The American Cancer Society indicates that ovarian cancer is the fifth most lethal of all cancers that specifically affect women. They estimate that in 2014 approximately 22,000 women will be diagnosed with ovarian cancer and about 14,000 will die of this disease. This high death rate has not changed much since the 1960s. We are therefore very interested in uncovering new ways to reverse this poor patient outcome.
We know that all ovary cancers are not the same. These cancers have different cell types and they also have specific defects or changes (mutations) in their DNA. Specific gene mutations are often more frequent or occur exclusively in certain histotypes of ovarian cancer, which likely imparts certain characteristics of individual tumors making some more deadly than others. These findings suggest to us that we should tailor our research to focus on cancer specific traits. Recent unbiased genomic approaches have clarified the genomic landscape for some of the different histotypes of ovarian cancer providing opportunities to identify new molecular targets for therapy. Among the genes identified is ARID1A.
ARID1A, the AT Rich DNA binding component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, has been described as a tumor suppressor. This complex is involved with nucleosome and chromatin remodeling and plays a role in regulation of gene expression and DNA repair. Recent unbiased genomic approaches show that ARID1A inactivating mutations have been reported in approximately 30% of ovarian endometrioid cancers and 50-60% of clear cell ovarian cancers. Mutation of ARID1A is uncommon in high grade serous cancers; however, loss of ARID1A protein expression occurs in some of these cancers by an unknown mechanism. We utilized a liquid chromatography tandem mass spectrometry (LC MS/MS) based approach and have identified differentially expressed proteins following ARID1A restoration in ARID1A mutant cells. Of these, we noted a dramatic down-regulation of AAA domain containing 2 (ATAD2) following ARID1A restoration. ATAD2 is known to associate with histone H3 via its bromodomain; it also acts as a co-factor for E2Fs, MYC, androgen and estrogen receptors. ATAD2 over-expression drives the expression of target genes that induce cell proliferation and resistance to apoptosis. However, the function of ATAD2 and relevance to ARID1A are unclear in ovarian cancer.
When we specifically inactivate ATAD2 in ovary cancer cells they stop dividing. This suggests to us that ATAD2 is one of the critical genes controlling ovarian cancer cell growth. We further investigated the effect of ATAD2 in ovarian cancer histotypes other than endometrioid and clear cell. We found that ATAD2 is also highly expressed in some serous cancers. When we look at the survival of patients with high ATAD2 expressing cancers compared to those with low expression, the patients with high expression levels of ATAD2 tend to do worse. Because ATAD2 appears to be especially important in ovarian cancers with ARID1A mutation and serous cancers with high ATAD2 expression, we propose to focus on this gene.
The goal of this project is to determine the mechanisms driving ATAD2 expression in ovarian cancer and to determine whether ATAD2 represents an opportunity for developing an ATAD2-targeted molecular therapy for the treatment of ovarian cancer.
This grant was made possible in part by Ovarian Cycle Tampa.
Yutaka Shoji, Ph.D., is currently an Assistant Professor in the Department of Obstetrics, Gynecology and Reproductive Biology at Collage of Human Medicine of Michigan State University. Dr. Shoji received a M.Sc. degree in Food Science as well as a Ph.D. degree in Nutrition and Environmental Science from Shizouka University (Japan). Following his doctoral degree, he has had significant training including a Post-Doctoral Research Resident Fellowship from the Foundation for Promotion of Cancer Research (Japan) in a Cancer Prevention Basic Research Project under the direction of Dr. Wakabayashi at National Cancer Center Research Institute (Japan). He completed an additional Post-Doctoral fellowship in the Department of Physiology of Dr. S. J. Tsai at the National Cheng Kung University Medical College (Taiwan). Following this post-doctoral training he was promoted to Research Assistant Professor in the Department of Obstetrics & Gyneocology, Keio University School of Medicine (Japan). In 2008, Dr. Shoji joined Memorial Health University Medical Center (GA, USA) as a post-doctoral scholar under the direction of Dr. John Risinger. In 2009, Dr. Shoji joined the Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine of Michigan State University under the direction of Dr. John Risinger as Visiting Research Associate (MI, USA). Dr. Shoji’s current research focus is on the role of ARID1A and ATAD2 function in ovarian cancers.