Loss of Specific MicroRNA Spurs Drug Resistance in Breast Cancer Cells

A study determined that development of resistance to the chemotherapeutic drug tamoxifen by breast tumors was due to the disappearance of a specific microRNA.

MicroRNAs are snippets of about 20 nucleotides that block gene expression by attaching to molecules of messenger RNA (mRNA) in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA.

In the study, investigators at the German Cancer Research Center (Heidelberg, Germany) related genome-wide miRNA microarray analyses of breast tumors to the appearance in the tumors of resistance to tazmoxifen.

They reported in the April 16, 2012, online edition of the journal Oncogene that the microRNA miRNA-375 was among the top downregulated miRNAs in resistant cells. Reexpression of miR-375 was sufficient to resensitize tumor cells to tamoxifen and partly reversed the epithelial–mesenchymal transition (EMT), which is characteristic of tumor cells.

A combination of mRNA profiling, bioinformatics analysis, and experimental validation identified the protein metadherin (MTDH) as a direct target of miR-375. Metadherin is an oncogenic protein that is normally blocked by miR-375. The importance of MTDH was confirmed in experiments with tumor cells that lacked the MTDH gene. In these tumors, even in the absence of miR-375, no resistance to tamoxifen arose.

“The analysis of microRNAs in breast cancer has put us on the track of metadherin. We will possibly be able to specifically influence the cancer-promoting properties of this protein in the future,” said coauthor Dr. Stefan Wiemann, associate professor of molecular genome analysis at the German Cancer Research Center. “Resistances to drugs are the main reason why therapies fail and disease progresses in many cancers. We want to understand what goes on in the cells when this happens so we can develop better therapies in the future.”

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German Cancer Research Center