The role of microenvironment in aging-related phenotypes of breast

55岁女性乳腺癌发病率成倍增加的机制 人们对年龄知之甚少。建立假设的一个有用的概念框架是与年龄相关的 表型的病因学根源是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，都是 与干细胞有关。一些研究干细胞随年龄变化的报告表明， 与年龄相关的表型可能是由于干细胞的内在或外在因素，但这种描绘似乎 是特定于组织的。比塞尔实验室和其他实验室已经表明，乳房微环境是 上皮性肿瘤细胞的突变对乳腺癌的发展同样重要。在许多情况下 甚至有研究表明，微环境可以支配强致癌基因。在 乳房老化，微环境是否会改变，从而催化肿瘤的发生？是否损坏或老化？ 乳腺干细胞不再倾听或曲解来自其微环境的调控信号？还是因为它 一种组合？我们现在正准备独一无二地为乳房解决这些问题。超过几个 几十年来，模仿人类乳腺和乳房许多方面的三维培养模型 癌症微环境是在比塞尔实验室开发的。最近，我们还开发了一种 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所发挥的作用。我们已经使用了这些模型 与原代人类乳房祖细胞一起证明微环境可以 主宰乳腺祖细胞命运的决定。在这里，我们建议合并这些资产，以解决 具体目标如下：(1)识别微环境导向的年龄相关的功能反应 乳腺前体细胞的调控，以及作为其基础的遗传回路。(2)确定是否 乳腺癌特有的突变赋予正常的乳腺祖细胞形成肿瘤的潜力，或者 以与年龄相关的方式改变他们对乳房微环境的反应频谱。(3)设计和实施 测试基于年龄相关的乳腺微环境和干细胞差异的治疗策略 使用生理上相关的3D器官类型分析的行为。

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.