Mechanisms of action of the zinc finger protein LMO4 in breast oncogenesis

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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.