Investigation of an LMO4- and BRCA1 -containing complex involved in breast cancer

涉及乳腺癌的含 LMO4 和 BRCA1 复合物的研究

• 批准号: nhmrc : 253662
• 负责人: Prof Jacqueline Matthews
• 金额: $ 29.36万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/investigation-an-lmo4-breast-cancer/96854
• 关键词: Investigation; LMO4; BRCA1; containing; complex

Breast cancer will affect one in twelve Australian women and a quarter of those will die from breast cancer. At present we still know little about what causes the disease, and there is currently a lot of activity in the field of breast cancer research that will ultimately increase our ability to both detect its development at early stages and to provide effective treatments for the disease. We do know that losing the function of a few genes (breast cancer susceptibility genes) leads to a very high likelihood of developing cancer, and we know that the normal roles of the proteins that are produced from these genes are to prevent cancers from occurring in a spontaneous fashion. However, the inheritance of mutations in breast cancer susceptibility genes accounts for only a few percent of breast cancer cases. A recently discovered protein, known as LMO4, has been found at abnormal levels in over 50% of non-inherited breast tumors. This protein has been found to both interact with the protein from the most commonly occurring breast cancer susceptibility gene, known as BRCA1, and to prevent the normal activity of BRCA1. Thus, if we could develop reagents that prevent LMO4 from interacting with BRCA1, we could use those reagents as lead compounds for the development of anti-breast cancer drugs. Before we can develop such reagents we need to fully understand both what these proteins look like and how they interact. We already know that two other proteins, known as ldb1 and CtIP are involved in the LMO4:BRCA1 interaction. We will investigate the ways in which all of these proteins interact, from determining how strong each interaction is, to getting atomic level information about which surfaces of the proteins make the most contribution to each interaction. This should let us identify good targets for the design and development of anti-breast cancer drugs.

乳腺癌将影响十二分之一的澳大利亚妇女，其中四分之一将死于乳腺癌。目前，我们仍然对导致这种疾病的原因知之甚少，目前在乳腺癌研究领域有很多活动，最终将提高我们在早期阶段检测其发展并为疾病提供有效治疗的能力。我们确实知道，一些基因（乳腺癌易感基因）的功能丧失会导致患癌症的可能性非常高，我们也知道这些基因产生的蛋白质的正常作用是防止癌症以自发的方式发生。然而，乳腺癌易感基因突变的遗传仅占乳腺癌病例的百分之几。最近发现的一种蛋白质，称为LMO4，在超过50%的非遗传性乳腺肿瘤中发现异常水平。这种蛋白质被发现与最常见的乳腺癌易感基因BRCA 1的蛋白质相互作用，并阻止BRCA 1的正常活性。因此，如果我们能够开发出阻止LMO4与BRCA1相互作用的试剂，我们就可以使用这些试剂作为开发抗乳腺癌药物的先导化合物。在我们开发这种试剂之前，我们需要完全了解这些蛋白质的外观以及它们如何相互作用。我们已经知道另外两种蛋白质，称为ldb1和CtIP，参与了LMO4：BRCA1的相互作用。我们将研究所有这些蛋白质相互作用的方式，从确定每个相互作用的强度，到获得关于蛋白质的哪些表面对每个相互作用的贡献最大的原子水平信息。这应该让我们为抗乳腺癌药物的设计和开发确定良好的目标。