Cancer<strong>Westmead</strong> <strong>Institute</strong> for Cancer ResearchThe <strong>Westmead</strong> <strong>Institute</strong> for Cancer Research aims toconduct research into the molecular and cellular basis ofhuman cancer and leukaemia to improve the prevention,treatment and cure of these devastating diseases.
Breast cancer researchThe Breast Cancer Research Group is investigating the role ofoestrogen and progesterone in the development of the normalbreast and in breast cancer. These hormones are fundamentalregulators of normal cell growth and differentiation, and are alsocrucial to the development and progression of breast cancer.Progesterone has a pivotal role in normal female reproduction in theuterus, ovary, mammary gland and brain. This group has previouslyidentified a change in expression of two forms of the progesteronereceptor, PRA and PRB, in cancer. Work in <strong>2005</strong> has focussed onfurther identifying the cellular consequences of this change. Geneexpression profiles have shown a distinct shift in the ability of a cellto respond to progesterone when the two forms of the PR areimbalanced, and this is associated with changes in signallingpathways important in maintenance of normal cell biology.The mechanisms through which PR controls gene expression havealso been explored, researchers demonstrating that receptorsaggregate with other key components of transcriptional machinerywhen they are activated. This aggregation process is disrupted inhuman cancers, and current studies in the group are aimed atexploring the aggregation process and identifying the functionalconsequences of its disruption in cancer.Cell cycle researchThe INK4a/ARF sequence on chromosome 9 encodes twodistinctly different proteins, known as p14ARF and p16INK4a. Bothof these tumour suppressor proteins have critical roles inmaintaining the genetic integrity of a wide range of cell types andresearchers in this group are investigating their function, movementand binding partners. Mutations that inactivate p14ARF orp16INK4a are common in many different human cancers. Whilep16INK4a is mutated in approximately a third of families with ahistory of melanoma, this group have found that a subset ofmelanoma-affected families also carry mutations that alter thelocalisation and function of p14ARF. The p14ARF tumoursuppressorprotein binds to a range of cellular targets, and thisgroup is investigating what impact these novel partners have on thefunctions of p14ARF.This group recently proposed that p14ARF mediates a processcalled sumoylation, by promoting the attachment of the proteinSUMO to other proteins. Sumoylation regulates cellular activity byaltering the location of some proteins and modulating the activity ofothers. Researchers are exploring the downstream effects ofp14ARF-induced sumoylation, and the consequences whenp14ARF is mutated. Melanoma cancers are notoriously resistant tochemotherapy and this group has confirmed that p14ARF can cooperatewith various chemotherapeutic agents to induceprogrammed cell death in melanoma cells. Thus, genes regulatedby p14ARF may provide alternative targets for new drugs to killmelanoma tumours that have lost p14ARF protection.Familial cancerMost cancers are due to genetic changes that accumulate in thecells with age, but in 5 to 10 per cent of cases a patient’s familyhistory suggests the presence of an inherited gene mutation thatincreases their cancer risk. The clinical arm of this group operates aservice assessing genetic susceptibility to breast, ovary, bowelcancer and melanoma. In conjunction, many patients are enrolled incollaborative, genetic-epidemiological studies investigating thefamilial aspects of cancer.The service is part of a study of breast ductal lavage, investigatingits use as a surveillance tool in women at high risk of breast canceras well as participating in the international GOG-199 study, aimedat assessing the usefulness of screening alone vs preventivesurgery in women at increased risk of ovary and fallopian tubecancer. Researchers have continued their role in the study oftamoxifen in breast cancer prevention for those at higher risk basedon family history. In addition, they have continued to collaborate inthe investigation of the psychosocial aspects of genetic testing forcancer susceptibility by participating in studies of decision aids forpatients considering genetic testing, the impact of genetic testingon males in breast cancer families, and the influence of genetictesting results on discrimination in relation to insurance.The laboratory’s research program has been successfully directedtowards improved screening for BRCA1 and BRCA2 mutations andcontinues to focus on improvements to screening and theunderstanding of the gene mutations that are detected byscreening. We have also worked with Translational Oncology toinvestigate the pathological features of breast cancer in womenwho carry a germline mutation in the ATM gene.Gene expression in cancerThe Gene Expression Group studies the effect of cancer mutationson specific proteins in the cell, with emphasis on cellular alterationsthat lead to breast and colon cancer. This group aims to discovernew pathways that control the action of proteins in normal cells,and to develop drugs or other reagents that correct defects inthese pathways in cancer cells.Mutations in the BRCA1 are common in many breast cancers andthis group is investigating how mutations disrupt the BRCA1protein’s normal function. The BRCA1 protein senses DNA damageby monitoring dividing cells and, in response to DNA damage,initiates gene repair processes in the nucleus to prevent errorsbeing transmitted to new cells. BRCA1 has a partner, BARD1;their interaction helps facilitate the DNA-repair process. This groupdiscovered that unbound BRCA1 and BARD1 proteins, arenormally free to shuttle between the nucleus and cytoplasm. Whenbound together they become confined to the nucleus, an essentialstep in activating the complexed proteins for their crucial role inDNA-repair and cell-survival. This group has also identified a classof BRCA1 gene mutations that display an unexpected influence on
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