Annual Report 2005 - Westmead Millennium Institute

Breast cancer research
The Breast Cancer Research Group is investigating the role of
oestrogen and progesterone in the development of the normal
breast and in breast cancer. These hormones are fundamental
regulators of normal cell growth and differentiation, and are also
crucial to the development and progression of breast cancer.
Progesterone has a pivotal role in normal female reproduction in the
uterus, ovary, mammary gland and brain. This group has previously
identified a change in expression of two forms of the progesterone
receptor, PRA and PRB, in cancer. Work in 2005 has focussed on
further identifying the cellular consequences of this change. Gene
expression profiles have shown a distinct shift in the ability of a cell
to respond to progesterone when the two forms of the PR are
imbalanced, and this is associated with changes in signalling
pathways important in maintenance of normal cell biology.
The mechanisms through which PR controls gene expression have
also been explored, researchers demonstrating that receptors
aggregate with other key components of transcriptional machinery
when they are activated. This aggregation process is disrupted in
human cancers, and current studies in the group are aimed at
exploring the aggregation process and identifying the functional
consequences of its disruption in cancer.
Cell cycle research
The INK4a/ARF sequence on chromosome 9 encodes two
distinctly different proteins, known as p14ARF and p16INK4a. Both
of these tumour suppressor proteins have critical roles in
maintaining the genetic integrity of a wide range of cell types and
researchers in this group are investigating their function, movement
and binding partners. Mutations that inactivate p14ARF or
p16INK4a are common in many different human cancers. While
p16INK4a is mutated in approximately a third of families with a
history of melanoma, this group have found that a subset of
melanoma-affected families also carry mutations that alter the
localisation and function of p14ARF. The p14ARF tumoursuppressor
protein binds to a range of cellular targets, and this
group is investigating what impact these novel partners have on the
functions of p14ARF.
This group recently proposed that p14ARF mediates a process
called sumoylation, by promoting the attachment of the protein
SUMO to other proteins. Sumoylation regulates cellular activity by
altering the location of some proteins and modulating the activity of
others. Researchers are exploring the downstream effects of
p14ARF-induced sumoylation, and the consequences when
p14ARF is mutated. Melanoma cancers are notoriously resistant to
chemotherapy and this group has confirmed that p14ARF can cooperate
with various chemotherapeutic agents to induce
programmed cell death in melanoma cells. Thus, genes regulated
by p14ARF may provide alternative targets for new drugs to kill
melanoma tumours that have lost p14ARF protection.
Familial cancer
Most cancers are due to genetic changes that accumulate in the
cells with age, but in 5 to 10 per cent of cases a patient’s family
history suggests the presence of an inherited gene mutation that
increases their cancer risk. The clinical arm of this group operates a
service assessing genetic susceptibility to breast, ovary, bowel
cancer and melanoma. In conjunction, many patients are enrolled in
collaborative, genetic-epidemiological studies investigating the
familial aspects of cancer.
The service is part of a study of breast ductal lavage, investigating
its use as a surveillance tool in women at high risk of breast cancer
as well as participating in the international GOG-199 study, aimed
at assessing the usefulness of screening alone vs preventive
surgery in women at increased risk of ovary and fallopian tube
cancer. Researchers have continued their role in the study of
tamoxifen in breast cancer prevention for those at higher risk based
on family history. In addition, they have continued to collaborate in
the investigation of the psychosocial aspects of genetic testing for
cancer susceptibility by participating in studies of decision aids for
patients considering genetic testing, the impact of genetic testing
on males in breast cancer families, and the influence of genetic
testing results on discrimination in relation to insurance.
The laboratory’s research program has been successfully directed
towards improved screening for BRCA1 and BRCA2 mutations and
continues to focus on improvements to screening and the
understanding of the gene mutations that are detected by
screening. We have also worked with Translational Oncology to
investigate the pathological features of breast cancer in women
who carry a germline mutation in the ATM gene.
Gene expression in cancer
The Gene Expression Group studies the effect of cancer mutations
on specific proteins in the cell, with emphasis on cellular alterations
that lead to breast and colon cancer. This group aims to discover
new pathways that control the action of proteins in normal cells,
and to develop drugs or other reagents that correct defects in
these pathways in cancer cells.
Mutations in the BRCA1 are common in many breast cancers and
this group is investigating how mutations disrupt the BRCA1
protein’s normal function. The BRCA1 protein senses DNA damage
by monitoring dividing cells and, in response to DNA damage,
initiates gene repair processes in the nucleus to prevent errors
being transmitted to new cells. BRCA1 has a partner, BARD1;
their interaction helps facilitate the DNA-repair process. This group
discovered that unbound BRCA1 and BARD1 proteins, are
normally free to shuttle between the nucleus and cytoplasm. When
bound together they become confined to the nucleus, an essential
step in activating the complexed proteins for their crucial role in
DNA-repair and cell-survival. This group has also identified a class
of BRCA1 gene mutations that display an unexpected influence on