Cancer researchers identify molecular switch for drug resistance

This phenomenon of multidrug-resistance in cancer patients has been known for more than 20 years when researchers detected a gene which is the cause of this resistance. They consequently named it multidrug-resistance gene - MDR-1. This gene contains the blueprint for a special protein (P-glycoprotein), which acts like a pump: it expels substances out of cells through the membrane. In specific tissues normal cells make use of this pump to protect themselves from being destroyed by chemicals. However, some breast cancer cells are also able to make use of this pump by ejecting anti-cancer-drugs thereby protecting themselves from being destroyed. Until now, it was unclear how this protein pump was switched on.

Now a group of cancer researchers at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin-Buch, a national research laboratory of the Helmholtz-Association in the northeast of Berlin, and the Virchow Clinic, Medical School Charité of the Humboldt-University of Berlin (Germany), have identified a molecular switch in breast cancer cells which activates the MDR-1 gene.

This molecular switch is a protein named YB-1 which functions as a transcription factor that turns genes on. In breast cancer cells the YB-1 protein activates the MDR-1 gene which in turn produces the protein pump causing multiple drug resistance. The research paper of Dr. Ralf Bargou, Dr. Hans-Dieter Royer and Professor Bernd Dörken has been published in the latest issue of Nature Medicine (Vol.3, pp 1-4, No.4, April 1997, News and Views, pp 378).

The cancer researchers were able to demonstrate for the first time that overexpressed YB-1 protein permanently activates the multidrug-resistance gene not only in breast cancer cells cultured in the laboratory but also in breast cancer tissue from patients as well. The result of activation of the protein pump was that breast cancer cells which had first been sensitive to treatment became resistant to chemotherapy. The researchers assume that, in breast cancer, multidrug-resistance is acquired during tumour progression through the activation of the YB-1 protein.

Now the researchers in Berlin-Buch want to determine whether the YB-1 protein might be a prognostic marker and target for breast cancer therapy. It may be several years before they reach a conclusion.

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