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38 39 > Research Report // AR 2006
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0.005.0486 research facilities 00.005.0459 at Westmead. The Bank 00.005.0458
was created to
provide a resource of breast cancer biospecimens and clinical
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The mechanisms through which PR controls gene expression
have also been explored in 2006, with the demonstration
that receptors aggregate with other key components of
transcriptional machinery when they are activated. Studies in
2006 demonstrated that these aggregations were functionally
significant, and identified some of the key functional
components of these aggregates. This aggregation process
is disrupted in human cancers, and ongoing studies in the
group are aimed at identifying the functional consequences
of its disruption in cancer. Most breast cancers are thought to
be initiated at puberty, and develop throughout reproductive
life. Although the vast majority of breast cancers are detected
after menopause, the influence of cyclical ovarian hormones
on their biology is profound. The studies from the Breast
Cancer Group aim to throw new light on the fundamental
question of how ovarian hormones influence breast cancer
initiation and progression.
Breast cancer tissue bank
WMI has led the establishment of the Breast Cancer Tissue
Bank with funding from the NHMRC, Cancer Institute
NSW and the National Breast Cancer Foundation. The
headquarters of the Bank are located within the clinical and
data to support breast cancer research throughout Australia.
Under the management of WMI a network of centres from
across New South Wales collected tissue for the Bank during
2006.
Materials in the bank are processed and stored using
international best practice methodologies to preserve the
integrity of the specimens and increase their value to research
scientists. Access to human tissue is essential for translating
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has important implications for determining the risk of genetic-epidemiological studies investigating the familial
developing melanoma and possibly the treatment strategy aspects of cancer. As many high-risk individuals have now
for patients carrying altered copies of the p16INK4a protein. been identified, the group established a risk-management
Furthermore, it is likely that unidentified p16INK4a clinic in 2006 that facilitates co-ordinated, multidisciplinary
functions (other then regulation of cell proliferation) may care of women at high risk of breast and ovarian cancer, as
add to its role as melanoma susceptibility gene. The Cell well as providing further opportunities for research. The
Cycle research group is investigating the role of p16INK4a in study of Magnetic Resonance Imaging of the breasts of highrisk
women in NSW has commenced at Westmead and the
novel biomolecular pathways.
group is now accumulating data to determine its usefulness
The BRAF oncogene is switched on in most melanomas
in comparison to standard mammographic screening. The
but intriguingly also in 80% of benign moles. Most moles
Service has completed the collaborative study of breast ductal
never transform into melanomas and their melanocytes are
lavage specimens, investigating its use as a surveillance tool in
normally growth arrested. Thus, although aberrant activation
women at high risk of breast cancer.
of BRAF plays a role in melanoma, normal melanocytes
apparently respond to active BRAF by growth arrest and The group continues to participate in the international
only additional genetic alterations allow these cells to become GOG-199 study, aimed at assessing the usefulness of
malignant. The Cell Cycle research group is exploring the screening versus preventive surgery in women at increased
mechanisms responsible for this BRAF-induced growth risk of cancer of the ovary and fallopian tubes. The group
arrest, which is clearly critical in protecting against melanoma has also continued its role in the study of tamoxifen in breast
formation. These investigations will also resolve the molecular cancer prevention for those at higher risk based on family
events necessary to transform a normal melanocyte into a history. In addition, the group has continued to collaborate
melanoma.
in the investigation of the psychosocial aspects of genetic
Melanoma cancers are notoriously resistant to chemotherapy.
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Through its research, the Cell Cycle team has confirmed
that cells in which p14ARF and p16INK4a are active are
more sensitive to chemotherapy. The impact of activated
BRAF on chemosensitivity is currently being investigated.
All these molecules are critical in the genesis of melanoma.
Therefore defining each of their functions is essential to the
development of a rational approach to targeted therapy for
this destructive disease.
Familial cancer research
Most cancers are due to genetic changes that accumulate in
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current research knowledge into clinical practice and in turn
basic researchers can utilise information derived from human
specimens to drive further investigation into the molecular
basis of disease.
Data and specimens stored in the Bank are available to
all Australian researchers following scientific review of the
proposed project.
Cell cycle research
In Australia, melanoma is the third most common cancer
in men and women with over 3,000 cases per year and an
overall lifetime risk of 3.7%. We know now that cancer is
caused by genetic changes, or mutations, in cells. However,
the precise sequence of mutations required to transform a
dormant melanocyte into a melanoma remains unresolved.
In recent years the group’s work has contributed to the
identification of several critical pathways crucial to this
process. In particular, the p16INK4a/p14ARF locus, which
encodes the tumour suppressor proteins p16INK4a and
p14ARF, is altered in 39% of melanoma-prone families and a
single base change that activates the BRAF oncogene is found
in 50-70% of melanomas. The Cell Cycle Research Group
is investigating how these proteins work and which cellular
targets they interact with.
This team recently proposed that the p14ARF protein
mediates the attachment of the small modifying protein,
SUMO, to a number of target proteins in a process called
sumoylation. Sumoylation regulates cellular activity of
these target proteins by altering their function. The group is
exploring the effects of p14ARF induced sumoylation, and
the consequences of p14ARF mutation on the functioning of
these proteins.
Some studies have reported that p14ARF can induce
programmed cell death, known as apoptosis, possibly by
activating the master apoptosis gene p53. The Cell Cycle
group has clarified that p14ARF induces apoptosis only
when co-expressed at normal physiological levels in cells
with a functional p53 gene; it cannot induce apoptosis by
itself. p14ARF is also known to stabilize proteins such as p53
by blocking the attachment of the small modifier protein
ubiquitination which acts as a degradation signal. The
effect of melanoma associated p14ARF mutations on the
degradation of essential proteins is also being investigated.
The p16INK4a tumour suppressor is frequently altered in
high risk melanoma families, and these altered p16INK4a
proteins may affect the function of the remaining
normal copy of p16INK4a. This important hypothesis is
currently being investigated by the Cell Cycle group and
the cells with age, but in 5 to 10 per cent of cases, patients
have a family history of multiple cases of early-onset cancer,
that suggests the presence of an inherited gene mutation that
greatly increases their risk of cancer.
The clinical arm of the Familial Cancer Research Group
operates a service where individuals with a strong family
history of breast, ovary, bowel cancer or melanoma, can be
assessed for genetic susceptibility. In conjunction with this
clinical service, many patients are enrolled in collaborative,
testing for cancer susceptibility by participating in studies of
decision aids and counselling tools for patients considering
genetic testing.
In 2006 the group established pilot telemedicine programs in
several rural centres to evaluate the usefulness of this clinical
tool to improve rural genetic health services.
The group’s laboratory provides a testing service for
individuals in the families described above, primarily
for mutations in the BRCA1 and BRCA2 breast cancer
susceptibility genes. In addition, there is some screening
for susceptibility to melanoma. 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.
Gene expression in cancer
Mutations in the tumour-suppressor gene BRCA1 are a
common factor in many breast cancers. The Gene Expression
laboratory is studying the effect of cancer mutations on