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关系是众所周知的，但知之甚少。重点放在肿瘤之间的差异作为年龄的功能上，而在衰老过程中正常发生在乳腺上皮中的变化，这可能促进肿瘤的发生，却很少受到关注。一种常用的解释与年龄有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，即使是携带最强致癌基因的细胞，在正常组织结构的控制下也会表现出正常的表型。随着年龄的增长，大多数组织表现出功能和再生能力的下降。我们的首要假设是，与年龄相关的乳腺癌可能部分源于功能改变的丧失，例如，维持正常组织组织和极性的结构和建筑看门人的改变，这导致祖细胞和更分化的上皮谱系活动的有害失衡或改变。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，这种变化与微环境恶化的结合可能是灾难性的。一些与年龄相关的乳房变化包括脂肪和雌激素受体表达增加；结缔组织、肺泡数量和乳腺总密度减少；胶原型表达的改变和乳腺基底膜的不连续性。我们根本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，这是一个从16-91岁的患者中建立的正常有限寿命HMEC菌株的大量集合，对正常HMEC作为年龄函数进行迄今为止不可能的定量和功能分析。将测量干细胞、祖细胞和更多分化谱系的种群和功能特性的变化，以及HMEC形成和维持正常有组织的双层结构的能力，这种能力在肿瘤发生早期失去，受到衰老过程的影响。在进行功能分析的同时，我们将对超过500个正常乳房的组织学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谱系在体内的组织变化。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，这些变化可能成为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.