway using the pharmacological inhibitors PD98059, U0126, and SB203580 in T98GLGI1-null cells inhibits MMP1 and MMP3 production in an ERK1/2-dependent manner. Treatment of LGI1-expressing cells with phorbol myristate acetate prevents the inhibition of MMP1/3 and restores invasiveness and ERK1/2 phosphorylation, suggesting that LGI1 acts through the ERK/MAPK pathway. Furthermore, LGI1 expression promotes phosphorylation of AKT, which leads to phosphorylation of Raf1Ser-259 , an event shown previously to negatively regulate ERK1/2 signaling. These data suggest that LGI1 plays a major role in suppressing the production of MMP1/3 through the phosphatidylinositol 3-kinase/ERK pathway. Loss of LGI1 expression, therefore, may be an important event in the progression of gliomas that leads to a more invasive phenotype in these cells.Glioblastoma multiforme is the most common malignant tumor of the adult central nervous system and has a median survival time of less than 12 months (1-2). The highly lethal nature of this tumor results from the acquisition of an invasive phenotype that allows the tumor cells to infiltrate surrounding brain tissue. Despite considerable heterogeneity in the genetic abnormalities detected in the various etiologies and histopathologies of these tumors (3), 90% of glioblastoma multiformes share losses of regions on chromosome 10 (4 -8). Using a positional cloning strategy, Chernova et al. (9) identified the LGI1 gene associated with an apparently reciprocal t(10, 19)(q24;q13) chromosome translocation in the T98G glioma cell line.LGI1 is expressed in low grade tumors but not in most of the high grade gliomas or permanent cell lines tested (9 -10). The coincident loss of LGI1 expression with loss of chromosome 10 suggested that it might be important in the malignant progression of gliomas.LGI1 carries a leucine-rich repeat (LRR) 1 motif (9) that places it in the F20 family of LRR genes. Members of this family are predominantly involved in either receptor functions or attachment to the extracellular matrix (11). The strongest homology of the LGI1 LRR is with the slit genes (9),...

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