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Molecular pathogenesis of granulosa cell tumours
Summary
Granulosa cell tumours (GCT) of the ovary are endocrine tumours of the ovary. They both make hormones and respond to hormones. The group seeks to understand the molecular events that lead to development of these tumours.
Description
Although granulosa cell tumours (CGTs) of the ovary represent only 5% of malignant ovarian cancers, they are of specific interest for the insights they can give both into normal granulosa cell function and into 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.
Very recently, a group in Canada identified a single mutation present in all granulosa cell tumours. Although this moves our understanding forward, it does not explain why some are more aggressive than others, nor does it provide a therapeutic option.
Our studies are focused on several aspects of the biology of these tumours.
Simon Chu has 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 might be used to block this pathway. These studies involve both the use of cancer cell biology approaches in vitro and also the use of microarray analysis to identify the critical genes and pathways regulated in this setting.
The role of the nuclear receptor superfamily has not been fully explored in GCT.
We have recently 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.
The role of tumour suppressor genes will be explored in these tumours by initiating a large-scale high density SNP array study in collaboration with Professor Ian Campbell at the Peter McCallum Cancer Centre and Professor Andrew Shelling in Auckland. This study has the potential to identify the genetic changes that define aggression or recurrence.
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 source when examining responses in the cell lines as we can then correlate them with the established tumour panels.
Funding
National Health and Medical Research Council
Cancer Council of Victoria
Ovarian Cancer Research Foundation
Granulosa Cell Tumor of the Ovary Foundation
Outcome
Identification of changes that contribute to the development of granulosa cell tumours and of possible therapeutic strategies that may be used in advanced disease.
Selected Publications
Bittinger, S., Alexiadis, M.,Fuller, P.J. (2009) Expression status and mutational analysis of the PTEN and P13K subunit genes in ovarian granulosa cell tumors. International Journal of Gynecological Cancer 19: 339-342.
Chu, S., Alexiadis, M.,Fuller, P.J. (2009) Proteasome Inhibition by bortezomib decreases proliferation and increases apoptosis in ovarian granulosa cell tumors. Reproductive Sciences 16:397-407.
Chu, S., Alexiadis, M.,Fuller, P.J. (2008) Expression, mutational analysis and in vitro response of imatinib mesylate and nilotinib target genes in ovarian granulosa cell tumors. Gynecologic Oncology 108: 182-190.
Jamieson, S., Fuller, P.J. (2008) Management of granulosa cell tumour of the ovary. Current Opinion in Oncology 20: 560-564.
Mcneilage, J., Alexiadis, M., Mamers, P., Laslett, G., Trajstman. A., Susil, B.J., Jobling, T., Fuller, P.J. (2007) Molecular characterisation of sarcomatous change in a granulosa cell tumor. International Journal of Gynecological Cancer 17:398-406.
Hussein-Fikret, S., Fuller, P.J. (2005) Expression of the nuclear receptor coregulators in ovarian stromal and epithelial tumours. Molecular and Cellular Endocrinology 229: 149-160.
Fuller, P.J. Alexiadis, M., Jobling, T., Mcneilage, J. Seladin (2005) 1/DHCR24 expression in ovarian epithelial and stromal tumours. Clinical Endocrinology 63: 111-115.
Fuller, P.J., Chu, S. (2004) Signaling pathways in the molecular pathogenesis of ovarian granulosa cell tumors. Trends in Endocrinology and Metabolism 15:122-128.
Chu, S. Nishi, Y., Yanase, T., Nawata, H. , Fuller, P.J. (2004) Transrepression of estrogen receptor β signaling by nuclear factor-κβ in ovarian granulosa cells. Molecular Endocrinology 18: 1919-1928.
Jamieson, S., Alexiadis, M., Fuller, P.J. (2004) Expression status and mutational analysis of the ras and B-raf genes in granulosa cell and epithelial tumors of the ovary. Gynecologic Oncology 95: 603-609.
Chu, S., Rushdi, S., Zumpe, E.T., Mamers, P., Healy, D.L., Jobling, T., Burger, H.G. ,Fuller, P.J. (2002) FSH regulated gene expression profiles in ovarian tumours and normal ovaries. Molecular Human Reproduction 8: 426-433.
Fuller, P.J., Zumpe, E.T., Chu, S., Mamers, P. ,Burger, H.G. (2002) Inhibin-activin receptor subunit gene expression in ovarian tumors. Journal of Clinical Endocrinology and Metabolism 87: 1395-1401.
Fuller, P.J., Chu, S., Fikret, S. , Burger, H.G. (2002) Molecular pathogenesis of granulosa cell tumours. Molecular and Cellular Endocrinology 191: 89-96.