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。我们正在研究通过激活乳腺癌和卵巢癌细胞中肿瘤坏死因子相关凋亡诱导配体（TRAIL）的死亡受体来诱导凋亡。以前，我们已经表明，许多乳腺癌和卵巢癌细胞系对TRAIL（死亡受体DR 4和DR 5的配体）诱导的凋亡具有抗性。我们已经证明，通过将细胞与化疗剂、半合成类维生素A（如4 HPR）或分子靶向剂（如抗HER-2抗体）共孵育，可以克服对TRAIL诱导的细胞凋亡的抗性。我们目前的工作利用生物化学和遗传学方法来确定乳腺癌和卵巢癌细胞中TRAIL配体诱导死亡的调节机制。最近，我们已经证明TRAIL选择性地杀死具有间充质特征的三阴性乳腺癌细胞。正在进行的工作是探索这一观察进一步使用临床相关的TRAIL激动剂单独和与其他靶向药物组合。我们也在研究这种选择性的分子基础。三阴性乳腺癌定义为缺乏激素受体和HER-2扩增，预后不良，目前只能用化疗治疗。这些数据表明，TRAIL激动剂可能在三阴性乳腺癌患者的子集中具有治疗功效。

Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. We are investigating the induction of apoptosis by activation of death receptors for the ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in breast and ovarian cancer cells. Previously, we have shown that many breast and ovarian cancer cell lines are resistant to the induction of apoptosis by TRAIL, the ligand for the death receptors DR4 and DR5. We have demonstrated that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, semi-synthetic retinoids (such as 4HPR), or molecularly targeted agents (such as anti-HER-2 antibodies). Our current work utilizes biochemical and genetic approaches to identify mechanisms that regulate the induction of death by TRAIL ligand in breast and ovarian cancer cells. Recently, we have shown that TRAIL selectively kills triple-negative breast cancer cells that have mesenchymal features. Ongoing work is exploring this observation further using clinically relevant TRAIL agonists alone and incombination with other targeted agents. We are also investigating the molecular basis for this selectivity. Triple negative breast cancer, defined by the absence of hormone receptors and the absence of HER-2 amplification has a poor prognosis and at present can only be treated with chemotherapy. These data suggest that TRAIL agonists may have therapeutic efficacy in a subset of triple negative breast cancer patients.