Par-4 Regulation and Function in Breast Cancer Dormancy and Recurrence

Par-4 在乳腺癌休眠和复发中的调节和功能

• 批准号: 10459140
• 负责人: James V Alvarez
• 金额: $ 6.12万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459140
• 关键词: Par; Regulation; Function; Breast; Cancer

Project Summary/Abstract Tumor progression – including resistance to therapy, metastasis, and recurrence – is responsible for the majority of cancer deaths. Understanding how cancer cells survive treatment, spread to distant sites, persist as dormant residual cells, and eventually recur is essential to improving the treatment of this disease. Our long-term goal is to identify the pathways that regulate these processes in order to prevent or treat tumor recurrence. To achieve this we are using conditional genetically engineered mouse (GEM) models of breast cancer that allow for the mechanistic dissection of the processes of dormancy and recurrence. Using these models, we have identified a functional role for the tumor suppressor par-4 in regulating survival and recurrence of breast cancer cells after therapy. Par-4 is down-regulated in recurrent tumors from three GEM models, and this down-regulation is both necessary and sufficient for tumor recurrence. Similarly, in women with breast cancer, low par-4 expression is associated with a poor response to neoadjuvant therapy and an increased risk of recurrence. However, nothing is known about the upstream pathways that regulate par-4 during dormancy and recurrence. In addition, it is not known what downstream pathways par-4 regulates to inhibit dormant cell survival and recurrence, or how par-4 affects metastasis. This proposal will address these questions. In Aim 1, we will elucidate the pathways that regulate par-4 following oncogene inhibition and in recurrent tumor cells, and determine how these contribute to dormant cell survival and recurrence. In Aim 2, we will identify the molecular pathways regulated by par-4 expression, and determine how these contribute to dormant cell survival and recurrence. In Aim 3, we will dissect the temporal requirements for par-4 down-regulation during dormancy, recurrence, and metastasis. Our work will provide insight into the regulation and function of par-4 during tumor recurrence and may identify opportunities to develop therapies that target dormant cells and prevent tumor recurrence.

项目概要/摘要 肿瘤进展——包括对治疗的抵抗、转移和复发——是 了解癌细胞如何在治疗中存活下来，是导致大多数癌症死亡的原因。 扩散到远处，作为休眠残留细胞持续存在，并最终复发，这对于改善病情至关重要 我们的长期目标是找出调节这些疾病的途径。 过程以预防或治疗肿瘤复发。 为了实现这一目标，我们使用条件性基因工程小鼠 (GEM) 乳房模型 允许对休眠和复发过程进行机械解剖的癌症。 在这些模型中，我们已经确定了肿瘤抑制因子 par-4 在调节生存中的功能作用 治疗后乳腺癌细胞的复发率在复发性肿瘤中 Par-4 下调。 三种 GEM 模型，这种下调对于肿瘤复发来说既是必要的也是充分的。 同样，在患有乳腺癌的女性中，par-4 表达低与对乳腺癌的反应较差相关。 新辅助治疗和复发风险增加。 然而，我们对休眠期间调节 par-4 的上游途径一无所知 此外，尚不清楚 par-4 调节哪些下游途径来抑制。 休眠细胞存活和复发，或 par-4 如何影响转移该提案将解决这些问题。 在目标 1 中，我们将阐明癌基因抑制后调节 par-4 的途径。 以及复发性肿瘤细胞，并确定它们如何促进休眠细胞存活和 在目标 2 中，我们将确定 par-4 表达调控的分子途径，以及 确定它们如何促进休眠细胞的存活和复发。在目标 3 中，我们将剖析 休眠、复发和转移期间 par-4 下调的时间要求。 这项工作将深入了解 par-4 在肿瘤复发过程中的调节和功能，并可能 寻找开发针对休眠细胞并预防肿瘤复发的疗法的机会。