A let-7b binding site SNP in the 3′-UTR of the Bcl-xL gene enhances resistance to 5-fluorouracil and doxorubicin in breast cancer cells

The development of acquired resistance to chemotherapy is a major obstacle in the successful treatment of cancer. In breast cancer cells, B-cell lymphoma-extra large (Bcl-xL) is involved in the development of resistance to various chemotherapeutic agents; therefore, preliminary biological prediction was performed to identify a putative binding site for let-7b in the 3′-untranslated region (UTR) of the Bcl-xL gene and a single nucleotide polymorphism (SNP) within this binding region. The present study investigated the association between the SNP rs3208684 A>C and chemotherapeutic agent resistance in breast cancer cells. The data indicated that let-7b negatively regulates the expression of Bcl-xL and appears to sensitize MCF-7 cells to the chemotherapeutic agents 5-fluorouracil (5-FU) and doxorubicin. Furthermore, the SNP rs3208684 A>C was demonstrated to enhance Bcl-xL protein expression by disrupting the binding of let-7b to the 3′-UTR of Bcl-xL and, in MCF-7 cells, overexpression of let-7b in the presence of a mutant Bcl-xL 3′-UTR (C allele) significantly increased 5-FU and doxorubicin resistance. Thus, the results of the present study demonstrate that the SNP rs3208684 A>C may upregulate Bcl-xL protein expression and enhance the resistance of the MCF-7 cells to 5-FU and doxorubicin by decreasing the binding of let-7b to the 3′-UTR of Bcl-xL.