The role of microenvironment in aging-related phenotypes of breast

描述（由申请人提供）：对55岁以上女性乳腺癌发病率呈指数增长的机制知之甚少。建立假说的一个有用的概念框架是，衰老相关的表型在病因学上植根于组织特异性干细胞或其调节的变化。事实上，常见的衰老相关表型，即癌症和组织再生缺陷都与干细胞有关。许多研究干细胞作为年龄的函数的报告已经证明，与年龄相关的表型是由于干细胞的内在和外在因素，但划定是组织特异性的。比塞尔实验室和其他人已经表明，乳腺微环境与上皮肿瘤细胞的突变对乳腺癌的发展同样重要。在许多情况下，甚至已经表明微环境可以对强致癌基因起主导作用。在衰老的乳腺中，微环境是否会发生变化从而催化肿瘤的发生？受损或老化的乳腺干细胞是否停止倾听或误解来自其微环境的调节信号？或者是两者的结合？我们现在正准备为乳房解决这些问题。几十年来，Bissell实验室开发了模拟人类乳腺和乳腺癌微环境许多方面的三维培养模型。最近，我们还开发了一种基于细胞的微环境微阵列技术，该技术有助于阐明单个微环境成分及其组合所发挥的功能作用。我们使用这些模型与原代人乳腺祖细胞一起证明微环境可以决定乳腺干细胞的命运。在这里，我们建议联合收割机这些资产，以解决以下具体目标：（1）确定年龄依赖性的功能反应，在微环境指导的乳腺祖细胞的调节，和遗传电路，他们的基础。(2)确定乳腺癌特征性突变是否赋予正常乳腺祖细胞肿瘤形成潜力，或以年龄依赖性方式改变其对乳腺微环境的反应谱。(3)设计和测试基于乳腺微环境和干细胞行为的年龄相关差异的治疗策略，使用生理学相关的3D器官型测定。 相关性：随着年龄的增长，癌症的风险增加，我们身体的组织再生效率降低;这些衰老的特征可以通过调节失调的成体干细胞来解释，否则这些干细胞会维持受影响的组织。每个细胞都存在于一个所谓的“微环境”中，已知它指导细胞功能，并在衰老过程中发生变化。在这里，我们正在探索乳腺微环境和基因表达的年龄相关变化如何合谋误导乳腺干细胞产生肿瘤。

DESCRIPTION (provided by applicant): 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 ageing- related 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 demonstrated that age-related phenotypes are due to stem cell-intrinsic and -extrinsic factors, but that the delineation is 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 of the two? We are now uniquely poised to address these questions for the breast. Over several decades, 3-dimensional culture models that mimic many aspects of the 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 stem 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. RELEVANCE: As we age the risk of cancer rises and our body's tissues regenerate less efficiently; these characteristics of aging could be explained by dysregulated adult stem cells that otherwise maintain the affected tissues. Every cell resides in a so called 'microenvironment', which is known to direct cellular functions, and is known to change during the aging process. Here we are exploring how age-associated changes to the breast microenvironment and to gene expression could conspire to misdirect mammary stem cells to generate tumors.