Fatty acid synthase activity regulates HER2 extracellular domain shedding into the circulation of HER2-positive metastatic breast cancer patients
Fatty acid synthase activity regulates HER2 extracellular domain shedding into the circulation of HER2-positive metastatic breast cancer patients
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DOI：
10.3892/ijo_00000455
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发表时间：
2009-12-01
影响因子：
5.2
通讯作者：
Menendez, Javier A.
中科院分区：
文献类型：
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作者：
Vazquez-Martin, Alejandro;Manuel Fernandez-Real, Jose;Menendez, Javier A.
HER2癌基因和肿瘤相关脂肪酸合成酶（FASN）之间功能关系的临床病理评估在很大程度上被排除，因为免疫组织化学和/或mRNA研究应该在乳腺癌患者的活检中进行。我们在此试图确定血清FASN （sFASN）是否与转移性乳腺癌（MBC）患者血液中循环HER2细胞外结构域（HER2 ECD）相关。采用ELISA法对201例转移性乳腺癌患者和31例健康人的血清中FASN和HER2 ECD浓度进行了回顾性测定。机械体外研究使用HER2和FASN的药理学抑制剂，以及培养过表达HER2和FASN人类基因的癌细胞。当将正常sFASN上限定义为对照组的平均值+ 2SD时，70例MBC患者（35%）的sFASN高于该临界值（12 ng/ml）。89例MBC患者（44%）HER2 ECD水平升高（HER2 ECD临界值= 15 ng/ml）。与HER2 ecd阴性的MBC患者相比，HER2 ecd阳性的MBC患者sFASN水平略有升高。与sfasn阴性MBC患者相比，sfasn阳性MBC患者的HER2 ECD水平显著升高（平均HER2 ECD=34 ng/ml， 95% CI分别为26-41 ng/ml和18 ng/ml -95% CI为15-21 ng/ml， p=0.002）。60%的sfasn阳性患者同时表现出高水平的HER2 ECD，而64%的sfasn阴性患者循环HER2 ECD呈阴性。体外研究显示，携带HER2基因扩增的BC细胞比HER2阴性的BC细胞释放更高水平的细胞外FASN。曲妥珠单抗诱导的HER2 ECD脱落阻断未能阻止FASN释放，逆转录病毒诱导的MCF-7细胞中HER2过表达并未增加细胞外FASN。值得注意的是，药物抑制FASN活性显著降低了HER2过表达的BC细胞上清液中HER2 ECD水平，而HBL100细胞中FASN基因的短暂过表达促进了FASN蛋白的释放，并同时增加了HER2 ECD向细胞外环境的脱落。后续的研究应该探索血液中FASN分子的定量测定是否可以成为一种快速、准确的非侵入性检测方法，以监测her2过表达的MBC患者接受her2靶向治疗的疾病进展和生存。
Clinicopathological assessment of the functional relationship between the HER2 oncogene and tumor-associated fatty acid synthase (FASN) is largely precluded because immunohistochemical and/or mRNA studies should be performed in biopsies from breast cancer patients. We here sought to determine whether serum FASN (sFASN) could associate with circulating HER2 extracellular domain (HER2 ECD) in the blood of metastatic breast cancer (MBC) patients. Concentrations of serum FASN and HER2 ECD were measured with ELISA in sera retrospectively obtained from 201 patients with metastatic breast cancer (MBC) and 31 healthy subjects. Mechanistical in vitro studies were performed using pharmacological inhibitors of HER2 and FASN as well as cultured cancer cells engineered to overexpress HER2 and FASN human genes. When the upper limit of normal sFASN was defined as the mean + 2SD of the control group, sFASN was elevated above this cut-off (12 ng/ml) in 70 MBC patients (35%). Eighty-nine MBC patients (44%) had elevated levels of HER2 ECD (HER2 ECD cut-off = 15 ng/ml). HER2 ECD-positive MBC patients slightly increased their sFASN levels compared with HER2 ECD-negative MBC patients. sFASN-positive MBC patients had significantly increased levels of HER2 ECD when compared with sFASN-negative MBC patients (mean HER2 ECD=34 ng/ml, 95% CI 26-41 ng/ml and 18 ng/ml -95% CI 15-21 ng/ml, respectively; p=0.002). Sixty percent of sFASN-positive patients concurrently exhibited high levels of HER2 ECD whereas 64% of sFASN-negative patients were negative for circulating HER2 ECD. In vitro studies revealed that BC cells bearing HER2 gene-amplification released higher levels of extracellular FASN than HER2-negative BC cells. Trastuzumab-induced blockade of HER2 ECD shedding failed to prevent FASN release and retrovirally-induced HER2 overexpression in MCF-7 cells did not increase extracellular FASN. Of note, pharmacological inhibition of FASN activity significantly decreased HER2 ECD levels in the supernatant of HER2-overexpressing BC cells while transient overexpression of FASN gene in HBL100 cells promoted FASN protein release and concomitantly increased HER2 ECD shedding into the extracellular milieu. Subsequent studies should explore if quantitative determination of FASN molecules in blood could become a rapid and accurate non-invasive test to monitor disease progression and survival in HER2-overexpressing MBC undergoing HER2-targeted therapies.