Phenformin inhibits growth and epithelial-mesenchymal transition of ErbB2-overexpressing breast cancer cells through targeting the IGF1R pathway.
Phenformin inhibits growth and epithelial-mesenchymal transition of ErbB2-overexpressing breast cancer cells through targeting the IGF1R pathway.
复制标题
DOI：
10.18632/oncotarget.19466
复制
发表时间：
2017-09-01
期刊：
影响因子：
--
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Guo Z;Zhao M;Howard EW;Zhao Q;Parris AB;Ma Z;Yang X
报告显示，二甲双胍，一种流行的抗糖尿病药物，通过各种全身作用，包括调节胰岛素样生长因子受体（IGFR）来预防乳腺癌。尽管二甲双胍的抗癌特性已经得到了充分的研究，但关于生物利用度更高/更有效的双胍类药物——苯双胍的报道仍然很少。苯双胍具有与二甲双胍相似的功能活性，据报道可抑制大鼠乳腺癌的发生。由于phenformin对特定乳腺癌亚型的作用尚未被充分探索，我们使用过表达erbb2的乳腺癌细胞和动物模型来测试phenformin的抗癌潜力。我们报道，phenformin （25-75 μM）可降低SKBR3和78617乳腺癌细胞的细胞增殖和细胞周期进程。在MMTV-ErbB2转基因小鼠同基因肿瘤模型中，苯双胍治疗（30 mg/kg/天）后肿瘤大小减小。在erbb2过表达的乳腺癌细胞和小鼠乳腺肿瘤源性组织中，苯双胍还能阻断上皮-间质转化，降低侵袭性表型，抑制酪氨酸激酶受体信号传导，包括胰岛素受体底物1和IGF1R。此外，苯双胍在体外抑制igf1刺激的增殖、受体酪氨酸激酶信号传导和上皮-间质转化标志物。总之，我们的研究表明，苯双胍介导的IGF1/IGF1R调节是一种潜在的抗癌机制，并支持苯双胍和其他双胍类药物作为乳腺癌治疗药物的发展。
Reports suggest that metformin, a popular anti-diabetes drug, prevents breast cancer through various systemic effects, including insulin-like growth factor receptor (IGFR) regulation. Although the anti-cancer properties of metformin have been well-studied, reports on a more bioavailable/potent biguanide, phenformin, remain sparse. Phenformin exerts similar functional activity to metformin and has been reported to impede mammary carcinogenesis in rats. Since the effects of phenformin on specific breast cancer subtypes have not been fully explored, we used ErbB2-overexpressing breast cancer cell and animal models to test the anti-cancer potential of phenformin. We report that phenformin (25–75 μM) decreased cell proliferation and impaired cell cycle progression in SKBR3 and 78617 breast cancer cells. Reduced tumor size after phenformin treatment (30 mg/kg/day) was demonstrated in an MMTV-ErbB2 transgenic mouse syngeneic tumor model. Phenformin also blocked epithelial-mesenchymal transition, decreased the invasive phenotype, and suppressed receptor tyrosine kinase signaling, including insulin receptor substrate 1 and IGF1R, in ErbB2-overexpressing breast cancer cells and mouse mammary tumor-derived tissues. Moreover, phenformin suppressed IGF1-stimulated proliferation, receptor tyrosine kinase signaling, and epithelial-mesenchymal transition markers in vitro. Together, our study implicates phenformin-mediated IGF1/IGF1R regulation as a potential anti-cancer mechanism and supports the development of phenformin and other biguanides as breast cancer therapeutics.
登录
查看更多内容
影响因子：
5.2
作者：
Malaguarnera R;Belfiore A
通讯作者：
Belfiore A
影响因子：
3.6
作者：
Freudenberg, Jaclyn A.;Wang, Qiang;Katsumata, Makoto;Drebin, Jeffrey;Nagatomo, Izumi;Greene, Mark I.
通讯作者：
Greene, Mark I.
苯甲曲作为预防和乳腺癌异种移植的治疗。
影响因子：
8.8
作者：
Appleyard, M. V. C. L.;Murray, K. E.;Coates, P. J.;Wullschleger, S.;Bray, S. E.;Kernohan, N. M.;Fleming, S.;Alessi, D. R.;Thompson, A. M.
通讯作者：
Thompson, A. M.
影响因子：
4.3
作者：
Liu, Bolin;Fan, Zeying;Thor, Ann D.
通讯作者：
Thor, Ann D.
影响因子：
9.7
作者：
DILMAN, VM;ANISIMOV, VN
通讯作者：
ANISIMOV, VN