Menendez J A, Lupu R
Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.
Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain.
Oncogenesis. 2017 Feb 27;6(2):e299. doi: 10.1038/oncsis.2017.4.
Fatty acid synthase (FASN), the key enzyme for endogenous synthesis of fatty acids, is overexpressed and hyperactivated in a biologically aggressive subset of sex steroid-related tumors, including breast carcinomas. Using pharmacological and genetic approaches, we assessed the molecular relationship between FASN signaling and estrogen receptor alpha (ERα) signaling in breast cancer. The small compound C75, a synthetic slow-binding inhibitor of FASN activity, induced a dramatic augmentation of estradiol (E)-stimulated, ERα-driven transcription. FASN and ERα were both necessary for the synergistic activation of ERα transcriptional activity that occurred following co-exposure to C75 and E: first, knockdown of FASN expression using RNAi (RNA interference) drastically lowered (>100 fold) the amount of E required for optimal activation of ERα-mediated transcriptional activity; second, FASN blockade synergistically increased E-stimulated ERα-mediated transcriptional activity in ERα-negative breast cancer cells stably transfected with ERα, but not in ERα-negative parental cells. Non-genomic, E-regulated cross-talk between the ERα and MAPK pathways participated in these phenomena. Thus, treatment with the pure antiestrogen ICI 182 780 or the potent and specific inhibitor of MEK/ERK, U0126, was sufficient to abolish the synergistic nature of the interaction between FASN blockade and E-stimulated ERα transactivation. FASN inhibition suppressed E-stimulated breast cancer cell proliferation and anchorage-independent colony formation while promoting the reduction of ERα protein. FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21 and p27, two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E-promoted anchorage-independent growth. The ability of FASN to regulate E/ERα signaling may represent a promising strategy for anticancer treatment involving a new generation of FASN inhibitors.
脂肪酸合酶（FASN）是内源性脂肪酸合成的关键酶，在包括乳腺癌在内的性类固醇相关肿瘤的生物学侵袭性亚群中过度表达且高度活化。我们使用药理学和遗传学方法，评估了乳腺癌中FASN信号传导与雌激素受体α（ERα）信号传导之间的分子关系。小分子化合物C75是一种FASN活性的合成慢结合抑制剂，可显著增强雌二醇（E）刺激的、ERα驱动的转录。FASN和ERα对于共同暴露于C75和E后发生的ERα转录活性的协同激活都是必需的：首先，使用RNA干扰（RNAi）敲低FASN表达可大幅降低（>100倍）最佳激活ERα介导的转录活性所需的E量；其次，FASN阻断在稳定转染ERα的ERα阴性乳腺癌细胞中协同增加E刺激的ERα介导的转录活性，但在ERα阴性亲本细胞中则不然。ERα和MAPK途径之间的非基因组、E调节的串扰参与了这些现象。因此，用纯抗雌激素ICI 182 780或MEK/ERK的强效特异性抑制剂U0126处理足以消除FASN阻断与E刺激的ERα反式激活之间相互作用的协同性质。FASN抑制可抑制E刺激的乳腺癌细胞增殖和非锚定依赖性集落形成，同时促进ERα蛋白的减少。FASN阻断导致细胞周期蛋白依赖性激酶抑制剂p21和p27的表达增加和核积累，这是抗雌激素在乳腺癌中治疗作用的两个关键介质，同时使AKT失活，AKT是E促进的非锚定依赖性生长的关键介质。FASN调节E/ERα信号传导的能力可能代表了一种有前景的抗癌治疗策略，涉及新一代FASN抑制剂。
