Breast cancer-specific TRAIL expression mediated by miRNA response elements of let-7 and miR-122

Abstract

Breast cancer is a highly aggressive malignancy and always has a poor prognosis. The current therapeutic strategies including surgery, chemotherapy and radiotherapy benefit little for patients survival. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in a wide range of cancer cells, such as breast cancer, it also has cytotoxicity to normal cells. To improve the selectivity of TRAIL expression to breast cancer cells, we inserted miRNA response elements (MREs) of let-7 and miR-122 into a TRAIL-expressing adenoviral vector (Ad-TRAIL-MRE-7-122) to restrict its expression within breast cancer cells. qPCR assay confirmed that the levels of let-7 and miR-122 were downregulated in breast cancer samples and cell lines, compared with normal tissues and cell lines. Luciferase assay indicated that MREs of let-7 and miR-122 was able to confer luciferase expression with the selectivity to breast cancer. Ad-TRAIL-MRE-7-122 highly expressed TRAIL in breast cancer cells, but not in normal cells. The breast cancer-specific apoptosis was detected after the infection of Ad-TRAIL-MRE-7-122. The viability of breast cancer cells, rather than normal cells, was reduced by the treatment of Ad-TRAIL-MRE-7-122. Animal experiments further confirmed that Ad-TRAIL-MRE-7-122 and Ad-TRAIL both greatly impeded the growth of breast cancer xenograft in mice. Taken together, we constructed a TRAIL-expressing recombinant adenovirus regulated by MREs of let-7 and miR-122 and showed evidences that this strategy may be promising for breast cancer treatment.