p53 mutation and tamoxifen resistance in breast cancer.
A substantial portion of patients with estrogen receptor-positive 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, estrogen-dependent, 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.
Elledge
R M
RM
Division of Medical Oncology and Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284, USA.
Lock-Lim
S
S
Allred
D C
DC
Hilsenbeck
S G
SG
Cordner
L
L
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D005822:Genetic Vectors; D006801:Humans; D009154:Mutation; D013629:Tamoxifen / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen