CAV-1 Epithelial-Stromal Interactions and Breast Cancer

CAV-1 上皮-间质相互作用与乳腺癌

• 批准号: 7880060
• 负责人: MICHAEL P LISANTI
• 金额: $ 29.45万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-03 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880060
• 关键词: Ablation; Acceleration; Adenocarcinoma; Adipocytes; Age; Alveolar; Anchorage-Independent Growth; Appearance; Cell Proliferation; Cells; Cholesterol; Cyclin D1; Cyclins; Development; Distant; Dominant-Negative Mutation; Duct (organ) structure; Ductal; EPSTI1 gene; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Epithelium; Equilibrium; Fatty acid glycerol esters; Female; Fibroblasts; Genetic; Golgi Apparatus; Human; Hyperplasia; Hypothalamic Hormones; In Vitro; Individual; Knock-out; Knockout Mice; Knowledge; Lesion; Lung; Mammary Dysplasia; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Milk; Milk Proteins; Modeling; Molecular; Morphology; Mouse Mammary Tumor Virus; Mus; Mutation; NIH 3T3 Cells; Neoplasm Metastasis; Nipples; Oncogenes; Organ; Peptides; Phenotype; Physiology; Play; Polyomaviruses Middle T Proteins; Pregnancy; Primary Neoplasm; Production; Prolactin; Proteins; Recombinants; Regulation; Regulatory Pathway; Reporting; Research Personnel; Rest; Role; Sampling; Signal Transduction; Signaling Protein; Staging; Stem cells; Stromal Cells; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Transplantation; Tumor Cell Line; Tumor Suppressor Proteins; Up-Regulation; base; bone; caveolin 1; cell transformation; in vivo; malignant breast neoplasm; mammary gland development; matrigel; mimetics; mutant; neoplastic; neoplastic cell; programs; reconstitution; research study; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand the role of caveolin-1 in mammary epithelial-stromal interactions, during mammary tumorigenesis (a.k.a., the tumor microenvironment). Here, we will investigate the development of epithelial cell hyperplasia in the mammary glands of Cav-1 null mice. More specifically, we will mechanistically dissect the individual contributions of epithelial or non-epithelial cells to this hyperplastic Cav-1 null phenotype. Using both in vitro and in vivo mammary reconstitution experiments, we will explore whether the specific loss of Cav-1 within mammary epithelial cells or non-epithelial cells (i.e. stromal cells, including fibroblasts and adipocytes) both contribute to a dysregulation of epithelial proliferation and tumorigenesis. The two Specific Aims (SAs) of the project are: SA1) To examine the role of Cav-1 in epithelial-stromal interactions during mammary tumorigenesis. For this purpose, we will explore whether the specific loss of Cav-1 within mammary epithelial cells or non-epithelial cells (i.e. stromal cells, including fibroblasts and adipocytes) both contribute to a dysregulation of epithelial cellular proliferation, hyperplasia, and tumorigenesis, using mammary reconstitution experiments. Additional studies will be carried out with human breast cancer samples to identify CAV-1 mutations in mammary stromal cells. SA2) To determine the effects of Cav-1 expression on Cyclin D1-induced mammary tumorigenesis. In this aim, we will evaluate how Cav-1 expression modulates Cyclin D1-induced mammary tumorigenesis, by crossing Cav-1 (-/-) null and Cav-1 transgenic (Tg) mice, with MMTV-Cyclin D1 transgenic mice. Complementary experiments will be carried out employing the therapeutic administration of a cell permeable caveolin-1-based mimetic peptide. In this context, epithelial-stromal contributions will also be evaluated. These studies will contribute fundamental knowledge toward understanding the role of Cav-1 in regulating epithelial-stromal interactions, during mammary cell transformation and tumorigenesis.

描述（由申请人提供）：本提案的长期目标是了解小窝蛋白-1在乳腺肿瘤发生期间乳腺上皮-基质相互作用中的作用（又名，肿瘤微环境）。 在这里，我们将调查上皮细胞增生的发展，在乳腺的Cav-1基因敲除小鼠。 更具体地说，我们将机械地剖析上皮或非上皮细胞的个人贡献，这种增生的Cav-1空表型。 使用体外和体内乳腺重建实验，我们将探索乳腺上皮细胞或非上皮细胞（即基质细胞，包括成纤维细胞和脂肪细胞）内Cav-1的特异性丢失是否都有助于上皮增殖和肿瘤发生的失调。 该项目的两个具体目标（SA）是：SA 1）检查Cav-1在乳腺肿瘤发生过程中上皮-基质相互作用中的作用。 为此目的，我们将探索Cav-1在乳腺上皮细胞或非上皮细胞（即基质细胞，包括成纤维细胞和脂肪细胞）内的特异性丢失是否都有助于上皮细胞增殖、增生和肿瘤发生的失调，使用乳腺重建实验。 将对人类乳腺癌样本进行额外的研究，以确定乳腺基质细胞中的CAV-1突变。 SA 2）确定Cav-1表达对Cyclin D1诱导的乳腺肿瘤发生的影响。 在这一目标中，我们将评估Cav-1表达如何调节细胞周期蛋白D1诱导的乳腺肿瘤发生，通过交叉Cav-1（-/-）空和Cav-1转基因（Tg）小鼠，与MMTV-Cyclin D1转基因小鼠。 采用细胞可渗透的小窝蛋白-1-基模拟肽的治疗性给药进行补充实验。 在这种情况下，还将评价上皮-基质的贡献。 这些研究将有助于了解Cav-1在乳腺细胞转化和肿瘤发生过程中调节上皮-基质相互作用的作用的基础知识。