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

每12名澳大利亚妇女中就有1人患有乳腺癌，其中四分之一将死于乳腺癌。目前，我们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该疾病提供有效治疗的能力。我们确实知道，失去一些基因（乳腺癌易感基因）的功能会导致患癌症的可能性很高，我们也知道，由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只占乳腺癌病例的百分之几。最近发现的一种名为LMO4的蛋白质在超过50%的非遗传性乳腺肿瘤中处于异常水平。研究发现，这种蛋白质既能与最常见的乳腺癌易感基因BRCA1的蛋白质相互作用，又能阻止BRCA1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，我们就可以将这些试剂用作开发抗乳腺癌药物的先导化合物。在我们开发这样的试剂之前，我们需要充分了解这些蛋白质的样子以及它们是如何相互作用的。我们已经知道另外两种蛋白质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，从确定每种相互作用的强度，到获得关于蛋白质的哪个表面对每种相互作用贡献最大的原子水平信息。这应该能让我们确定设计和开发抗乳腺癌药物的良好靶点。

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.