Okamoto Yoshinori, Aoki Akira, Ueda Koji, Jinno Hideto
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.
Toxicol Lett. 2018 May 15;288:65-70. doi: 10.1016/j.toxlet.2018.02.017. Epub 2018 Feb 15.
Estrogen is reported to be involved in mammary tumorigenesis. To unveil metabolic signatures for estrogen-induced mammary tumorigenesis, we carried out serum metabolomic analysis in an estrogen-induced mammary tumor model, female August Copenhagen-Irish/Segaloff (ACI/Seg) rats, using liquid chromatography-mass spectrometry. In contrast to the control group, all rats with an implanted 17β-estradiol (E2) pellet developed mammary tumors during this experiment. E2 treatment significantly suppressed body weight gain. But no significant differences in food consumption were observed between the two groups, suggesting that metabolic alteration depended on E2 treatment. Serum metabolomic analysis detected 116 features that were statistically different (p < 0.01) between the groups. Quantitation analysis revealed that several phospholipids such as phosphatidylcholines and lysophosphatidylcholines (LPCs) were identified as significantly different metabolites. E2-treated rat serum stimulated the proliferation of human breast cancer MDA-MB-231 cells. In addition, the proliferation effect was diminished by pretreating cells with either autotaxin inhibitor or antagonist for lysophosphatidic acid receptor whose ligands are metabolites of LPCs via autotaxin-mediated hydrolysis. In summary, our results suggest that not only are phospholipids potential biomarkers for mammary tumors but importantly, LPCs themselves could be associated with E2-induced mammary tumorigenesis in female ACI/Seg rats.
据报道，雌激素与乳腺肿瘤发生有关。为了揭示雌激素诱导的乳腺肿瘤发生的代谢特征，我们使用液相色谱 - 质谱法，在雌激素诱导的乳腺肿瘤模型——雌性奥古斯塔·哥本哈根 - 爱尔兰/塞加洛夫（ACI/Seg）大鼠中进行了血清代谢组学分析。与对照组相比，所有植入17β - 雌二醇（E2）药丸的大鼠在本实验期间都发生了乳腺肿瘤。E2处理显著抑制了体重增加。但两组之间在食物消耗方面未观察到显著差异，这表明代谢改变取决于E2处理。血清代谢组学分析检测到两组之间有116个具有统计学差异（p < 0.01）的特征。定量分析表明，几种磷脂，如磷脂酰胆碱和溶血磷脂酰胆碱（LPCs）被鉴定为显著不同的代谢物。E2处理的大鼠血清刺激了人乳腺癌MDA - MB - 231细胞的增殖。此外，通过用自分泌运动因子抑制剂或溶血磷脂酸受体拮抗剂预处理细胞，其增殖效应减弱，溶血磷脂酸受体的配体是LPCs通过自分泌运动因子介导的水解产物。总之，我们的结果表明，磷脂不仅是乳腺肿瘤的潜在生物标志物，而且重要的是，LPCs本身可能与雌性ACI/Seg大鼠中E2诱导的乳腺肿瘤发生有关。
