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Estrogen receptor mutations in tamoxifen-resistant breast cancer
P S Karnik1, S Kulkarni, X P Liu
1Experimental Therapeutics Program, Cleveland Clinic Research Foundation, Ohio 44195-5069.
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.
Insights
Mutations in the estrogen receptor (ER) are not the primary cause of tamoxifen resistance in most breast cancers. While some ER mutations were found in resistant tumors, they occurred infrequently, suggesting other mechanisms are at play.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clinical resistance to antiestrogens, such as tamoxifen, poses a significant challenge in treating hormone-dependent breast cancers.
- The estrogen receptor (ER) is crucial in mediating the effects of estrogens and antiestrogens, making it a potential target for understanding resistance mechanisms.
Purpose of the Study:
- To investigate whether mutations in the estrogen receptor (ER) contribute to the development of tamoxifen resistance in breast tumors.
- To determine the frequency of ER mutations in both tamoxifen-resistant and tamoxifen-sensitive breast cancer.
Main Methods:
- Screening of the eight exons of estrogen receptor complementary DNA (cDNA) from 40 breast tumors (20 resistant, 20 sensitive) using Single Strand Conformation Polymorphism (SSCP).
- Sequencing of variant conformers to identify specific nucleotide changes in the ER gene.
Main Results:
- Two distinct mutations in exon 6 of the ER gene were identified in tamoxifen-resistant tumors: a 42-base pair replacement and a single base pair deletion.
- These mutations, if translated, could lead to truncated ER proteins with impaired hormone-binding domains, potentially causing constitutive gene activation.
- The majority (18 out of 20) of tamoxifen-resistant tumors analyzed did not exhibit mutations in the screened ER exons.
Conclusions:
- Mutations in the estrogen receptor (ER) are found at a low frequency in tamoxifen-resistant breast tumors.
- ER mutations do not appear to be the predominant mechanism driving estrogen-independent, tamoxifen-resistant breast cancer.