The role of AMPK and CD36 in breast cancer tumorigenesis and metastasis

AMPK和CD36在乳腺癌肿瘤发生和转移中的作用

• 批准号: 10377328
• 负责人: Nissim Hay
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377328
• 关键词: Acetyl-CoA Carboxylase; Address; Antioxidants; Applications Grants; Atherosclerosis; Attenuated; Blood Circulation; Brain; Breast Cancer Cell; Breast Cancer Risk Factor; Breast Cancer cell line; Breast cancer metastasis; CD36 gene; Cancer Patient; Cause of Death; Cell Death; Cell Survival; Cell membrane; Cells; Consumption; Data; Development; Disease; Distant; Doxycycline; Extravasation; Fatty Acids; Glucose; Homeostasis; Human; Impairment; Implant; In Vitro; Knock-out; Knockout Mice; Lead; MDA MB 231; Malignant Neoplasms; Mammary gland; Mediating; Metabolic; Metabolism; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Metastatic to; Morbidity - disease rate; Mouse Mammary Tumor Virus; Mus; NADP; Neoplasm Circulating Cells; Neoplasm Metastasis; Organ; Outcome; Pathway interactions; Pentosephosphate Pathway; Pharmacotherapy; Phosphorylation; Phosphorylation Inhibition; Population; Primary Neoplasm; Process; Publications; Reactive Oxygen Species; Rest; Role; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Therapeutic; Time; Tissues; Transplantation; Tumor stage; Tumorigenicity; Veterans; Woman; bone; cancer cell; cancer type; combat; fatty acid oxidation; glucose uptake; high risk; in vivo; inhibitor; long chain fatty acid; malignant breast neoplasm; military women; mortality; mouse model; neoplastic cell; obese patients; targeted cancer therapy; translational impact; translocase; tumor; tumor initiation; tumorigenesis; tumorigenic

Breast cancer is the most frequently occurring cancer in women. Military women are at increased risk of breast cancer. The mortality and morbidity from breast cancer is due to its metastatic spread. The role of AMPK in tumorigenesis is controversial. Although AMPK inhibition was implicated in promoting tumorigenesis, we showed, several years ago, that AMPK activation is required for tumor cells survival during solid tumor formation. In recent years this assertion was independently corroborated by others in various types of cancer. In this grant application we propose that AMPK and its downstream effector the fatty acid translocase, CD36, are required for breast cancer metastasis. It is known that high ROS levels in disseminating cells is an impediment for metastasis and therefore the metabolic rewiring of key signaling pathways is critical to confer enhanced antioxidant metabolism to overcome this hurdle. Combating high ROS levels during metastatic colonization requires increased glucose uptake and utilization. We propose that the excess of ROS levels in disseminating breast cancer cells is a consequence of impaired glucose uptake and utilization. This impairment inhibits the oxidative pentose phosphate pathway (oxPPP) that generates NADPH to combat ROS. The limited glucose utilization during dissemination also leads to the activation of AMPK. By inhibiting fatty acid synthesis (FAS) and by elevating fatty acid oxidation (FAO), AMPK could maintain intracellular NADPH levels to combat ROS even when glucose utilization is impaired. In the first part of this grant application we will delineate the mechanism by which AMPK activation is required for breast cancer metastasis. In the second part of the grant application we will determine if the fatty acid translocase, CD36, is required for tumorigenesis and metastasis mediated by AMPK activation, and whether CD36 could be systemically targeted to inhibit breast cancer metastasis. We will use human breast cancer cell lines and PDOs and orthotopic transplantation as well as a mouse models for breast cancer metastasis in these studies. The proposed studies have a translational impact as they will determine whether drug therapy that activates AMPK directly or indirectly could have worse outcomes with respect to breast cancer metastasis, and whether targeting CD36 could inhibit breast cancer metastasis particularly in obese patients.

乳腺癌是女性中最常见的癌症。军事妇女的风险增加 乳腺癌。乳腺癌的死亡率和发病率是由于其转移性扩散所致。的作用 肿瘤发生中的AMPK是有争议的。尽管AMPK抑制与促进有关 几年前，我们表明肿瘤发生的AMPK活化是肿瘤细胞存活所必需的 在实体瘤形成期间。近年来，这种断言得到了其他人的独立证实 各种类型的癌症。在此赠款应用中，我们建议AMPK及其下游效应器 乳腺癌转移需要脂肪酸易位酶CD36。众所周知，高ROS水平 在传播细胞中，是转移的障碍，因此是钥匙的代谢重新布线 信号通路对于赋予增强的抗氧化代谢以克服这一障碍至关重要。 在转移性定植期间对抗高ROS水平需要增加葡萄糖摄取和 利用率。我们建议在传播乳腺癌细胞中的ROS水平过高是 葡萄糖摄取和利用受损的结果。这种障碍抑制了氧化五颗 磷酸盐途径（OXPPP）产生NADPH以对抗ROS。有限的葡萄糖利用 在传播过程中，还导致AMPK的激活。通过抑制脂肪酸合成（FAS）和 抬高脂肪酸氧化（FAO），AMPK可以维持细胞内NADPH水平以对抗ROS 即使葡萄糖利用受损。在本赠款申请的第一部分中，我们将划定 乳腺癌转移需要AMPK激活的机制。在第二部分 授予应用我们将确定脂肪酸易位酶CD36是否需要进行肿瘤发生和 由AMPK激活介导的转移，以及是否可以系统地靶向CD36 乳腺癌转移。我们将使用人类乳腺癌细胞系，PDOS和原位 在这些研究中，移植以及乳腺癌转移的小鼠模型。提议 研究具有翻译影响，因为他们将确定激活AMPK的药物治疗是否 直接或间接的乳腺癌转移可能会有更糟糕的预后，以及是否是否 靶向CD36可以抑制乳腺癌转移，尤其是在肥胖患者中。