miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors
miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors
复制标题
DOI：
10.1158/0008-5472.can-15-2038
复制
发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Morandi, Andrea
中科院分区：
文献类型：
--
作者：
Bacci, Marina;Giannoni, Elisa;Morandi, Andrea
芳香化酶抑制剂（AI）已成为绝经后雌激素受体阳性（ER+）乳腺癌患者首选的一线内分泌治疗药物，但耐药性仍然是一个主要挑战。代谢重编程是癌症的一个标志，可能有助于耐药性。在这里，我们使用AI抗性和敏感的乳腺癌细胞、患者肿瘤样本和AI敏感的人类异种移植物研究了乳腺癌代谢改变与AI抗性之间的联系。我们发现，长期雌激素剥夺（LTED） （AI耐药的一种模型）与糖酵解依赖性增加有关。以糖酵解启动酶己糖激酶2 （HK2）为靶点，与AI、来曲唑联合使用，可协同降低AI敏感模型中的细胞活力。相反，mcf7 - ltd细胞表现出高度的代谢可塑性，当糖酵解受损时，它们会切换到氧化磷酸化。这种效应依赖于内质网，因为内质网水平检测不到的乳腺癌细胞无法表现出代谢可塑性。mcf7 - ltd细胞也比亲本细胞更具运动性，并且在2-脱氧葡萄糖（2-DG）抑制糖酵解时具有变形体样的侵袭能力。机制研究进一步揭示了miR-155在代谢重编程中的重要作用。miR-155的抑制导致mcf7 - ltd细胞对二甲双胍治疗的敏化和2- dg诱导的运动性损伤。值得注意的是，在接受新辅助阿那曲唑治疗的ER+乳腺癌队列中，高基线miR-155表达与对AI治疗的不良反应相关。这些发现表明，miR-155是一种潜在的生物标志物，能够识别出最有可能适应人工智能治疗并复发的乳腺癌亚群。(c) 2016年aacr。
Aromatase inhibitors (AI) have become the first-line endocrine treatment of choice for postmenopausal estrogen receptor-positive (ER+) breast cancer patients, but resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer and may contribute to drug resistance. Here, we investigated the link between altered breast cancer metabolism and AI resistance using AI-resistant and sensitive breast cancer cells, patient tumor samples, and AI-sensitive human xenografts. We found that long-term estrogen deprivation (LTED), a model of AI resistance, was associated with increased glycolysis dependency. Targeting the glycolysis-priming enzyme hexokinase-2 (HK2) in combination with the AI, letrozole, synergistically reduced cell viability in AI-sensitive models. Conversely, MCF7-LTED cells, which displayed a high degree of metabolic plasticity, switched to oxidative phosphorylation when glycolysis was impaired. This effect was ER dependent as breast cancer cells with undetectable levels of ER failed to exhibit metabolic plasticity. MCF7-LTED cells were also more motile than their parental counterparts and assumed amoeboid-like invasive abilities upon glycolysis inhibition with 2-deoxyglucose (2-DG). Mechanistic investigations further revealed an important role for miR-155 in metabolic reprogramming. Suppression of miR-155 resulted in sensitization of MCF7-LTED cells to metformin treatment and impairment of 2-DG-induced motility. Notably, high baseline miR-155 expression correlated with poor response to AI therapy in a cohort of ER+ breast cancers treated with neoadjuvant anastrozole. These findings suggest that miR-155 represents a biomarker potentially capable of identifying the subset of breast cancers most likely to adapt to and relapse on AI therapy. (C) 2016 AACR.