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细胞凋亡。我们正在研究通过激活肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的死亡受体来诱导乳腺癌细胞和卵巢癌细胞的凋亡。此前，我们已经证明，许多乳腺和卵巢癌细胞株对死亡受体DR4和DR5的配体TRAIL诱导的细胞凋亡具有抵抗力。我们已经证明，细胞对TRAIL诱导的细胞凋亡的抵抗可以通过与化疗药物、半合成维甲酸(如4HPR)或分子靶向药物(如抗HER-2抗体)共同孵育来克服。我们目前的工作利用生化和遗传学方法来确定调控TRAIL配体在乳腺和卵巢癌细胞中诱导死亡的机制。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。正在进行的工作是进一步探索这一观察结果，单独使用临床相关的TRAIL激动剂，并与其他靶向药物联合使用。我们还在利用功能基因组学方法研究这种选择性的分子基础。三阴性乳腺癌，定义为激素受体缺失和HER-2扩增缺失，预后较差，目前只能通过化疗进行治疗。这些数据表明，TRAIL激动剂可能对三阴性乳腺癌患者的子集具有治疗效果。

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 in combination with other targeted agents. We are also investigating the molecular basis for this selectivity by using a functional genomic approach. 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.