The anthracycline drugs doxorubicin, daunorubicin, and epirubicin are commonly used to treat breast cancers that are neither estrogen sensitive nor HER-2 positive. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite this treatment. To explain the molecular basis for this situation, investigators at Harvard Medical School (Cambridge, MA, USA) examined tissues taken from 85 patients that had been obtained during surgery and before drug treatment.

They reported in the January 24, 2010, online edition of the journal Nature Medicine that by using a system of integrated genomics they had identified in about 20% of the samples a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based chemotherapy.

Use of small interfering RNA (siRNA) technology to knockdown this gene activity showed that either of two genes, the anti-apoptotic gene YWHAZ or a lysosomal gene LAPTM4B, was able to sensitize tumor cells to anthracyclines. Overexpression of either of the genes induced anthracycline resistance. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a chemotherapy trial in women with primary breast cancer. The tumors were, however, susceptible to other drugs such as cisplatin and paclitaxel.

"No tests are done before treatment begins to predict who is going to be resistant or sensitive to different compounds," said collaborating author Dr. Andrea Richardson, assistant professor of pathology at Harvard Medical School. "Most breast cancer patients are initially given the same drugs. These results suggest that tumors resistant to anthracyclines may still be sensitive to other agents, so this would be very useful as a test to help pick the therapy that is going to be most effective for these patients."

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