Jun John Yoonkeun, Griffith James W, Bruggeman Richard, Washington Sharlene, Demers Laurence M, Verderame Michael F, Manni Andrea
Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Breast Cancer Res Treat. 2008 Jan;107(1):33-40. doi: 10.1007/s10549-007-9533-8. Epub 2007 Feb 27.
Increased polyamine synthesis has been associated with proliferation and progression of breast cancer, and thus, is a potential target for anticancer therapy. Polyamine depletion by alpha-difluoromethylornithine (DFMO) has been shown to decrease pulmonary and bone metastasis from human breast cancer cell xenografts. Following these observations, this study was designed to test the effects of DFMO on in vitro and in vivo features of the highly invasive and metastatic 4T1 murine mammary cancer cells. DFMO inhibited proliferation, caused G1-S arrest, and suppressed in vitro invasiveness of 4T1 cells. In contrast to our previous findings with MDA-MB-435 cells, DFMO did not affect the activation of signal transducers and activator of transcription 3, c-Jun N-terminal kinase, and extracellular signal-regulated kinase, but decreased phosphorylation of p38. DFMO did not alter the expression of Twist. DFMO delayed the orthotopic growth of 4T1 xenografts in association with suppressed putrescine and spermidine levels but increased levels of spermine. DFMO did not affect pulmonary metastasis when primary tumors of control and DFMO-treated mice were matched for size. Interestingly, DFMO reduced Ki-67 expression only in the primary tumors but did not affect its expression in the metastatic tumors in the lung. Cleaved caspase-3 expression was not affected by DFMO in either the primary tumors or the pulmonary metastasis. In summary, DFMO treatment markedly inhibited in vitro proliferation and invasiveness of 4T1 cells and retarded the growth of orthotopic xenografts in mice. The failure of DFMO to inhibit pulmonary metastasis in this system appears to be due, at least in part, to its lack of antiproliferative effect at the metastatic sites.
多胺合成增加与乳腺癌的增殖和进展相关，因此是抗癌治疗的一个潜在靶点。已表明，α-二氟甲基鸟氨酸（DFMO）消耗多胺可减少人乳腺癌细胞异种移植瘤的肺和骨转移。基于这些观察结果，本研究旨在测试DFMO对高侵袭性和转移性4T1小鼠乳腺癌细胞的体外和体内特性的影响。DFMO抑制4T1细胞的增殖，导致G1-S期阻滞，并抑制其体外侵袭性。与我们之前对MDA-MB-435细胞的研究结果不同，DFMO不影响信号转导和转录激活因子3、c-Jun氨基末端激酶和细胞外信号调节激酶的激活，但可降低p38的磷酸化水平。DFMO不改变Twist的表达。DFMO与腐胺和亚精胺水平受抑制但精胺水平升高相关，延缓了4T1异种移植瘤的原位生长。当对照小鼠和DFMO处理小鼠的原发性肿瘤大小匹配时，DFMO不影响肺转移。有趣的是，DFMO仅降低原发性肿瘤中Ki-67的表达，但不影响其在肺转移瘤中的表达。在原发性肿瘤或肺转移灶中，DFMO均不影响裂解的caspase-3的表达。总之，DFMO处理显著抑制4T1细胞的体外增殖和侵袭性，并延缓小鼠原位异种移植瘤的生长。在该系统中，DFMO未能抑制肺转移，这似乎至少部分是由于其在转移部位缺乏抗增殖作用。
