School of Medicine


Cancer genetics

Genetics studies of ovarian cancer


Epithelial ovarian cancer is often diagnosed at advanced stages of disease and is the leading cause of death from gynaecological neoplasia. Unfortunately, the genetic changes occurring during the progression of epithelial ovarian cancer are poorly understood, and therefore much research is centred upon identifying the genes involved. We have focussed our studies on the transforming growth factor beta (TGFß) regulatory pathway, including inhibin and activin. It is proposed that the pathway of genes act as a functional unit, and mutations in any one subunit could lead to disruption of the pathway and subsequent loss of cell cycle control.

Analysis of the activin pathway in ovarian cancer


ovarysection

There is strong evidence that activin is involved in the development of ovarian cancer. Activin is a member of the TGFß regulatory superfamily of ligands, and shares its intracellular signaling cascade with TGFß, a potent inhibitor of epithelial cell proliferation. Like TGFß, activin is capable of suppressing the growth of many cancers of an epithelial origin. Our research has shown the growth regulatory roles of activin in our collection of ovarian cancer cell lines, which shows that activin is growth suppressive. This is opposite to what had been previously published, but we have been able to confirm and establish a better understanding of the role of activin in the development of ovarian cancer.

Analysis of the TGFß fuctional pathway


We have focused our studies on the transforming growth factor beta (TGFß) growth regulatory pathway. It is proposed that the pathway of genes act as a functional unit, and mutations in any one subunit could lead to disruption of the pathway and subsequent loss of cell cycle control. We have found that mutations in the TGFß pathway occur primarily in TGFßRII, and these mutations appear to be important in the development of ovarian cancer. We have also shown that there are other ways in which the TGFß pathway is dysregulated in ovarian cancer, whereby the expression of other members of the TGFß pathway are altered in ovarian cancer.

Genetic studies of Granulosa Cell Tumours of the ovary


pcr

The majority of malignant ovarian cancer arise from the ovarian surface epithelia, and are called epithelial ovarian cancer. Other ovarian cancers arise from other cell types in the ovary. Sex cord stromal tumours (SCSTs) arise from cells of the stroma of the ovary and account for approximately 5% of all ovarian tumours. An important subtype of this group are granulosa cell tumours (GCTs), which arise from follicular granulosa cells. Due to its unique biology, GCTs are seen to behave quite differently to the more common epithelial ovarian cancers. Little research has been undertaken on GCT’s and little is known about its origin. They are thought to arise from cells of the developing gonad, or precursor cells surrounding the developing gonad. No clear aetiological pathways exist, and are likely to be multifactorial, but include chromosomal abnormalities and autocrine/endocrine abnormalies such as the production of high levels of oestrogen and inhibin, and these are often used in the diagnosis of presence of the tumour. We plan to analyse gene expression in GCTs, and identify which genes and pathways are aberrant in these tumours, to determine what is the best approach to developing new therapeutic targets for improving treatment options for patients. This project is supported by theGranulosa Cell Tumour Foundation of New Zealand.

Analysis of molecular markers of hormone resistance in breast cancer biopsies


gel

Breast cancer is the most common cause of cancer death in New Zealand women, and the cause remains unclear. Many breast cancers have oestrogen receptors on the surface of the cells. The female hormone oestrogen, binds to its receptors and can cause cell growth. This oestrogen receptor positive subtype of breast cancer is treated with hormonal therapies, that either block the effect or reduce the levels of oestrogen. However, for some patients hormonal therapies become ineffective, and their breast cancer progresses or recurs. This study aims to determine what genes are involved in the development of breast cancer, by comparing tumour tissue from cancer patients, and normal breast tissue. Comparisons of genes expressed in both oestrogen receptor positive and oestrogen receptor negative tumours will be made. We will focus specifically on a family of genes known as Forkhead transcription factors or FOX genes. Members of this family have now been shown to interact with other abnormally expressed genes and growth pathways known to be important in breast cancer development. Fox genes are also thought to influence the way in which many tumours become resistant to treatment over time. We have collected approximately 40 New Zealand breast cancer samples from women who have undergone surgical removal of their breast cancer, and are currently studying whether there are distinctive patterns of altered gene expression in New Zealand breast cancer samples, compared to other international studies. We will also search for new gene pathways involved in the process of normal breast tissue transforming into cancer. A better understanding of the causes of breast cancer will lead to better outcomes for women with the disease. This project is funded by the Breast Cancer Research Trust.