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: 10602886
• 负责人: James V Alvarez
• 金额: $ 1.79万
• 依托单位: FRED HUTCHINSON CANCER 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602886
• 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.

项目总结/摘要 肿瘤进展-包括对治疗的抵抗、转移和复发-是 导致了大多数癌症死亡。了解癌细胞如何在治疗后存活， 扩散到遥远的地方，作为休眠的残留细胞持续存在，最终复发对改善 这种疾病的治疗。我们的长期目标是确定调节这些的途径 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）模型， 允许休眠和复发过程的机械解剖的癌症。使用 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。 以及治疗后乳腺癌细胞的复发。Par-4在复发性肿瘤中下调， 三个GEM模型，这种下调对于肿瘤复发是必要的和充分的。 同样，在乳腺癌女性中，par-4低表达与对化疗的不良反应有关。 新辅助治疗和复发风险增加。 然而，对于在休眠期间调节PAR-4的上游途径，我们一无所知 和复发。此外，目前还不知道par-4调节抑制的下游途径是什么 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。 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 和复发性肿瘤细胞，并确定这些如何有助于休眠细胞的存活， 复发在目标2中，我们将确定par-4表达调控的分子途径， 确定这些如何有助于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。我们 这项工作将提供对肿瘤复发过程中PAR-4的调节和功能的深入了解， 确定开发针对休眠细胞和预防肿瘤复发的疗法的机会。

项目成果

Adaptation and selection shape clonal evolution of tumors during residual disease and recurrence.

• DOI: 10.1038/s41467-020-18730-z
• 发表时间: 2020-10-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Walens A;Lin J;Damrauer JS;McKinney B;Lupo R;Newcomb R;Fox DB;Mabe NW;Gresham J;Sheng Z;Sibley AB;De Buysscher T;Kelkar H;Mieczkowski PA;Owzar K;Alvarez JV
• 通讯作者: Alvarez JV

CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors.

CCL5 通过在残余肿瘤中募集巨噬细胞促进乳腺癌复发。

• DOI: 10.7554/elife.43653
• 发表时间: 2019
• 期刊: eLife
• 影响因子: 7.7
• 作者: Walens,Andrea;DiMarco,AshleyV;Lupo,Ryan;Kroger,BenjaminR;Damrauer,JeffreyS;Alvarez,JamesV
• 通讯作者: Alvarez,JamesV