Regulation and Impact of Cytoplasmic ARID1A in Ovarian Cancer
Abstract
ARID1A is broadly accepted to be a tumor suppressor in an increasing number of cancers, including ovarian. Silencing ARID1A in ovarian surface epithelium stimulates growth and restoration of activity in ARID1A null ovarian and endometrial cancer cells reduces proliferation, with the latter having been verified in a xenograft murine model. Immunohistochemistry studies in OCCC showed that loss of nuclear ARID1A was associated with shorter progression-free survival (PFS) and similar overall survival (OS) or with advanced stage, higher grade, suboptimal resection and nodal metastasis, though reports have been inconsistent relative to clinicopathologic associations. These prior investigations focused on nuclear localized ARID1A as a logical consequence of its tumor suppressor role in chromatin remodeling and transcriptional regulation. We recently used a well annotated ovarian cancer tissue microarray spanning histologic subtypes to evaluate the association between ARID1A and OS (N=259). Categorization of ovarian cancers by both nuclear and cytoplasmic ARID1A staining revealed a statistically significant difference in OS between the four groups with median survival times spanning more than 5 yr (p less than 0.001). In terms of the extremes, women with loss of nuclear ARID1A and prevalent cytoplasmic ARID1A had the worse survival overall with a median survival time of 7 mo. In contrast, ovarian cancer patients with loss of nuclear ARID1A without prevalent cytoplasmic ARID1A had the best OS with a median survival time of 74 mo.This Pilot Award application is focused on determining the mechanism underlying cytoplasmic quarantine of ARID1A and whether the oncogenic effect of its cytoplasmic localization is due to a simple inactivation of a tumor suppressor, or if ARID1A possesses a hitherto unknown oncogenic activity when localized to the cytoplasm, as is the case for other tumor suppressors, such as p21 and p27.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2016
- Accession Number
- AD1011377
Entities
People
- Thomas P Conrads
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine