title: Estrogen receptor mutations in tamoxifen-resistant breast cancer.
abstract: Clinical resistance to antiestrogens like tamoxifen is a major problem in the treatment of hormone-dependent breast cancers. Since the estrogen receptor plays a central role in mediating the effects of estrogens and antiestrogens, we hypothesized that mutations in the estrogen receptor could be one mechanism by which breast tumors evolve from a hormone-dependent to a hormone-independent phenotype. The eight exons of the estrogen receptor complementary DNA from 20 tamoxifen-resistant and 20 tamoxifen-sensitive tumors were screened by Single Strand Conformation Polymorphism (SSCP), and the variant conformers were sequenced to identify the nucleotide changes. A 42-base pair replacement was found in exon 6 of a tamoxifen-resistant tumor. A single base pair deletion in exon 6 of a tamoxifen-resistant metastatic tumor but not in the primary tumor was detected in another case. If translated, both these mutations could generate truncated receptors with an intact DNA-binding domain and a defective hormone-binding domain that could constitutively activate transcription of previously estrogen-responsive genes. The remaining 18 of 20 tamoxifen-resistant tumors did not contain mutations in any of the 8 exons of the estrogen receptor complementary DNA. These results suggest that mutations in the estrogen receptor occur at a low frequency and do not account for most estrogen-independent, tamoxifen-resistant breast tumors.
authors.affiliation: Experimental Therapeutics Program, Cleveland Clinic Research Foundation, Ohio 44195-5069.
authors.forename: P S
authors.initials: PS
authors.lastname: Karnik
authors.forename: S
authors.initials: S
authors.lastname: Kulkarni
authors.forename: X P
authors.initials: XP
authors.lastname: Liu
authors.forename: G T
authors.initials: GT
authors.lastname: Budd
authors.forename: R M
authors.initials: RM
authors.lastname: Bukowski
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics*; D018076:DNA, Complementary / Q000737:chemistry; D004273:DNA, Neoplasm / Q000737:chemistry; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry / Q000235:genetics; D010641:Phenotype; D011960:Receptors, Estrogen / Q000235:genetics*; D013629:Tamoxifen; D014158:Transcription, Genetic
chemical_list: D018076:DNA, Complementary; D004273:DNA, Neoplasm; D011960:Receptors, Estrogen; D013629:Tamoxifen