The role of microenvironment in aging-related phenotypes of breast

描述(由申请人提供)：55岁女性乳腺癌发病率呈指数级增长的机制尚不清楚。建立假设的一个有用的概念框架是，与衰老相关的表型在病因学上植根于组织特异性干细胞的变化或它们的调节。事实上，常见的与衰老相关的表型，即癌症和组织再生缺陷，都与干细胞有关。许多研究干细胞与年龄的关系的报告表明，与年龄相关的表型是由于干细胞的内在和外在因素，但这种描绘是组织特有的。比塞尔实验室和其他实验室已经表明，乳腺微环境和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，甚至已经证明微环境可以支配强致癌基因。在衰老的乳房中，微环境是否发生了变化，从而催化了肿瘤的发生？受损或老化的乳腺干细胞是否会停止倾听或曲解来自其微环境的调控信号？还是两者兼而有之？我们现在正准备独一无二地为乳房解决这些问题。在几十年的时间里，比塞尔实验室开发出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起的功能作用。我们将这些模型与原代人类乳房祖细胞一起用来证明微环境可以决定乳房干细胞的命运。在这里，我们建议结合这些资源来解决以下具体目标：(1)确定微环境导向的乳腺前体细胞调控中年龄相关的功能反应，以及它们背后的遗传回路。(2)确定乳腺癌特有的突变是否使正常乳腺祖细胞具有致瘤潜能，或使其对乳腺微环境的反应谱随年龄而改变。(3)根据乳腺微环境和干细胞行为的年龄差异，利用生理相关的3D器官类型分析，设计和测试治疗策略。 相关性：随着我们年龄的增长，患癌症的风险增加，我们身体组织的再生效率降低；这些衰老的特征可以通过调节失调的成人干细胞来解释，否则这些干细胞就会维持受影响的组织。每个细胞都生活在一个所谓的“微环境”中，这是已知的指导细胞功能的微环境，并且在衰老过程中会发生变化。在这里，我们正在探索与年龄相关的乳房微环境和基因表达的变化如何共同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.