Involution-based biomarkers of breast cancer risk

项目摘要/摘要 乳小叶是哺乳期妇女产生乳汁的结构，也是乳汁的主要来源。 乳腺癌的发源地。年龄相关性小叶退缩(LI)是一个生理过程，在这个过程中 乳腺小叶的上皮组织随着年龄的增长而逐渐退化，与消除这种需要相对应 用于产奶量超过育龄年龄。分析了我们对14,000多名患有 良性乳腺疾病(BBD)显示，LI与随后发生乳房的风险降低密切相关 因此，LI构成了预防乳腺癌的一种自然机制。然而，超过40%的人 绝经后患有BBD的妇女中，有一半没有完成LI，这些妇女面临的风险要大得多 与已经完成复旧过程的同龄女性相比，女性患乳腺癌的风险更高。在……里面 在这一应用中，我们建议进行实验来识别LI的关键效应器，并确定这些效应如何 用于改善未接受过LI的女性的乳腺癌风险评估。在目标1中，我们将定义 延迟性LI和高危细胞表型之间的联系的介体。我们将使用一种新的- 从妇女来源的极早期传代的原代人乳腺上皮细胞(HMECs)的培养板 用BBD和不同程度的LI，结合人源化的小鼠异种移植模型，其中LI HMEC的状态是明显的。在目标2中，我们将确定与正在进行的LI和延迟的LI相关的调解人 新定义的围绝经期和绝经后妇女多发、序贯良性疾病的临床队列 可以做活组织检查。在目标3中，目标1和目标2中发现的生物标记物(加上其他有希望的生物标记物)将 在一组绝经后妇女的患者队列中，评估其与随后的乳腺癌的相关性。 AIMS 2和AIMS 3中询问的队列都将从Mayo Clinic BBD队列中抽取，即 主要由白人/高加索女性组成，底特律BBD队列由 黑人/非裔美国女性，这将使我们能够在分析中将种族作为一个生物变量进行评估。通过 提供对控制LI的过程的洞察，并通过开发易于处理的实验模型来 评估调制这些过程的效果，我们的工作将提供更好的理解LI延迟 以及它与乳腺癌的联系，并将指出在这一过程中诱导女性发生LI的方法 停滞或延迟，作为一种从生理上衍生的预防乳腺癌的方法。

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.