Epithelial-stromal cell interactions in breast cancer

乳腺癌中的上皮-基质细胞相互作用

• 批准号: 7786274
• 负责人: KORNELIA POLYAK
• 金额: $ 29.47万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7786274
• 关键词: AREG gene; Acute; Biological Models; Breast; Breast Cancer Treatment; Breast Carcinoma; CXCL12 gene; Carcinoma; Cell Communication; Cell Differentiation process; Cells; Child; Coculture Techniques; Conditioned Culture Media; DNA Methylation; Data; Epigenetic Process; Epithelial; Epithelial Cells; Fibroblasts; GDF15 gene; Gene Expression; Generations; Genes; Genetic; Goals; Growth; Histology; Human; In Situ; In Vitro; Injection of therapeutic agent; Karyotype determination procedure; Lead; Malignant Neoplasms; Malignant lymphoid neoplasm; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Methods; Methylation; Modeling; Morphology; Mus; Mutation; Myoepithelial; Myoepithelial cell; Myoepithelioma; Noninfiltrating Intraductal Carcinoma; Pathologic; Pattern; Phenotype; Physiological; Play; Property; Proteins; Research Personnel; Role; Stem cells; Stromal Cells; Stromal Neoplasm; System; Time; Xenograft Model; Xenograft procedure; base; breast tumorigenesis; cell type; connective tissue growth factor; digital; genetic profiling; genome-wide; in vitro Model; in vivo; malignant breast neoplasm; mammary gland development; novel; overexpression; paracrine; progenitor; programs; research study; serial analysis of gene expression; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): We analyzed the gene expression and genetic profiles of all cell types composing normal breast tissue and in situ and invasive breast carcinomas using Serial Analysis of Gene Expression and SNP arrays, respectively. Based on these data we determined that gene expression changes occur in all cell types during breast tumor progression, while clonally selected genetic alterations were only found in cancer epithelial cells. To investigate the role of epigenetic alterations in breast tumorigenesis, we developed a novel genome-wide methylation profiling method, methylation specific digital karyotyping (MSDK). MSDK analysis of epithelial and myoepithelial cells and stromal fibroblasts isolated from normal breast tissue and in situ and invasive breast carcinomas identified cell type and tumor specific DNA methylation patterns in all three cell types. To investigate the role of myoepithelial cells and stromal fibroblasts in breast tumorigenesis we analyzed the MCFDCIS.com human xenograft model and determined that MCFDCIS.com cells are able to give raise to both epithelial and myoepithelial cells. The differentiation of these cells and the histology of the resulting xenografts are influenced by co-injected myoepithelial cells and fibroblasts: normal myoepithelial cells promote while fibroblasts inhibit the DCIS tumor phenotype. The goal of this application is to characterize the role of myoepithelial cells and stromal fibroblasts in the in situ to invasive carcinoma progression and in the differentiation of breast epithelial progenitors using in vivo and in vitro model systems, and human breast tumors. Specific aims: (1) To determine the role of epithelial-myoepithelial/fibroblast cell interactions in breast tumor progression and in the differentiation of mammary epithelial progenitor cells using human xenograft models in mice and in vitro 3D co-culture systems. (2) To evaluate the role of genes epigenetically altered in tumor myoepithelial and stromal cells in breast tumorigenesis using models described in Aim 1. Aberrantly methylated genes identified in preliminary studies will be characterized and their role in breast cancer investigated. (3) To validate the findings of Aims 1 and 2 in human breast tumors. The completion of this project will not only help us understand the role of epithelial-stromal cell interactions in breast cancer, but epigenetically altered genes and abnormally expressed paracrine factors in the tumor microenvironment may provide new targets for breast cancer treatment.

描述（由申请人提供）：我们分别使用基因表达系列分析和SNP阵列分析了组成正常乳腺组织和原位和浸润性乳腺癌的所有细胞类型的基因表达和遗传谱。 基于这些数据，我们确定基因表达变化发生在乳腺肿瘤进展过程中的所有细胞类型中，而克隆选择的遗传改变仅在癌上皮细胞中发现。 为了研究表观遗传学改变在乳腺肿瘤发生中的作用，我们开发了一种新的全基因组甲基化分析方法，甲基化特异性数字核型分析（MSDK）。 从正常乳腺组织和原位和浸润性乳腺癌中分离的上皮细胞和肌上皮细胞以及基质成纤维细胞的MSDK分析鉴定了所有三种细胞类型中的细胞类型和肿瘤特异性DNA甲基化模式。 为了研究肌上皮细胞和基质成纤维细胞在乳腺肿瘤发生中的作用，我们分析了MCFDCIS.com人类异种移植模型，并确定MCFDCIS.com细胞能够产生上皮细胞和肌上皮细胞。 这些细胞的分化和所得异种移植物的组织学受到共注射的肌上皮细胞和成纤维细胞的影响：正常肌上皮细胞促进而成纤维细胞抑制DCIS肿瘤表型。 本申请的目的是使用体内和体外模型系统和人乳腺肿瘤来表征肌上皮细胞和基质成纤维细胞在原位至浸润性癌进展中以及在乳腺上皮祖细胞分化中的作用。 具体目标：（1）使用小鼠中的人异种移植模型和体外3D共培养系统，确定上皮-肌上皮/成纤维细胞相互作用在乳腺肿瘤进展和乳腺上皮祖细胞分化中的作用。(2)使用目标1中描述的模型评估肿瘤肌上皮细胞和基质细胞中表观遗传改变的基因在乳腺肿瘤发生中的作用。 在初步研究中发现的异常甲基化基因将被表征，并研究它们在乳腺癌中的作用。 (3)验证目的1和2在人乳腺肿瘤中的发现。 该项目的完成不仅有助于我们了解上皮-基质细胞相互作用在乳腺癌中的作用，而且肿瘤微环境中表观遗传改变的基因和异常表达的旁分泌因子可能为乳腺癌治疗提供新的靶点。