Role of ARID1A in endometrial proliferation, endometriosis and endometriosis-associated ovarian cancer pathogenesis

Ovarian cancer is one of the leading causes of death from cancer in women. There are 4 major types of ovarian cancer. The clear-cell and endometrioid types of ovarian cancer are related to a condition called endometriosis. The latter is a common cause of pelvic pain and infertility. Clear-cell cancer in particular, is very difficult to treat when it has spread because currently available chemotherapies are not effective. Recent research has identified a gene, called ARID1A, which appears to play a role in these two types of ovarian cancer. Specifically, mutations of this gene are found in approximately a third of endometrioid cancers and a half of clear cell cancers as well as in endometriosis. This research project aims to find out how mutations in ARID1A cause cancer. This will involve testing the effects of the mutation on growth and hormonal control in cells cultured in a petri dish. It will also involve experiments in mice that have this gene mutation. If we are able to understand better how this mutation causes cancer, then we will be able to design better treatments that will allow these patients to live longer or have less symptoms.

Ovarian cancer is the leading cause of death from gynaecologic malignancies in the western world. Together, endometrioid and clear-cell ovarian adenocarcinomas account for approximately 20% of ovarian cancer and are epidemiologically related to endometriosis. Very recent work has identified mutations in ARID1A, a component of the SWI/SNF chromatin remodelling complex, in 57% of ovarian clear-cell adenocarcinomas (OCCA). Importantly, in 2 examined cases of OCCA, adjacent foci of atypical endometriosis carried the same ARID1A mutation, implying that ARID1A mutations are an early driver event in carcinogenesis. Previous work has shown that ARID1A plays a role in the maintenance of an embryonic stem-cell phenotype, cell differentiation, cell cycle arrest and steroid-hormone mediated gene transactivation.
The first aim of this project is to study the role of ARID1A in the control of oestrogen and progesterone regulation of normal endometrium and endometriotic lesions. This will involve in vitro assays of proliferation in disaggregated and explanted endometrial tissue from ARID1Aflox mice as well as in vivo experimentation following site-specific inactivation of ARID1A in the same mouse model. To identify the transcriptional targets of ARID1A, microarray and ChIP-Seq experiments are planned.
The second aim of the project is to create a mouse model of OCCA that will reflect the association between endometriosis and OCCA observed in humans. For this, ARID1A will be knocked down or out on a background of endometriosis mouse models.
Current medical treatments for OCCA are unsatisfactory. In particular, and in stark contrast to the more common high grade serous ovarian cancers, these tumours are resistant to standard platinum-based chemotherapy. An improved understanding of the molecular and cellular events that result from ARID1A mutation has the potential to identify novel treatment targets for this difficult to treat malignancy. The parallel development of a mouse model of OCCA will provide the opportunity and possibility for preclinical testing of therapeutics.