Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
Department of Microbiology & Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
Clin Cancer Res. 2020 Jul 15;26(14):3707-3719. doi: 10.1158/1078-0432.CCR-20-0269. Epub 2020 Apr 22.
Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies.
Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy.
Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the antidiabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival.
AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER breast cancer.
尽管针对雌激素受体α（ER）阳性乳腺癌患者进行了辅助内分泌治疗，但休眠性残留疾病仍可能持续多年，最终导致肿瘤复发。我们试图推断出休眠癌细胞持续存在的机制，以确定治疗策略。
为了模拟用于治疗患者的芳香酶抑制剂诱导的雌激素水平耗竭，我们在小鼠中建立了由雌激素剥夺诱导的 ER 乳腺癌休眠的临床前模型。我们分析了肿瘤异种移植物和培养的癌细胞对雌激素剥夺和药物治疗的分子和细胞反应。分析了公开的临床乳腺癌肿瘤基因表达数据集，以评估对新辅助内分泌治疗的反应。
休眠的乳腺癌细胞表现出上调的 5' 腺苷一磷酸激活蛋白激酶（AMPK）水平和活性，以及上调的脂肪酸氧化。虽然抗糖尿病 AMPK 激活药物二甲双胍可减缓雌激素驱动的细胞和肿瘤生长，但二甲双胍通过脂肪酸氧化驱动的线粒体呼吸增加促进了雌激素剥夺细胞和肿瘤的持续存在。AMPK 的药理学或遗传学抑制或脂肪酸氧化促进了休眠性残留疾病的清除，而饮食中的脂肪增加了肿瘤细胞的存活。
AMPK 在癌症中有上下文相关的作用，这告诫我们不要在疾病环境中广泛使用 AMPK 激活剂。针对 ER 乳腺癌中的脂肪代谢开发治疗方法是合理的。
