Genomic Analysis of ER Negative Breast Cancer

描述（由申请人提供）： 该项目的目标是确定化学预防的潜在靶点和ER阴性乳腺癌和乳腺癌发生的卵巢无反应小鼠模型之间共享的化学预防功效的生物标志物。由于实体瘤的发展与遗传改变的获得和基因表达的相应变化有关，这些变化改变了正常的生长控制和生存途径，我们将使用基因组分析，包括基于阵列的DNA拷贝数改变和基因表达的测量，以确定ER阴性肿瘤和小鼠模型中DNA和mRNA表达水平的改变。在目标1中，我们将根据拷贝数和表达表型对ER阴性乳腺肿瘤进行分类，并通过确定p53突变和端粒酶活性的状态进一步表征肿瘤。在目标2中，我们将使用阵列CGH和表达谱来鉴定每种亚型的最常发生的畸变或改变的基因表达特征的区域。这些畸变将作为周围组织学“正常”或增生组织和细胞培养系统中的候选早期病变进行评价。在目标3中，我们将表征乳腺肿瘤发生的小鼠模型，以确定哪些模型最接近于目标1和2中确定的人类肿瘤类别。然后，我们将确定在人类中有用的早期标记物是否也在相应的小鼠模型中提供信息。这些研究的成功结论将定义ER阴性乳腺肿瘤的特征，并将导致适合用作替代生物标志物的复发性异常的表征。此外，这些研究将确定哪些小鼠模型在分子水平上与ER阴性肿瘤的不同亚型最相似，从而增强其作为临床前模型的实用性。

DESCRIPTION (provided by applicant): The goal of this project is to identify potential targets for chemoprevention and biomarkers of chemopreventive efficacy shared between ER negative breast cancers and hormonally non-responsive mouse models of mammary carcinogenesis. Since the development of solid tumors is associated with the acquisition of genetic alterations and corresponding changes in gene expression that modify normal growth control and survival pathways, we will use genomic analyses, including array-based measurements of DNA copy number alterations and gene expression to identify alterations occurring at both the DNA and mRNA expression levels in ER negative tumors and mouse models. In Aim 1, we will classify ER negative breast tumors according to copy number and expression phenotypes and further characterization of the tumors by determining the status of p53 mutations and telomerase activity. In Aim 2, we will use the array CGH and expression profiles to identify regions of most recurrent aberration or altered gene expression characteristic of each subtype. These aberrations will be evaluated as candidate early lesions in surrounding histologically "normal" or hyperplastic tissue and in cell culture systems. In Aim 3, we will characterize mouse models of mammary tumorigenesis to determine which ones correspond most closely to the human tumor classes identified in Aims 1 and 2. We will then determine if the early markers that were useful in the human are also informative in the corresponding mouse models. The successful conclusion of these studies will define the features of ER negative breast tumors and will lead to the characterization of recurrent abnormalities suitable for use as surrogate biomarkers. In addition, these studies will determine which mouse models most closely resemble different subtypes of ER negative tumors at the molecular level, thereby enhancing their utility as preclinical models.