The role of microenvironment in aging-related phenotypes of breast

55岁以上女性乳腺癌发病率呈指数增长的潜在机制 年龄不太了解。建立假说的一个有用的概念框架是， 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， 与干细胞有关。一些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，但这种描述似乎 组织特异性。Bissell实验室和其他人已经表明，乳腺微环境是 上皮肿瘤细胞的突变对于乳腺癌的发展同样重要。在一些 在某些情况下，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，微环境是否改变从而催化肿瘤发生？损坏或老化 乳腺干细胞停止倾听或误解来自其微环境的调节信号？还是 密码？我们现在正准备为乳房解决这些问题。在几 几十年来，三维培养模型，模拟了人类乳腺和乳房的许多方面， 癌症微环境是在Bissell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所起的作用。我们使用这些模型 与原代人乳腺祖细胞一起，以证明微环境可以 决定乳腺祖细胞的命运。在这里，我们建议将这些资产联合收割机，以解决 以下具体目标：（1）确定微环境导向的年龄依赖性功能反应 乳腺祖细胞调节，以及它们背后的遗传电路。(2)以确定是否 乳腺癌特征性突变赋予正常乳腺祖细胞肿瘤形成潜能，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中与年龄相关的差异的治疗策略 使用生理学相关的3D器官型测定法进行行为分析。

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.