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

乳腺上皮谱系和组织稳态的年龄相关变化

基本信息

批准号：
8163181
负责人：
Mark A LaBarge
金额：
$ 40.31万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8163181
关键词：
Affect Age Aging Aging-Related Process Algorithms Alveolus Architecture Atlases Attention Basement membrane Benign Biological Biomedical Engineering Breast Breast Cancer Risk Factor Cell Aging Cell Culture Techniques Cell Lineage Cells Cellular biology Collagen Collection Connective Tissue Data Elderly Employee Strikes Epigenetic Process Epithelial Epithelial Cells Epithelium Estrogen Receptors Exhibits Fatty acid glycerol esters Future Gatekeeping Gene Mutation Genomics Gland Goals Histology Homeostasis Human Image Image Analysis In Vitro Incidence Individual Knowledge Laboratories Lasers Libraries Life Longevity Malignant Neoplasms Mammary Gland Parenchyma Mammary gland Measures Microdissection Microscopy Modeling Molecular Molecular Profiling Mutation Myoepithelial Myoepithelial cell Normal tissue morphology Oncogenes Organoids Pancreas Patients Phenotype Population Predisposition Property Prostate Research Resources Sampling Specimen Telomerase Time Tissues Tumor Bank Woman age related aged breast density cell age design in vivo loss of function malignant breast neoplasm malignant state mammary epithelium normal aging novel progenitor prophylactic receptor expression regenerative self organization stem telomere trait tumor tumorigenesis

项目摘要

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. PUBLIC HEALTH RELEVANCE: It has been known for decades that aging is one of the principle risk factors for breast cancer, yet the impact of the normal aging process on function and architecture of normal breast epithelium is not well characterized. This proposal uses unique biological and technological assets that were developed at the Lawrence Berkeley National Laboratory to generate a previously unrealizable atlas of functional and architectural changes that occur during the process of aging. We will identify normal age-associated changes that may create a predisposition towards malignant states when combined with additional genetic mutations, with a goal of informing future prophylactic or preventative strategies.