1. ¹Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, Texas, USA
2. ²South Texas Veterans Health Care System, Texas, USA

Correspondence: Dr Irene Kazhdan, MD, PhD, Division of Medical Oncology, Department of Medicine, University of Texas Health Science, Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. E-mail: kazhdan@uthscsa.edu

Received 11 October 2003; Published online 3 September 2004.

Abstract

Breast cancer cells are generally resistant to induction of apoptosis by treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we demonstrate that both TRAIL-sensitive and TRAIL-resistant breast cancer cell lines can be efficiently killed by overexpression of the TRAIL receptor, death receptor 4 (DR4). The extent of cell death depended on the strength of the promoter driving DR4 expression. When driven by the strong CMV promoter, expression of DR4 killed over 90% of cells in five out of six cell lines tested in the absence of exogenous TRAIL. When driven by the relatively weak tumor-specific hTERT promoter, DR4 was less effective alone, but sensitized cells to killing by TRAIL. The extent of TRAIL sensitization depended on the magnitude of hTERT promoter activity. MCF-7 cells were relatively resistant to the action of DR4. We compared expression of the genes involved in transduction and execution of the death receptor-initiated apoptotic stimuli between MCF-7 and DR4-sensitive cell lines. We confirmed that in the panel of cell lines, MCF-7 was the only line deficient in expression of caspase 3. Bcl-2 and FLIP proteins, implicated in suppression of TRAIL-induced apoptosis, were expressed at a higher level.