乳腺癌已成为威胁妇女生命和健康的头号杀手而倍受世界重视。临床治疗乳腺癌也已从单纯手术治疗发展到根据生物学行为制定综合治疗策略的时代。基因治疗成为乳腺癌生物治疗的一个新兴手段并显示出良好的应用价值。根据细胞凋亡受到干扰会诱导肿瘤的发生、发展和治疗障碍，通过激活肿瘤细胞凋亡诱导机制可能是一种肿瘤治疗的新方法。本研究旨在开发一种针对乳腺癌细胞的新型基因治疗方法，利用Caspase-3/8是细胞凋亡信号通路中的关键因子；HIV-1调节蛋白Vpr（病毒蛋白R）具有促进细胞凋亡、可包装入病毒颗粒、还可运载其他大分子到病毒颗粒中的特性，本研究拟利用HIV慢病毒颗粒将Casp-3/8及Vpr-Casp-3/8蛋白转导入乳腺癌细胞并使其表达，以达到抑制乳腺癌细胞生长的目的。在此基础上本课题还将探讨Caspase-3/8和Vpr-Caspase-3/8的慢病毒质粒对SCID小鼠原发性乳腺癌发展中的抗癌效果。

It is well known that disruption of apoptosis can promote tumor initiation, progression and treatment resistance. Thus, the direct activation of potent inducers of apoptosis in tumor cells might be a new approach for the treatment of cancer. Since Caspase-3/8 (Caspase-3/8) plays a vital role in the propagation of enzamatic cascade that results in cell apoptosis and HIV-1 Vpr protein effectively induces apoptosis after arrest of cells at G2/M checkpoint, we hypothesis that Lentiviral vector-mediated delivery of Caspase-8 gene or Vpr-Caspase-8 proteins into breast cancer cells will selectively kill tumor cells by inducing apoptosis and inhibit the in vivo growth of primary breast tumor. In this proposed study, we will develop a novel gene therapy with Caspase-3/8 gene or Vpr-Caspase-3/8 protein target to breast cancer cells. Our research will focuses on 1) Delivery and expression of Casp-3/8 gene or Vpr-Casp-3/8 proteins in breast cancer cell lines (MCF-7 and MCF-10) and tumorigenic breast cancer cells by HIV-1-derived lentiviral vector, and investigation of the inhibitory effects of Casp-3/8/Vpr on cancer cell growth. 2) Investigation of the anticancer effect of Casp-8 and Vpr-Casp-8 lentiviral vector on the development of primary breast cancer in SCID Mice. A novelty of this proposal study is that we will use a lentiviral vector to deliver a Tet-on inducible Casp-8 that only triggers apoptosis to recipient cancer cells upon its activation with doxycycline. The system can induce long-term expression of Casp-3/8 gene and allow for discontinuation if a verse effects are observed in the patient, or if gene therapy is no longer need. Another specific feature of this research is that the cancer cell apoptosis induced by Vpr and Casp-3/8 are through different signal transduction pathways. Together with the advantage of safety of Vpr-Casp-3/8 lentiviral vector, this system will offer a powerful new strategy for breast cancer as well as other cancer treatment.