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Mechanisms Of Action Of The Zinc Finger Protein LMO4 In Breast Oncogenesis
Funder
National Health and Medical Research Council
Funding Amount
$272,859.00
Summary
Breast cancer is the most common cancer to strike Australian women, affecting one in 12 women by age 75. Although treatment of breast cancer has substanially improved over the last few years, approximately 25% of women diagnosed with this cancer will die from the disease. A major objective of cancer research is the identification of genes involved in tumour development and definition of their precise role in both normal and cancer cells. The design of new effective therapeutic inhibitors of canc ....Breast cancer is the most common cancer to strike Australian women, affecting one in 12 women by age 75. Although treatment of breast cancer has substanially improved over the last few years, approximately 25% of women diagnosed with this cancer will die from the disease. A major objective of cancer research is the identification of genes involved in tumour development and definition of their precise role in both normal and cancer cells. The design of new effective therapeutic inhibitors of cancer requires an understanding of the basic molecular and cellular biology behind the genetic changes that contribute to cancer. The focus of our research is to understand normal cellular mechanisms that drive growth and differentiation of breast tissue, and those changes that lead to breast cancer. We are particularly interested in 'master regulators' that are located in the cell nucleus. Nuclear regulators have been implicated in many different types of cancer and leukaemias. We aim to identify the key regulators in breast tissue, characterising both their biological roles and mechanism of action, with the ultimate view of understanding how they divert a normal cell to a cancerous cell. This proposal centres on the characterisation of a specific nuclear regulatory molecule, LMO4, which we have demonstrated to be overexpressed in 56% of human primary breast cancers. Significantly, we have recently shown that overexpression of LMO4 predicts poor outcome in breast cancer patients. We have also shown that this protein interacts with the breast tumour suppressor protein BRCA1, as well as a number of other proteins. These studies will include defining LMO4 s role in governing cell growth in breast cancer cells and that of the proteins that bind to this regulator. We will also assess the role of LMO4 in controlling cell invasion and metastasis of breast cancer cells in mouse models since we have preliminary evidence that it may be a critical regulator of these processes.Read moreRead less
In this project we aim to define the role of the Siah proteins in tumour angiogenesis and inflammatory responses. Hypoxia, a decrease in oxygen tension, places constrains on tumour growth where access to oxygen is yet to be established via new blood vessel formation. In addition hypoxia is common in areas of inflammation and wound healing, where blood vessels have been shut down to help in recovery. With the use of our Siah knockout mice we have a unique model that allows us, for the first time, ....In this project we aim to define the role of the Siah proteins in tumour angiogenesis and inflammatory responses. Hypoxia, a decrease in oxygen tension, places constrains on tumour growth where access to oxygen is yet to be established via new blood vessel formation. In addition hypoxia is common in areas of inflammation and wound healing, where blood vessels have been shut down to help in recovery. With the use of our Siah knockout mice we have a unique model that allows us, for the first time, to investigate the role of Siah in the hypoxia signalling cascade. How cells sense and react to low oxygen levels is complex and involves several proteins. A key protein is called Hypoxia induced factor, Hif-1. It accumulates under hypoxia and is responsible for the expression of genes enabling the cell to tolerate and function under hypoxic conditions. tolerate and function under hypoxic conditions, which is involved in new blood vessel formation. PHD protein directs the degradation of Hif1, while Siah directs the degradation of PHD, when oxygen is limiting. Loss of Siah proteins (eg in our knockout models) leads to an increase in PHD proteins under hypoxia thus no stabilisation of Hif-1 and impaired response to hypoxia. Thus, sitting on the top of a cascade, which controls the trashing of proteins in the cell (focus of this year's Nobel price for medicine), Siah has primary control on the response to oxygen deprivation. The relative immunity of multicellular organisms to acquired defects is through redundancy. Oxygen is a unique case, for which organisms can not bypass the defect via redundancy, making it an attractive target for future therapy. Therefore, understanding the molecular and cellular response to hypoxia may allow us to identify key molecules which could be targeted for the development of novel anti inflammatory and cancer drugs. The scope of this study is to understand the key role of Siah utilising our knockout mice in models of inflammation and cancer.Read moreRead less
Australasian Leukaemia Lymphoma Group (ALLG) National Leukaemia And Lymphoma Tissue Bank (NLLTB)
Funder
National Health and Medical Research Council
Funding Amount
