Our previous data has clearly implicated members of the claudin family in ovarian tumorigenmesis. In this fiscal year, we have made significant progress in identifying the mechanisms of claudin-3 and -4 regulation as well as the possible roles these proteins may have in ovarian cancer progression. We have shown that both claudin -3 and claudin-4 are phosphorylated in ovarian cancer cells (by PKA and PKC, respectively) and that this phosphorylation has significant functional consequences. Indeed, we have shown that this phosphorylation can contribute to the dismantlement of tight junctions in ovarian cancer. In addition, we have also continued our work investigating the mechanisms regulating the CLDN3 and CLDN4 promoters. We have found that these promoters are highly affected by DNA methylation and histone acetylation and that they require the SP1 transcription factor for activity. We are currently identifying enhancers that may be important in the co-regulation of CLDN3 and CLDN4. We are also studying claudin-7, another claudin that involved in ovarian cancer. We have now demonstrated that claudin-7 is expressed in a large number of ovarian tumors and that it may have roles in survival and cell invasion. Drug resistance represent a major clinical problem in the treatment of ovarian cancer, but the exact mechanisms involved in the development of resistance are unclear. In this fiscal year, we have use microarrays to identify gene differentially expressed in our model of ovarian cancer drug resistance. We have identified several interesting candidate genes and pathways that may be involved in this phenomenon. We are hoping that a better understanding of the mechanisms leading to drug resistance may suggest approaches for alternative therapies or for strategies aimed at reversing drug resistance.