DESCRIPTION (provided by applicant): Cancer cells often appear in a deviant stage of differentiation, and dedifferentiation is a feature of malignancy. In the last funding period, we investigated the loss of the developmental transcription factors GATA4 and GATA6 in ovarian cancer development. The hypothesis was that the loss of GATA4 and GATA6 lead to the dedifferentiation phenotypes in ovarian cancer cells, and that the loss of GATA4 and GATA6 is an important causative factor in ovarian tumorigenesis. Our results show that aberrant chromatin modifications/histone hypo-acetylation account for the loss of GATA4 and GATA6 in ovarian cancer cells. We also established the role of GATA6 in regulating Dab2 and the consequent loss of Dab2 in epithelial transformation in our proposed experiments. In searching for additional GATA4 and GATA6-regulated effectors, we found in ovarian surface epithelial cells that suppression of GATA6 leads to nuclear morphological deformation and aneuploidy, two hallmarks of ovarian cancer cells. The close correlation between loss of GATA6 and nuclear deformation and aneuploidy was also correlated in human ovarian cancer. Preliminary studies also suggest that the loss of the nuclear envelope protein emerin may account for the nuclear morphological deformation and aneuploidy. We present a proposal to continue our study of the loss of GATA4 and GATA6 in the transformation and tumorigenesis of ovarian surface epithelial cells using conditional GATA6 knockout models (Aim 1). We also propose to investigate the in vivo consequence of emerin loss in ovarian surface epithelial cells (Aim 2), and the mechanism for the loss of emerin in ovarian cancer cells (Aim 3) with a hypothesis that loss of emerin causes nuclear morphological deformation and results in chromosomal numerical instability and subsequent ovarian tumorigenesis. These experiments may establish the role and mechanism for the loss of GATA4 and GATA6 in ovarian epithelial dedifferentiation and tumorigenesis. The further understanding will reveal the molecular details in the initiation and development of ovarian epithelial cancer, leading to development of more advanced diagnostic and therapeutic approaches.

Project Narrative The proposal studies GATA4 and GATA6 genes in ovarian cancer in the aspects of nuclear morphological deformation and chromosomal instability, which are fundamentally important questions in tumor biology. If successful and proven to be correct, this study will identify the cause of chromosomal instability and nuclear deformation, two highly prevalent hallmarks of ovarian cancer. The understanding may gain insights into the etiology and biology of ovarian cancer, and possibly provide improvement and potential refinement for the diagnostic and prognostic indicator of ovarian malignancy based on the nuclear deformation of cancer cells.