Abstract
Introduction: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can kill tumor cells while leaving normal cells unharmed. However, many breast and ovarian cancer cells are resistant to TRAIL-mediated apoptosis. Breast cancers can be divided into those which express the estrogen (ER) and progesterone (PR) receptors, those with HER-2 amplification, and those without expression of ER, PR, or HER-2 amplification (referred to as basal or triple-negative breast cancer). Due to the lack of specific target there is no targeted therapy for triple negative breast cancer. Recently, we demonstrated that a set of triple negative breast cancer cell lines with mesenchymal features are sensitive to TRAIL. Still TRAIL has very little or no effect on the triple negative cells with epithelial characteristics. We are investigating if this is true for the cell lines derived from different ethnic group.
Method: Both epithelial (viz., MDA-MB-468, from African American and HCC1937 from non Hispanic white) and mesenchymal cell lines (viz., MDA-MB-157 from African American, and MDA-MB-231 from non Hispanic white patient) were selected for this study. All of the cell lines were grown in MEM medium supplemented with 10% FCS with or without 1ug/ml TRAIL for 16h. Percentage of growth inhibition was determined by MTS assay. Correlation between growth inhibition and apoptosis were established by mitochondrial membrane depolarization, caspase assay, and DNA fragmentation.
Result: Both of the epithelial triple negative cells were non responsive to TRAIL. Only some (10.5% for MB-468 and 18.6% for HCC1937) growth inhibition was observed even with highest concentration (5ug/ml) of TRAIL irrespective to the ethnicity differences. The effect of TRAIL in these cell lines was not dose dependant. On the other hand, both cell lines with mesenchymal feature from both ethnicities were highly responsive to TRAIL. More than 70% (71.5% for MB-157 and 75.2% for MB-231) of growth inhibition was achieved with TRAIL at 1ug/ml concentration and the effect was dose dependent. In epithelial cells both the TRAIL-receptor-1 (TR-1) and TRAIL receptor-2 (TR-2) expression were very low. In MB-231 silencing of only TR-2 reduces the effect of TRAIL but not TR-1.
Conclusions: Though cells from non Hispanic white patients were a little more sensitive to TRAIL than cells from African American patient, the difference was minor and it was not statistically significant. Low level or TR-2 expression in epithelial cell lines may contribute to TRAIL resistant to these cell lines. We think TRAIL could be used either alone or in combination to treat breast cancer with mesenchymal phenotype. Appropriate combination could be searched for TRAIL therapy for breast cancer with epithelial phenotype. We are investigating additional cell lines derived from different racial or ethnic groups to determine if there is any correlation between ethnicity and TRAIL sensitivity and underlying possible molecular mechanism.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B45.
RSS Feeds