Molecular pathogenesis of granulosa cell tumours of the ovary

Project Leaders

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• Professor Peter Fuller AM

Granulosa cell tumours (GCT) of the ovary account for about five per cent of all malignant ovarian tumours. They both make and respond to hormones. Our research aims to provide critical insights into the molecular events that lead to development of these tumours.

Although they account for only five per cent of malignant ovarian cancers, investigation of granulosa cell tumours (CGTs) of the ovary can provide valuable insights into both normal granulosa cell function and tumourigenesis.

GCTs differ from the more common epithelial ovarian cancers and thus require targeted investigation if they are to have effective specific therapies. Although most have a good prognosis, those that recur or are aggressive do not. Aside from surgery, other therapeutic options are limited. Recently, we identified a single mutation in the FOXL2 gene that is present in ~ 97 per cent of all adult granulosa cell tumours. We have confirmed this finding in a large cohort of GCT. Although this moves our understanding forward, it still does not explain why some are more aggressive, nor does it provide a therapeutic option.

Our studies continued to focus on several aspects of the biology of these tumours.

We have identified overactivity of two critical cell-signalling pathways in two GCT-derived cell lines. We are currently dissecting the signalling pathways to identify the basis of this constitutive activity. We are also exploring possible novel therapeutic interventions that may block this pathway. These studies involve both the use of cancer cell biology approaches in vitro and microarray analysis to identify the critical genes and pathways regulated in this setting.

Apoptosis plays a fundamental role in granulosa cell biology; however, GCT cells evade this fate. Current studies are exploring the key elements of this process with a view to identifying novel therapeutic strategies.

We have screened all 48 nuclear receptors for their expression in GCT and have currently focused on several of these to explore their role and regulation. Some represent possible therapeutic targets.

We have established microarray profiles for granulosa cell tumours and are currently applying bioinformatic analysis to identify critical changes, patterns, and pathways. This array data becomes an important resource when examining responses in the cell lines as we can then correlate them with the established tumour panels. Current studies are using Next Gen Sequencing to identify mutations in advanced disease.

This project has resulted in the identification of changes that contribute to the development of granulosa cell tumours as well as possible therapeutic strategies for possible use in advanced disease.

Collaborators:

Associate Professor Tom Jobling, Gynaecology Oncology, Monash Health
Dr Andrew Stephens, MIMR-PHI Institute, OCRF Research Fellow
Dr Adam Rainczuk, MIMR-PHI Institute, OCRF Witchery Research Fellow
Associate Professor John Silke, Walter & Eliza Hall Institute
Mr Powel Crosley, Granulosa Cell Tumor Research Foundation

Selected publications

• Alexiadis, A., Eriksson, N., Jamieson, S., Davis, M., Drummond, A.E., Chu, S., Clyne, C.D, Muscat, G.E, and Fuller, P.J.Nuclear receptor profiling of ovarian granulosa cell tumors. Hormones and Cancer 2:157-69, 2011.

• Jamieson, S., and Fuller, P.J. Molecular pathogenesis of granulosa cell tumors of the ovary. Endocrine Reviews 33: 109-144, 2012.

• Jamieson, S., Bützow, R., Andersson, N., Alexiadis, M., Unkila-Kallio, L., Heikinheimo, M., Fuller, P.J. and Anttonen, M. The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary: independent confirmation from two centers. Modern Pathology 23:1477-85, 2010.

• Chu, S. Nishi, Y., Yanase, T., Nawata, H. and Fuller, P.J.Transrepression of estrogen receptor β signaling by nuclear factor-kB in ovarian granulosa cells. Molecular Endocrinology 18: 1919-1928, 2004.

• Chu, S., Alexiadis, M. and Fuller, P.J.Expression, mutational analysis and in vitro response of imatinib mesylate and nilotinib target genes in ovarian granulosa cell tumors. Gynecologic Oncology 108: 182–190, 2008.

• Jamieson, S. and Fuller, P.J.Characterization of the inhibitor of kappaB kinase (IKK) complex in granulosa cell tumors of the ovary and granulosa cell tumor-derived cell lines. Hormones and Cancer 4: 277-292, 2013.

• Stewart, C.J.R., Alexiadis, M., Crook, M.L. and Fuller, P.J.An immunohistochemical and molecular analysis of problematic and unclassified ovarian sex cord-stromal tumors. Human Pathology 44: 2774-2781, 2013.

• Chu, S., Alexiadis, M. and Fuller, P.J.Proteasome Inhibition by bortezomib decreases proliferation and increases apoptosis in ovarian granulosa cell tumors. Reproductive Sciences 16:397-407, 2009.