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

• 批准号: 7779032
• 负责人: KORNELIA POLYAK
• 金额: $ 57.52万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 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/7779032
• 关键词: Age; BRCA1 Mutation; Carcinoma; Cell Differentiation process; Cell Fraction; Cells; Clinical; Color; Data; Defect; Disease; Epithelial Cells; Ethnic Origin; Event; Gene Expression; Genes; High Risk Woman; Human; In Situ; Instruction; Intervention; Lead; MME gene; Mammary Gland Parenchyma; Mammary Neoplasms; Messenger RNA; Modeling; Molecular; Molecular Profiling; Myoepithelial; Myoepithelial cell; Noninfiltrating Intraductal Carcinoma; Normal Cell; Pathway interactions; Pattern; Phenotype; Population; Prevention; Primary Cell Cultures; Process; Prognostic Marker; Relative (related person); Risk; Sampling; Signal Pathway; Signal Transduction; Site; Stem cells; Testing; Tissue Sample; Validation; Woman; Xenograft procedure; base; cancer therapy; cell type; follow-up; genome-wide; human tissue; improved; malignant breast neoplasm; mutation carrier; novel; parity; progenitor; programs; stem cell differentiation; therapeutic target; tumor; tumor initiation; tumor progression

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. RELEVANCE (See Instructions): The transition of DCIS to invasive carcinoma is a poorly understood key event in breast tumor progression The proposed project will investigate normal myoepithelial cell differentiation programs and whether their perturbation in DCIS may explain progression to invasion using primary human tissue samples Understanding these processes may open new venues for cancer therapy and prevention.

描述（由申请人提供）：DCIS进展为浸润性癌是乳腺肿瘤进展中的一个关键步骤，人们对此知之甚少。我们先前已经证明，在肿瘤进展过程中，所有细胞类型都发生了分子变化，并且肌上皮细胞的丢失导致MCF 10 DCIS异种移植物中的侵袭性肿瘤。我们已经表征了来自正常人乳腺组织的假定祖细胞样和分化的肌上皮细胞的综合基因表达谱，并确定了可用于其鉴定的标记物。基于我们的数据，我们假设祖细胞向肌上皮细胞的分化受到来自肿瘤上皮细胞和构成微环境的细胞的信号的渐进性抑制。因此，肌上皮细胞层逐渐丢失并最终消失，导致向侵入过渡。我们提出了三个具体的目标来测试这些假设。目的1：鉴定DCIS中正常肌上皮细胞分化及其异常的分子决定因素。我们将从健康女性和BRCA 1突变携带者的正常乳腺组织以及DCIS的不同亚型中分离CD 10+细胞亚群。将使用全基因组方法表征每个细胞群的分子谱，然后在单细胞水平上在更大的样品组中进行验证。目的2：确定DCIS中肌上皮分化异常是否与进展为浸润性疾病的风险相关。我们将确定DCIS中肌上皮细胞分化调节因子的表达是否与浸润性进展相关。目的3：测试调节信号通路是否会影响肌上皮细胞分化向侵袭的进展. involved.in使用原代细胞培养模型，我们将确定是否肌上皮细胞分化的调节因子的扰动导致肌上皮细胞的损失和进展到入侵。确定DCIS中正常肌上皮细胞分化及其异常的决定因素将提高我们对干细胞分化的理解，并为治疗和预防干预提供新的预后标志物和靶点。相关性（见说明）：DCIS向浸润性癌的转变是乳腺肿瘤进展中一个知之甚少的关键事件。拟议的项目将研究正常的肌上皮细胞分化程序，以及它们在DCIS中的扰动是否可以解释使用原代人体组织样本的侵袭进展。