$2,106,750.00
Summary
Recent advances in knowledge about how cancer differ from normal cells, why some people are susceptible to cancer, and how new treatments can target cancer have all occurred through research on cancer cells from patients. To benefit patients with cancers of the blood and the immune system, we established a National Leukaemia and Lymphoma Tissue Bank in 2002. It is proposed to dramatically expand its size, add relevant clinical data, and streamline access and utility for Australian researchers. U ....Recent advances in knowledge about how cancer differ from normal cells, why some people are susceptible to cancer, and how new treatments can target cancer have all occurred through research on cancer cells from patients. To benefit patients with cancers of the blood and the immune system, we established a National Leukaemia and Lymphoma Tissue Bank in 2002. It is proposed to dramatically expand its size, add relevant clinical data, and streamline access and utility for Australian researchers. Ultimately, this will lead to better treatment and prevention of blood cancers.Read moreRead less
Molecular Determinants Of Risk, Progression And Treatment Response In Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$8,381,820.00
Summary
Melanoma is a major Australian health problem. NSW figures for 2002 show it to be the second most common cancer in men and women. It has a disproportionately heavy impact on productive years of the life of young Australians because it is the commonest cancer in those aged 15-45 years. The investigators are all associated with the Sydney Melanoma Unit (SMU), the world�s largest clinical service dedicated to the treatment of melanoma, treating >1200 new melanoma patients annually. We have also ....Melanoma is a major Australian health problem. NSW figures for 2002 show it to be the second most common cancer in men and women. It has a disproportionately heavy impact on productive years of the life of young Australians because it is the commonest cancer in those aged 15-45 years. The investigators are all associated with the Sydney Melanoma Unit (SMU), the world�s largest clinical service dedicated to the treatment of melanoma, treating >1200 new melanoma patients annually. We have also recruited large cohorts of individuals with high susceptibility to melanoma, both familial and population-based, throughout southeastern Australia. We aim to utilise these unique, internationally-recognised resources to develop a scientific basis for 1) improved management of individuals at high risk for development and progression of melanoma, and 2) improved treatment of patients with early and disseminated melanoma. We will base this on consolidation of existing collaborative research into molecular predictors of risk, progression and treatment response in melanoma.Read moreRead less
Identification Of Clinically Significant Subtypes Of Head And Neck Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$469,122.00
Summary
Squamous cell carcinoma of the head and neck region (HNSCC) is amongst the top 10 most prevalent cancers. It is a life threatening cancer that is associated with a mortality rate of approximately 40%. Whilst most patients are treated with a combination of surgery, radiation and chemotherapy a significant fraction of patients relapse and eventually succumb to the cancer. The molecular basis for relapse in these patients is still unknown. One possible explanation for treatment failure is the notio ....Squamous cell carcinoma of the head and neck region (HNSCC) is amongst the top 10 most prevalent cancers. It is a life threatening cancer that is associated with a mortality rate of approximately 40%. Whilst most patients are treated with a combination of surgery, radiation and chemotherapy a significant fraction of patients relapse and eventually succumb to the cancer. The molecular basis for relapse in these patients is still unknown. One possible explanation for treatment failure is the notion that the cancer contains biologically distinct subtypes of cancer cells. Some these cells may respond to therapy whilst a small fraction of cells may not. If this small fraction of resistant cells were able to divide and repopulate the tissue then this would provide an explanation for relapse in these patients. However, as yet no such data has been available to support this argument. Most recently, studies with another cancer called acute myelocytic leukaemia has shown that they do contain a small subtype of cancer cells that are resistant to therapy and can regenerate the disease in patients. These cells have been called tumour initiating cells (TIC). In this application we will use patient tumour samples to try to isolate TICs from HNSCC. We will first determine whether these TICs exist and whether they express markers of normal human stem cells. We will also test whether these TICs are more resistant to chemotherapeutics or radiation than the rest of the tumour cells. In addition we will enrich for these TICs and identify new protein markers that could be used to test patient samples before or after treatment. This would be of considerable assistance in making decisions about treatment choice or prognosis. Since TICs have not been reported in HNSCC previously their identification would lead to a considerable advance in our undesratnding of how these tumours form.Read moreRead less