Analysis of the cellular and molecular determinants of the human breast hierarchy

描述（由申请人提供）：人乳腺祖细胞的鉴定和了解其调节对于列举控制病理状况的起源和事件至关重要。确定正常原始细胞的身份和活性可以更好地理解干细胞生物学和癌症之间的联系。我们的研究旨在了解人类乳腺发育的机制和原始祖细胞通过乳腺生长因子信号传导的调节。对人类乳腺发育和干细胞生物学的有限理解在很大程度上是由于缺乏适当的模型系统和检测，分析和表征干细胞特性的测定。近年来，我们的实验室已经开发并优化了各种体内和体外工具来研究人类乳房发育的生物学和机制。我们已经开创并实施了使用创新的体内模型来研究人类乳房发育，其通过利用免疫受损小鼠的小鼠乳房脂肪垫作为重要的内分泌信号传导事件的来源，并使用移植的人类基质来支持生长，人乳腺上皮的分化。在最近的工作中，我们已经确定了i）四个可区分的上皮分化状态（ii）在人乳腺组织内存在基于CD 24、EpCAM和CD 49 f表达而不同的两种管腔表型和两种基底表型，（导管和小叶/肺泡），iii）增强人上皮细胞内的干细胞/祖细胞活性的激素组合，和iv）通过TBX 3表达的激素生长因子机制可以调节乳腺干细胞样细胞。在本项目的目标1中，我们将描绘成人乳腺组织中的上皮层次结构。在目标2中，我们将确定乳腺生长因子信号传导如何调节人乳腺祖细胞活性。我们的研究为人类乳腺祖细胞的身份提供了创新性的见解，并提供了关键的分子基础，通过这些分子基础，激素驱动人类乳腺祖细胞的形态发生，可以在病理条件的发展过程中作为焦点。

DESCRIPTION (provided by applicant): The identification of human mammary progenitor cells and understanding their regulation is critical to enumerating the origins and events that control pathologic conditions. Determining the identity and activity of normal primitive cells could lead t a better understanding to the connection between stem cell biology and cancer. Our study is directed towards understanding the mechanisms that underlie human breast development and the regulation of primitive progenitor cells by hormone-growth factor signaling. The limited understanding of human breast development and stem cell biology has largely been due to the lack of appropriate model systems and assays to detect, analyze, and characterize stem cell properties. In recent years, our laboratory has developed and optimized various in vivo and in vitro tools to study the biology and mechanisms governing human breast development We have pioneered and implemented the use of an innovative in vivo model to study human mammary development by exploiting the mouse mammary fat pad of immunocompromised mice as a source of important endocrine signaling events and using grafted human stroma to support the growth and differentiation of the human mammary epithelium. In recent work, we have identified i) four distinguishable epithelial differentiation states (two luminal phenotypes and two basal phenotypes) within human breast tissues that differ on the basis of CD24, EpCAM and CD49f expression, ii) the existence of bipotent progenitors that contribute to structurally distinct elements (ducts and lobule/alveoli), iii) the hormonal combinations that enhance stem/progenitor cell activity within human epithelial cells, and iv) a hormone growth factor mechanism through TBX3 expression can regulate breast stem-like cells. In Aim 1 of this project, we will delineate the epithelial hierarchy in adult human breast tissue. In Aim 2, we will determine how hormone-growth factor signaling regulates human breast progenitor cell activity. Our studies provide innovative insight into the identity of human breast progenitor cells and provide critical molecula underpinnings by which hormones drive human breast progenitor cell morphogenesis that could serve as focal points during the development of pathological conditions.