Age-related shifts in epithelial lineages and tissue homeostasis in mammary gland

描述（由申请人提供）：衰老与乳腺癌发病率增加的相关性是众所周知的，但了解甚少。重点放在肿瘤之间的差异作为年龄的函数，而相当少的关注，通常发生在乳腺上皮细胞在衰老过程中，这可能会促进肿瘤发生的变化。一个通常被用来解释与年龄相关的癌症的机制是突变和表观遗传变化的逐渐积累。然而，众所周知，当被正常组织结构控制时，即使是携带最强致癌基因的细胞也可以表现为表型正常。随着年龄的增长，大多数组织的功能和再生能力都会下降。我们的过度假设是，年龄相关性乳腺癌可能部分由功能丧失改变引起，例如，维持正常组织组织结构和极性的结构和建筑守门人的变化，这导致祖细胞和更分化的上皮谱系的活性的有害失衡或变化。大多数女性都过着健康的无癌生活，这表明与年龄相关的乳腺组织变化通常是良性的，但在有害的基因组变化也存在的情况下，与恶化的微环境相结合可能是灾难性的。一些与年龄相关的乳腺变化包括脂肪和雌激素受体表达增加;结缔组织、肺泡数量和整体乳腺密度减少;胶原类型表达变化以及乳腺基底膜不连续。我们只是不知道这些变化对上皮细胞生物学或腺体的结构和组织有什么影响。该提案将使用人类乳腺上皮细胞（HMEC）老化资源，其是从年龄范围为16-91岁的患者建立的正常有限寿命HMEC菌株的大集合，以进行迄今为止不可能的正常HMEC作为年龄的函数的定量和功能分析。将测量干细胞、祖细胞和更分化谱系的群体和功能特性的变化，以及HMEC形成和维持正常组织化双层结构的能力，这种能力在肿瘤发生早期丧失，受衰老过程的影响。在我们的功能分析的同时，我们将对500多个正常乳腺组织切片进行自动定量分析，以生成乳腺组织中与衰老相关的变化图谱，并确定不同HMEC谱系中体内组织的变化。我们的目标是确定大多数女性在衰老过程中发生的潜在有害变化，这些变化可能是未来预防和预防策略的目标。

DESCRIPTION (provided by applicant): The association of aging with increased incidence of breast cancer is well known, but little understood. Emphasis has been placed on differences among tumors as a function of age, while considerably less attention is given to changes that occur normally in mammary epithelium during the process of aging, which may facilitate tumorigenesis. A commonly invoked mechanism to help explain age-related cancer is the gradual accumulation of mutations and epigenetic changes. However, it is known that cells harboring even the strongest oncogenes can appear phenotypically normal when held in check by normal tissue architecture. Most tissues exhibit functional and regenerative decline with advancing age. Our over-arching hypothesis is that age-associated breast cancer may partly result from loss-of-function alterations, e.g. changes to structural and architectural gatekeepers that maintain normal tissue organization and polarity, which leads to deleterious imbalances of or changes in the activity of progenitors and more differentiated epithelial lineages. That the majority of women live healthy cancer-free lives suggests age-related changes to the breast tissue are usually benign, but in cases when deleterious genomic changes also are present the combination with deteriorating microenvironments may be catastrophic. Some age-associated changes in breast includes increased fat and estrogen receptor expression; decreased connective tissue, numbers of alveoli and overall breast density; changes in collagen-type expression, and discontinuities in the basement membrane of the mammary gland. We simply do not know what impact these changes have on epithelial cell biology or on the architecture and organization with the gland. This proposal will use the Human Mammary Epithelial Cell (HMEC) Aging Resource, which is a large collection of normal finite-life span HMEC strains that were established from patients ranging in age from 16-91, to perform heretofore impossible quantitative and functional analysis of normal HMEC as a function of age. Changes in populations and functional properties of stem, progenitor, and more differentiated lineages will be measured, as will the ability of HMEC to form and maintain a normal organized bilayered architecture, an ability that is lost early in tumorigenesis, is affected by the aging process. In parallel with our functional analysis, we will perform an automated quantitative analysis of over 500 histological sections of normal breast to generate an atlas of aging-associated changes in the breast tissue, and to identify changes in organization in vivo among the different HMEC lineages. Our goal is to identify potentially deleterious changes that occur in most women during the aging process that could be targets of future prophylactic and preventative strategies.