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

乳腺癌是女性最常见的癌症。女军人患癌症的风险增加 乳腺癌。乳腺癌的死亡率和发病率是由于其转移扩散造成的。的作用 AMPK在肿瘤发生中的作用存在争议。尽管AMPK抑制在促进 几年前，我们发现AMPK的激活是肿瘤细胞生存所必需的 在实体瘤形成过程中。近年来，这一断言得到了其他人的独立证实 各种类型的癌症。在这项授权申请中，我们建议AMPK及其下游效应器 脂肪酸转移酶CD36是乳腺癌转移所必需的。众所周知，高水平的ROS 细胞的扩散是转移的障碍，因此关键的代谢重排 信号通路对于增强抗氧化剂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。我们认为在乳腺癌细胞扩散过程中ROS水平过高是一种 葡萄糖摄取和利用受损的后果。这种损伤抑制了氧化戊糖。 产生NADPH以对抗ROS的磷酸途径(OxPPP)。有限的葡萄糖利用 在传播过程中也导致AMPK的激活。通过抑制脂肪酸合成(FAS)和通过 升高脂肪酸氧化(FAO)，AMPK可维持细胞内NADPH水平以对抗ROS 即使葡萄糖的利用受到损害。在这项拨款申请的第一部分，我们将描述 乳腺癌转移需要激活AMPK的机制。在第二部分中， 批准申请我们将确定脂肪酸转位酶CD36是否在肿瘤发生和发展中所必需 AMPK激活介导的肿瘤转移及CD36能否被系统靶向抑制 乳腺癌转移。我们将使用人类乳腺癌细胞株和PDO和原位移植 移植以及小鼠乳腺癌转移模型的这些研究。建议数 研究具有翻译影响，因为它们将确定激活AMPK的药物疗法 在乳腺癌转移方面，直接或间接可能会有更糟糕的结果，以及 靶向CD36可以抑制乳腺癌的转移，特别是在肥胖患者。

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.