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
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
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 the Granulosa Cell Tumour Foundation of
New Zealand.
Analysis of molecular markers of hormone resistance in breast cancer biopsies
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.
