Yu Zhenming, Xia Weiya, Wang Hong-Ying, Wang Shao-Chun, Pan Yong, Kwong Ka Yin, Hortobagyi Gabriel N, Hung Mien-Chie
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.
Mol Carcinog. 2006 Sep;45(9):667-75. doi: 10.1002/mc.20212.
Polyomavirus enhancer activator 3 (PEA3) is a member of the Ets family of transcription factors. We demonstrated in a previous study that, by downregulating the HER-2/neu oncogene at the transcriptional level, PEA3 can inhibit the growth and development into tumors of HER-2/neu-overexpressing ovarian cancer cells. Here, we establish stable clones of the human breast cancer cell line MDA-MB-361DYT2 that express PEA3 under the control of a tetracycline-inducible promoter. Ectopic expression of PEA3 in this cell line inhibited cell growth and resulted in cell cycle accumulation in the G1 phase. We demonstrate that expression of PEA3 in an orthotopic breast cancer model inhibited tumor growth and prolonged the survival of tumor-bearing mice. In a parallel experiment with another breast cancer cell line, BT474M1, we were unable to obtain stable PEA3-inducible transfectants, suggesting that PEA3 may exert a strong growth inhibition effect in this cell line. Indeed, PEA3 coupled with the liposome SN2 demonstrated therapeutic effects in mice bearing tumors induced by BT474M1. These results provide evidence for the antitumor activity of PEA3 in human breast cancers.
多瘤病毒增强子激活因子3（PEA3）是Ets转录因子家族的成员。我们在之前的研究中证明，通过在转录水平下调HER-2/neu癌基因，PEA3可以抑制HER-2/neu过表达的卵巢癌细胞的生长和肿瘤形成。在此，我们建立了人乳腺癌细胞系MDA-MB-361DYT2的稳定克隆，该克隆在四环素诱导型启动子的控制下表达PEA3。PEA3在该细胞系中的异位表达抑制了细胞生长，并导致细胞周期在G1期积累。我们证明，在原位乳腺癌模型中PEA3的表达抑制了肿瘤生长并延长了荷瘤小鼠的生存期。在与另一种乳腺癌细胞系BT474M1的平行实验中，我们无法获得稳定的PEA3诱导型转染子，这表明PEA3可能在该细胞系中发挥强大的生长抑制作用。事实上，PEA3与脂质体SN2联合应用对荷BT474M1诱导肿瘤的小鼠显示出治疗效果。这些结果为PEA3在人类乳腺癌中的抗肿瘤活性提供了证据。
