SPECIFIC P53 MUTATIONS ARE ASSOCIATED WITH DE-NOVO RESISTANCE TO DOXORUBICIN IN BREAST-CANCER PATIENTS

The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that differen t forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis(1). The tumor suppressor gene P53 has a pivotal role inducin g apoptosis in response to cellular damage. In vitro investigations ha ve shown intact p53 to play a critical role executing cell death in re sponse to treatment with cytotoxic drugs like 5-fluorouracil, etoposid e and doxorubicin(2). Recently, mutations in the P53 gene were found t o confer resistance to anthracyclines in a mouse sarcoma tumor model(3 ) 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 cancer(4). Previo us studies have shown mutations in the P53 gene or overexpression of t he p53 protein to predict a poor prognosis(5-7), but also a beneficial effect of adjuvant radiotherapy(8) or chemotherapy(9) in breast cance r. In this study we present data linking specific mutations in the P53 gene to primary resistance to doxorubicin therapy and early relapse i n breast cancer patients.