Molecular Pathogenesis of Basal-like Breast Cancer

描述(申请人提供)：乳腺癌是一种异质性疾病，具有不同的结果和治疗反应。基底细胞样乳腺癌(BBC)占所有乳腺癌的15%-20%，具有不同的基因表达模式，包括基础细胞角蛋白和DNA复制因子升高。另一方面，基底细胞样乳腺癌在转移潜能和基因改变方面具有异质性。因此，必须确定BBC生长和预后不良的驱动力，然后才能开发出成功机会很高的治疗策略。该计划的长期目标是确定在不同形式的BBC中发挥作用的癌基因和肿瘤抑制通路，以更好地预测它们的临床行为，并开发攻击这些肿瘤的方法。我们和其他人已经确定，作为一个类别，BBC经常放松对MYC、P53、PTEN、BRCA1的调控，我们有初步数据显示Hausp也是如此。这些变化如何或何时在任何特定的BBC发展中合作尚不清楚。新修订的申请中的每个项目都专注于定义导致基底样癌的途径，然后识别它们对肿瘤表型的贡献的基础。项目1将试图了解PTEN和其他PI3K途径调节因子在BBC中的作用。项目2将确定Hausp在调节PTEN泛素化和BBC肿瘤抑制中的功能。项目的重点将是BRCA1在遗传性BBC肿瘤抑制中的泛素连接酶功能，以及开发更准确的疾病模型。项目4将研究MYC诱导DNA复制应激的能力，以及通过使肿瘤抑制基因PTEN、P53和BRCA1失活来逃逸产生DNA复制的机制。这些项目将得到管理/分析和乳房病理学核心的支持。该计划依赖于分子病理学、乳腺细胞工程、生物化学、遗传学、系统生物学、生物信息学、生物统计学和细胞功能分析等领域不同专业知识的整合。最终，我们希望更好地了解基底细胞样乳腺癌中改变的通路网络驱动肿瘤生长的机制，以便更好地预测肿瘤表型，即转移，并制定治疗策略。

DESCRIPTION (provided by applicant): Breast cancer is a heterogeneous disease with diverse outcomes and response to therapy. Basal-like breast cancers (BBC), which account for 15-20% of all breast cancer, share a distinct pattern of gene expression that includes elevated basal cytokeratins and DNA replication factors. On the other hand, basal-like breast cancers are heterogeneous among themselves with regard to metastatic potential and genetic alterations. Therefore, the driving forces for the growth and poor prognosis of BBC must be identified before therapeutic strategies with a high chance of success can be developed. The long-term objective of this program is to define the oncogene and tumor suppressor pathways at work in different forms of BBC to better predict their clinical behavior and to develop approaches for attacking these tumors. We and others have established that, as a class, BBC frequently deregulate MYC, p53, PTEN, BRCA1, and we have preliminary data showing the same for HAUSP. How or when these alterations cooperate in any specific BBC development is not understood. Each of the projects in the newly revised application is focused on defining the pathways that cause basal-like cancer and then discerning the basis for their contribution to the tumor phenotype. Project 1 will seek to understand the role of PTEN and other PI3K pathway regulators in BBC. Project 2 will determine the function of HAUSP in the regulation of PTEN ubiquitination and BBC tumor suppression. Projects will focus on the ubiquitin-ligase function of BRCA1 in hereditary BBC tumor suppression and the development of a more accurate model of the disease. Project 4 will study the ability of MYC to induce DNA replication stress and mechanisms of escape to produce DNA replication through the inactivation of tumor suppressors PTEN, p53 and BRCA1. The projects will be supported by cores for administration/analysis and breast pathology. The program relies on the integration of different expertise in the areas of molecular pathology, mammary cell engineering, biochemistry, genetics, systems biology, bioinformatics, biostatistics, and cell function analysis. Ultimately, we hope to better understand the mechanisms through which the network of altered pathways in basal-like breast cancer drives tumor growth in order to better predict tumor phenotype, i.e., metastasis, and develop strategies for therapy.