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

项目摘要/摘要 肿瘤进展--包括治疗抵抗、转移和复发-- 对大多数癌症死亡负有责任。了解癌细胞如何在治疗后存活， 扩散到遥远的部位，作为休眠的残留细胞持续存在，最终复发是改善的关键 这种疾病的治疗方法。我们的长期目标是确定调控这些因素的途径 以防止或治疗肿瘤复发。 为了实现这一点，我们正在使用条件基因工程小鼠(Gem)乳房模型。 可以机械地解剖休眠和复发过程的癌症。vbl.使用 在这些模型中，我们已经确定了肿瘤抑制基因PAR-4在调节生存中的功能作用 以及治疗后乳腺癌细胞的复发。PAR-4在复发肿瘤中表达下调 三种GEM模型，这种下调对于肿瘤复发既是必要的，也是充分的。 同样，在患有乳腺癌的女性中，PAR-4的低表达与对 新辅助治疗和复发风险增加。 然而，对休眠期间调节par-4的上游通路一无所知。 和复发。此外，目前还不知道PAR-4调节什么下游通路来抑制 休眠细胞的存活和复发，或PAR-4如何影响转移。这项提案将解决这些问题 问题。在目标1中，我们将阐明癌基因抑制后par-4的调控途径。 和复发的肿瘤细胞中，并确定这些因素如何促进休眠细胞的存活和 复发。在目标2中，我们将确定受PAR-4表达调控的分子通路，并 确定这些因素是如何促进休眠细胞存活和复发的。在目标3中，我们将剖析 在休眠、复发和转移过程中PAR-4下调的时间要求。我们的 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 寻找机会开发针对休眠细胞和防止肿瘤复发的治疗方法。

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.