P53 Mutation and Tamoxifen Resistance in Breast Cancer

A substantial portion of patients with estrogen receptorpositive breast cancer fail to respond to estrogen depletion or to the antiestrogen tamoxifen. The molecular changes that lead to tamoxifen resistance and estrogen–independent growth are unknown. To test the hypothesis that a p53 mutation could result in tamoxifen resistance and estrogen– independent growth, the MCF–7 cell line was transfected with p53 cDNA which was mutated at codon 179 (histidine to glutamine). MCF–7 is an estrogen receptor–positive, estrogendependent, tamoxifen–sensitive cell line with only wild–type p53. The presence of transfected mutant p53 cDNA was verified by the PCR, and overexpression of p53 protein was assessed by Western blotting. Five separate mutant–transfected clones were selected and tested in subsequent growth experiments. In monolayer culture, there was no consistent evidence of estrogen–independent growth or tamoxifen resistance in the mutant transfectants compared with vector–only controls or the parental cell line. In soft agar growth experiments, four of five mutant transfectants remained sensitive to tamoxifen in a dose–dependent manner. In the presence of wild–type p53, mutant 179 p53 protein does not result in estrogen–independent growth or tamoxifen resistance. These results do not exclude the possibility that other p53 mutational types could result in tamoxifen resistance, or that loss of the remaining wild–type allele may be necessary to result in this phenotype.