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

乳腺癌是澳大利亚妇女最常见的癌症，到75岁时，每12名妇女中就有一名患有乳腺癌。尽管乳腺癌的治疗在过去几年中有了实质性的改善，但大约25%的被诊断患有这种癌症的妇女将死于这种疾病。癌症研究的一个主要目标是鉴定与肿瘤发展有关的基因，并确定它们在正常细胞和癌细胞中的确切作用。设计新的有效的癌症治疗抑制剂需要了解导致癌症的遗传变化背后的基本分子和细胞生物学。我们研究的重点是了解驱动乳腺组织生长和分化的正常细胞机制，以及导致乳腺癌的变化。我们特别感兴趣的是位于细胞核中的“主调节器”。核调节因子与许多不同类型的癌症和白血病有关。我们的目标是确定乳腺组织中的关键调节因子，描述它们的生物学作用和作用机制，最终了解它们如何将正常细胞转化为癌细胞。该提案集中在一种特定的核调节分子LMO4的特征上，我们已经证明LMO4在56%的人类原发性乳腺癌中过表达。值得注意的是，我们最近发现LMO4的过度表达预示着乳腺癌患者的预后不良。我们还表明，这种蛋白质与乳腺肿瘤抑制蛋白BRCA1以及许多其他蛋白质相互作用。这些研究将包括定义LMO 4在控制乳腺癌细胞生长中的作用以及与该调节剂结合的蛋白质的作用。我们还将评估LMO4在小鼠模型中控制乳腺癌细胞的细胞侵袭和转移中的作用，因为我们有初步证据表明它可能是这些过程的关键调节因子。

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.