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.

项目摘要/摘要 肿瘤进展 - 包括对治疗，转移和复发性的抗性 - 负责大多数癌症死亡。了解癌细胞如何生存治疗， 扩散到远处的位置，持续为休眠的残留细胞，有时反复出现对于改善至关重要 这种疾病的治疗。我们的长期目标是确定规范这些规范的途径 为了预防或治疗肿瘤复发的过程。 为了实现这一目标，我们正在使用有条件的基因工程鼠标（GEM）乳房模型 癌症可以机械解剖休眠和复发过程。使用 这些模型，我们已经确定了抑制肿瘤par-4在控制存活中的功能作用 治疗后乳腺癌细胞的复发。 Par-4在复发性肿瘤中被下调 三种宝石模型，这种下调对于肿瘤复发既需要又足够。 同样，在患有乳腺癌的女性中，低4杆表达与对 新辅助治疗和复发风险增加。 但是，关于在休眠期间调节Par-4的上游途径尚无 和复发。另外，尚不知道下游途径是什么par-4调节抑制 休眠的细胞存活和复发，或者4 par-4如何影响转移。该建议将解决这些问题 问题。在AIM 1中，我们将阐明在癌基抑制后调节Par-4的途径 在复发性肿瘤细胞中，并确定这些细胞如何促进休眠细胞的存活和 复发。在AIM 2中，我们将确定由Par-4表达调节的分子途径，并确定 确定这些如何促进休眠细胞的存活和复发。在AIM 3中，我们将剖析 在休眠，复发和转移过程中PAR-4下调的临时要求。我们的 工作将洞悉肿瘤复发期间Par-4的调节和功能，可能 确定开发靶向休眠细胞并防止肿瘤复发的疗法的机会。