Myoepithelial cell differentiation defects in ductal carcinoma in situ (DCIS)

导管原位癌 (DCIS) 中的肌上皮细胞分化缺陷

基本信息

批准号：
8528505
负责人：
MINA BISSELL
金额：
$ 41.74万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528505
关键词：
Age BRCA1 Mutation Basement membrane Behavior CD44 gene Carcinoma Cell Differentiation process Cell Fraction Cell physiology Cells Clinical Coculture Techniques Color Data Defect Disease Endothelial Cells Epigenetic Process Epithelial Epithelial Cells Ethnic Origin Event Extracellular Matrix Fatty acid glycerol esters Fibroblasts Gene Expression Genes Gland High Risk Woman Human In Situ Instruction Intervention Laminin Lead Leukocytes MME gene Malignant - descriptor Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Messenger RNA Modeling Molecular Molecular Profiling Myoepithelial Myoepithelial cell Myofibroblast Noninfiltrating Intraductal Carcinoma Normal Cell Pathway interactions Pattern Phenotype Play Population Primary Cell Cultures Process Production Prognostic Marker Publishing Relative (related person)Risk Role Sampling Signal Pathway Signal Transduction Site Source Stem cells Testing Tissue Sample Validation Woman Xenograft procedure base cancer prevention cancer therapy cell type follow-up genome-wide human tissue improved in vivo macrophage malignant breast neoplasm mutation carrier new therapeutic target novel parity progenitor programs stem cell differentiation therapeutic target tumor tumor initiation tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): The progression of DCIS to invasive carcinoma is a poorly understood key step in breast tumor progression. We have previously demonstrated that molecular changes occur in all cell types during tumor progression and that the loss of myoepithelial cells leads to invasive tumors in MCF10DCIS xenografts. We have characterized the comprehensive gene expression profiles of putative progenitor-like and differentiated myoepithelial cells from normal human breast tissue and identified markers that can be used for their identification. Based on our data we hypothesize that the differentiation of progenitors to myoepithelial cells is progressively inhibited by signals coming from tumor epithelial cells and cells composing the microenvironment. As a consequence of this, the myoepithelial cell layer is gradually lost and eventually disappears, leading to transition to Invasion. We propose three specific aims to test these hypotheses. Aim 1: To identify molecular determinants of normal myoepithelial cell differentiation and their abnormalities in DCIS. We will isolate CD10+ subpopulations of cells from normal breast tissue of healthy women and BRCA1 mutation carriers, and from different subtypes of DCIS. Molecular profiles of each of the cell populations will be characterized using genome-wide approaches followed by validation in a larger set of samples at the single cell level. Aim 2: To determine if abnormalities of myoepithelial differentiation in DCIS correlate with the risk of progression to invasive disease. We will determine if the expression of regulators of myoepithelial cell differentiation in DCIS is associated with invasive progression. Aim 3: To test if modulating signaling pathways involved.in myoepithelial cell differentiation would effect progression to invasion. Using primary cell culture models, we will determine if perturbations of regulators of myoepithelial cell differentiation lead to loss of myoepithelial cells and progression to invasion. Identification of determinants of normal myoepithelial cell differentiation and their abnormalities in DCIS would improve our understanding of stem cell differentiation and provide novel prognostic markers and targets for therapeutic and preventative interventions.

描述（由申请人提供）：DCI到浸润性癌的发展是乳腺肿瘤进展的关键一步。我们先前已经证明，在肿瘤进展过程中，所有细胞类型中都会发生分子变化，并且肌上皮细胞的丧失导致MCF10DCIS异种移植物中浸润性肿瘤。我们已经表征了假定的祖细胞样和分化的肌上皮细胞与正常乳腺组织的综合基因表达谱，并鉴定出可用于鉴定的标记。根据我们的数据，我们假设祖细胞对肌上皮细胞的分化受到来自肿瘤上皮细胞和组成微环境的细胞的信号的逐步抑制。因此，肌上皮细胞层逐渐消失并最终消失，导致向入侵过渡。我们提出了三个特定的目标来检验这些假设。目标1：确定正常肌上皮细胞分化及其异常在DCIS中的分子决定因素。我们将从健康女性和BRCA1突变载体的正常乳腺组织中分离细胞的CD10+亚群，以及DCI的不同亚型。每个细胞种群的分子谱将使用全基因组方法进行表征，然后在单个细胞水平的较大样品集中进行验证。目的2：确定DCIS中肌上皮分化的异常是否与发展为侵袭性疾病的风险相关。我们将确定DCI中肌上皮细胞分化的调节剂的表达是否与侵入性进展有关。目的3：测试是否调节涉及的信号通路。在肌上皮细胞分化将影响侵袭。使用原发性细胞培养模型，我们将确定肌上皮细胞分化调节剂的扰动是否会导致肌上皮细胞的丧失并发展为侵袭。鉴定正常肌上皮细胞分化及其在DCI中的异常的决定因素将提高我们对干细胞分化的理解，并为治疗和预防性干预提供新颖的预后标记和靶标。