The role of microenvironment in aging-related phenotypes of breast

微环境在乳腺衰老相关表型中的作用

• 批准号: 8012022
• 负责人: Mark A LaBarge
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012022
• 关键词: 3-Dimensional; Address; Affect; Age; Age-Years; Aging; Aging-Related Process; Biological Assay; Breast; Cell physiology; Cells; Characteristics; Cues; Development; Epithelial; Gene Expression; Genetic; Human; Incidence; Individual; Laboratories; Link; Malignant Neoplasms; Mammary gland; Microarray Analysis; Modeling; Mutation; Natural regeneration; Oncogenes; Phenotype; Plant Roots; Play; Regulation; Reporting; Role; Stem cells; Testing; Therapeutic; Tissues; Woman; adult stem cell; age related; aged; base; cancer risk; cell behavior; design; malignant breast neoplasm; neoplastic cell; response; tissue regeneration; tumor; tumorigenesis

The mechanisms underlying the exponentially increased incidence of breast cancer in women >55 years of age are poorly understood. A useful conceptual framework from which to build hypotheses is that agingrelated phenotypes are etiologically rooted in changes In tissue-specific stem cells or in their regulation. Indeed, common aging-related phenotypes i.e. cancers and deficits in tissue regeneration both have been linked to stem cells. A number of reports that studied stem cells as a function of age have suggested that age-related phenotypes can be due to stem cell-intrinsic or-extrinsic factors, but that delineation appears to be tissue specific. The Bissell laboratory and others have shown that the mammary microenvironment is as important as are the mutations in epithelial tumor cells for development of breast cancers. In a number of cases it has even been shown that the microenvironment can be dominant over strong oncogenes. In the aging breast, does the microenvironment change so as to catalyze tumorigenesis? Do damaged or aged mammary stem cells cease listening to, or misinterpret regulatory cues from their microenvironment? Or is it a combination? We are now uniquely poised to address these questions for the breast. Over several decades, 3-dimensional culture models that mimic many aspects ofthe human mammary gland and breast cancer microenvironments were developed in the Bissell laboratory. Recently, we also have developed a cell-based microenvironment microarray technology that facilitates elucidation of the functional roles that are played by individual microenvironmental constituents and combinations thereof. We have used these models together with primary human mammary progenitor cells to demonstrate that the microenvironment can dictate mammary progenitor cell fate decisions. Here we propose to combine these assets to address the following specific aims: (1) To identify age-dependent functional responses in microenvironment-directed mammary progenitor cell regulation, and the genetic circuitry that underlies them. (2) To determine whether mutations characteristic of breast cancers endow normal mammary progenitor cells with tumor-forming potential, or shifts their spectrum of response to mammary microenvironments in an age-dependent manner. (3) To design and test a therapeutic strategy based on age-related differences in mammary microenvironments and stem cell behavior using physiologically relevant 3D organotypic assays.

55 岁以上女性乳腺癌发病率呈指数增加的机制 对年龄了解甚少。建立假设的一个有用的概念框架是与衰老相关的 表型的病因学根源于组织特异性干细胞或其调节的变化。 事实上，常见的与衰老相关的表型，即癌症和组织再生缺陷都已被 与干细胞有关。许多研究干细胞与年龄关系的报告表明， 与年龄相关的表型可能是由于干细胞内在或外在因素造成的，但这种描述似乎 具有组织特异性。比塞尔实验室和其他实验室已经表明，乳腺微环境是 上皮肿瘤细胞的突变对于乳腺癌的发展也很重要。在一些 甚至有研究表明，微环境可以压倒强癌基因。在 乳房老化，微环境是否发生变化从而催化肿瘤发生？是否损坏或老化 乳腺干细胞停止倾听或误解来自微环境的调节线索？或者是 组合？我们现在已经准备好解决这些乳房问题。超过几个 几十年来，三维培养模型模仿了人类乳腺和乳房的许多方面 癌症微环境是在比塞尔实验室开发的。最近我们还开发了一个 基于细胞的微环境微阵列技术，有助于阐明 由单个微环境成分及其组合发挥作用。我们已经使用过这些模型 与原代人类乳腺祖细胞一起证明微环境可以 决定乳腺祖细胞的命运。在这里，我们建议结合这些资产来解决 以下具体目标：（1）确定微环境导向中年龄依赖性功能反应 乳腺祖细胞调节及其背后的遗传电路。 (2)判断是否 乳腺癌特征性的突变赋予正常乳腺祖细胞以肿瘤形成的潜力，或者 以年龄依赖的方式改变它们对乳腺微环境的反应范围。 (3) 设计与 测试基于乳腺微环境和干细胞的年龄相关差异的治疗策略 使用生理相关的 3D 器官型分析来分析行为。