TRAIL-induced Cell Death in Breast Cancer Cells

癌细胞通过多种遗传和表观遗传机制避免凋亡。TNF家族死亡受体（如TNFR、Fas、DR3、TRAIL受体1和TRAIL受体2）在其各自的配体（如TNF、Fas配体和TRAIL）激活后，通过募集和激活半胱天冬酶，诱导细胞凋亡。我们正在研究TRAIL死亡受体（TNFR家族成员）及其配体（如TRAIL和激动抗体）在乳腺癌细胞中的表达和功能，以选择性地触发癌细胞凋亡。在我们早期的工作中，我们发现大多数乳腺癌细胞系对TRAIL诱导的细胞凋亡具有抗性。最近，我们已经证明，具有三阴性/基底样特征的乳腺癌细胞亚群对trail诱导的细胞凋亡非常敏感，而其他乳腺癌亚型对trail诱导的细胞凋亡相对耐药。这类乳腺癌的侵袭性特别强，最需要靶向治疗。我们还发现，在这些敏感细胞中，抑制EGFR会增强TRAIL的毒性。此外，我们发现TRAIL受体2，而不是TRAIL受体1，是TRAIL诱导的敏感乳腺癌细胞凋亡所必需的。后一项发现将有助于选择TRAIL激动剂用于乳腺癌患者的最终临床试验。此外，我们发现，对trail诱导的细胞凋亡的耐药性可以通过与化疗药物、靶向药物（如曲妥珠单抗）和EGFR抑制剂共孵育来克服。最近，我们已经证明G2/M检查点RTK Wee1的抑制或缺失会增强基底样乳腺癌细胞中trail介导的细胞凋亡，我们已经启动了RNAi筛选，以确定trail介导的乳腺癌细胞凋亡的调节因子。总之，这些研究开始为单独使用TRAIL配体或与其他药物联合用于乳腺癌患者的研究提供明确的临床前依据。正在进行的工作是：1)利用功能基因组学鉴定和表征TRAIL受体激动剂诱导乳腺癌细胞凋亡的调节蛋白。2)新型TRAIL受体激动剂在乳腺癌细胞中的作用。

Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. TNF family death receptors (e.g., TNFR, Fas, DR3, TRAIL Receptor 1, and TRAIL Receptor 2) induce apoptosis in cells by recruiting and activating caspases upon activation by their respective ligands (e.g., TNF, Fas Ligand, and TRAIL). We are investigating the expression and function of TRAIL death receptors (members of the TNFR family) and their ligands (e.g., TRAIL and agonistic antibodies) in breast cancer cells in order to selectively trigger apoptosis in the cancer cells. In our early work, we found that most breast cancer cell lines are resistant to the induction of apoptosis by TRAIL. Recently, we have demonstrated that a subset of breast cancer cells, those with triple-negative/basal-like features are very sensitive to TRAIL-induced apoptosis while other breast cancer subtypes are relatively resistant to TRAIL-induced apoptosis. This subset of breast cancers is particularly aggressive and most in need of targeted therapies. We have also shown that in these sensitive cells, inhibition of the EGFR enhances the toxicity of TRAIL. Further, we found that TRAIL Receptor 2, and not TRAIL Receptor 1, is required for TRAIL induced apoptosis in the sensitive breast cancer cells. This latter finding will help in the selection of TRAIL agonists for eventual clinical trials in breast cancer patients. In addition, we have found that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, targetes agents such as trastuzumab, and EGFR inhibitors. More recently, we have demonstrated that inhibition or loss of the G2/M checkpoint RTK Wee1 enhances TRAIL-mediated apoptosis in basal-like breast cancer cells and we have intitated an RNAi screen to identify regulators of TRAIL-mediated apoptosis in breast cancer cells. Together these studies are beginning to provide clear preclinical rationales for studies of TRAIL ligands alone or in combination with other drugs in patients with breast cancer. Ongoing work is: 1) using functional genomics to identify and characterize the proteins that regulate apoptosis induced by TRAIL receptor agonists in breast cancer cells. 2) characterizing novel TRAIL receptor agonist in breast cancer cells.