Involution-based biomarkers of breast cancer risk

项目概要/摘要 乳腺小叶是哺乳期妇女产生乳汁的结构，也是哺乳期妇女的主要乳腺结构。 乳腺癌的起源部位。心脏病相关的小叶退化（LI）是一个生理过程， 乳腺小叶的上皮组织随着年龄的增长而逐渐退化，与消除需要相对应。 在生育年龄之后的牛奶生产。我们对14，000多名女性的队列分析， 良性乳腺疾病（BBD）显示LI与随后乳腺癌风险降低密切相关， 因此，LI构成了预防乳腺癌的天然机制。然而，超过40%的 的绝经后BBD女性未完成LI，这些女性的风险明显更高， 与已经完成退化过程的同龄女性相比，患乳腺癌的风险更低。在 在此应用中，我们提出了实验来确定LI的关键效应器，并确定这些效应器如何被 用于改善未接受LI的女性的乳腺癌风险评估。在目标1中，我们定义 延迟LI与高风险细胞表型之间联系的介导物。我们将使用新的- 产生了一组来源于女性的极早代原代人乳腺上皮细胞（HMEC） 与人源化小鼠异种移植模型组合，其中LI HMEC的状态很明显在目标2中，我们将确定与进行性LI和延迟性LI相关的介质， 一个新定义的绝经期和绝经后女性的临床队列， 活组织检查可用。在目标3中，目标1和2中发现的生物标志物（加上其他有希望的生物标志物）将 评估绝经后妇女患者队列中与随后乳腺癌的相关性。 目标2和3中询问的队列将从马约诊所BBD队列中抽取， 主要由白色/高加索女性组成，底特律BBD队列由 黑人/非洲裔美国妇女，这将使我们能够评估种族作为一个生物变量在我们的分析。通过 提供控制LI的过程的洞察力，并通过开发易于处理的实验模型， 评估调节这些过程的影响，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LI的方法。 停滞或延迟，作为预防乳腺癌的生理衍生方法。

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.