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Involution-based biomarkers of breast cancer risk

基于复合的乳腺癌风险生物标志物

基本信息

批准号：
9886777
负责人：
Amy C Degnim
金额：
$ 55.48万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9886777
关键词：
Abbreviations Address Affect African American Age Aging Benign Biological Biological Markers Biopsy Breast Breast Cancer Prevention Breast Cancer Risk Factor Breast Diseases Breast Epithelial Cells Breast biopsy Caucasians Cells Clinic Clinical Control Groups Cytometry Data Development Diagnosis Epithelial Epithelial Cells Epithelium Evaluation Experimental Models Future Goals Human Immunohistochemistry Incidence Investigation Knowledge Lactation Link Lobular Lobule Malignant Neoplasms Mammary Gland Parenchyma Mediator of activation protein Menopause Methods Modeling Molecular Myoepithelial cell Pathway interactions Patients Perimenopause Phenotype Physiological Physiological Processes Population Population Heterogeneity Postmenopause Prevention Process Publishing Race Research Research Design Risk Risk Assessment Risk Management Signal Pathway Site Source Structure Testing Time Tissue Sample WNT Signaling Pathway Woman Work Xenograft Model age related base benign state cancer risk case control child bearing cohort experimental study high risk human disease humanized mouse improved innovation insight malignant breast neoplasm mammary epithelium milk production mouse model nano-string novel periostin predictive marker surveillance strategy

项目摘要

PROJECT SUMMARY/ABSTRACT The breast lobules are the structures that produce milk in lactating women, and are also the primary site of origin for breast cancer. Age-related lobular involution (LI) is a physiological process in which the epithelial tissue of the breast lobules gradually regresses with age, corresponding with elimination of the need for milk production beyond the child-bearing years. Analysis of our cohort of more than 14,000 women with benign breast disease (BBD) revealed that LI is strongly associated with reduced risk of subsequent breast cancer, and thus LI constitutes a natural mechanism for prevention of breast cancer. However, more than 40% of postmenopausal women with BBD have not completed LI, and these women are at substantially greater risk of developing breast cancer compared to women of similar age whose involution process has completed. In this application, we propose experiments to identify critical effectors of LI and to determine how these can be used to improve breast cancer risk assessment for women who have not undergone LI. In Aim 1, we will define the mediators that underlie the link between delayed LI and a high risk cellular phenotype. We will use a newly- generated panel of very early passage primary human mammary epithelial cells (HMECs) derived from women with BBD and varying degrees of LI, in combination with humanized mouse xenograft models in which the LI status of the HMECs is manifest. In Aim 2, we will identify mediators associated with ongoing vs delayed LI in a newly-defined clinical cohort of peri- and post-menopausal women for whom multiple, sequential benign biopsies are available. In Aim 3, biomarkers discovered in Aims 1 and 2 (plus other promising biomarkers) will be evaluated for association with subsequent breast cancer in a patient cohort of postmenopausal women. The cohorts interrogated in Aims 2 and 3 will be drawn both from the Mayo Clinic BBD cohort, which is primarily composed of White/Caucasian women, and the Detroit BBD cohort, which is composed of Black/African-American women, which will allow us to evaluate race as a biological variable in our analyses. By providing insight into the processes that control LI and by developing tractable experimental models in which to evaluate the effects of modulating those processes, our work will provide a better understanding of LI delay and its link to breast cancer and will point toward methods for inducing LI in women for whom this process is stalled or delayed, as a physiologically-derived method for breast cancer prevention.

项目概要/摘要乳腺小叶是哺乳期妇女产生乳汁的结构，也是主要的泌乳结构。乳腺癌的起源部位。与年龄相关的小叶退化（LI）是一个生理过程，其中乳腺小叶的上皮组织随着年龄的增长而逐渐退化，与需要的消除相对应育龄期后的产奶量。对超过 14,000 名女性的队列分析良性乳腺疾病 (BBD) 表明 LI 与降低随后发生乳腺疾病的风险密切相关癌症，因此 LI 构成了预防乳腺癌的天然机制。然而，超过40% 患有 BBD 的绝经后女性尚未完成 LI，这些女性面临的风险要大得多与已完成消退过程的同龄女性相比，患乳腺癌的几率。在在此应用中，我们提出了实验来识别 LI 的关键效应器并确定如何将这些效应器用于改善未接受 LI 的女性患乳腺癌的风险评估。在目标 1 中，我们将定义延迟性 LI 与高风险细胞表型之间联系的中介因子。我们将使用一个新的—— 生成源自女性的极早期传代原代人乳腺上皮细胞 (HMEC) 组具有 BBD 和不同程度的 LI，与人源化小鼠异种移植模型相结合，其中 LI HMEC 的地位显而易见。在目标 2 中，我们将确定与持续性 LI 和延迟性 LI 相关的中介因素。新定义的围绝经期和绝经后妇女临床队列，这些妇女患有多发性连续良性病变可以进行活检。在目标 3 中，目标 1 和 2 中发现的生物标志物（以及其他有前途的生物标志物）将在绝经后妇女患者队列中评估其与后续乳腺癌的关联。目标 2 和 3 中询问的队列均来自 Mayo Clinic BBD 队列，该队列是主要由白人/高加索女性组成，底特律 BBD 群体由黑人/非裔美国女性，这将使我们能够在分析中将种族作为生物变量进行评估。经过深入了解控制 LI 的过程，并开发易于处理的实验模型评估调节这些过程的效果，我们的工作将提供对 LI 延迟的更好理解及其与乳腺癌的联系，并将指出在女性中诱导 LI 的方法，该过程适用于女性停止或延迟，作为预防乳腺癌的生理学方法。