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Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients

Abstract

The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that different forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis1. The tumor suppressor gene P53 has a pivotal role inducing apoptosis in response to cellular damage. In vitro investigations have shown intact p53 to play a critical role executing cell death in response to treatment with cytotoxic drugs like 5–fluorouracil, etoposide and doxorubicin2. Recently, mutations in the P53 gene were found to confer resistance to anthracyclines in a mouse sarcoma tumor model3, and overexpression of the p53 protein (which, in most cases, is due to a mutated gene) was found to be associated with lack of response to cisplatin–based chemotherapy in non–small cell lung cancer4. Previous studies have shown mutations in the P53 gene or overexpression of the p53 protein to predict a poor prognosis5–7, but also a beneficial effect of adjuvant radiotherapy8 or chemotherapy9 in breast cancer. In this study we present data linking specific mutations in the P53 gene to primary resistance to doxorubicin therapy and early relapse in breast cancer patients.

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Aas, T., Børresen, AL., Geisler, S. et al. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 2, 811–814 (1996). https://doi.org/10.1038/nm0796-811

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