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An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer

Zhang, Q X ; Borg, A LU ; Wolf, D M ; Oesterreich, S and Fuqua, S A (1997) In Cancer Research 57(7). p.9-1244
Abstract

Thirty tumors from metastatic breast cancer patients were screened for mutations in the estrogen receptor (ER) gene using single-strand conformation polymorphism and sequence analysis. Three missense mutations, Ser47Thr, Lys531Glu, and Tyr537Asn, were identified in these lesions. To investigate these mutated ERs or altered transcriptional activation function, expression vectors containing wild-type (wt) and mutant ERs were constructed and cotransfected with different estrogen response element reporter gene constructs into HeLa cells and MDA-MB-231 human breast cancer cells. The first two ER mutants were similar to wt ER. However, the Tyr537Asn ER mutant possessed a potent, estradiol-independent transcriptional activity, as compared to... (More)

Thirty tumors from metastatic breast cancer patients were screened for mutations in the estrogen receptor (ER) gene using single-strand conformation polymorphism and sequence analysis. Three missense mutations, Ser47Thr, Lys531Glu, and Tyr537Asn, were identified in these lesions. To investigate these mutated ERs or altered transcriptional activation function, expression vectors containing wild-type (wt) and mutant ERs were constructed and cotransfected with different estrogen response element reporter gene constructs into HeLa cells and MDA-MB-231 human breast cancer cells. The first two ER mutants were similar to wt ER. However, the Tyr537Asn ER mutant possessed a potent, estradiol-independent transcriptional activity, as compared to wt ER. Moreover, the constitutive activity of the Tyr537Asn ER mutant was virtually unaffected by estradiol, tamoxifen, or the pure antiestrogen ICI 164,384. Tyr537 is located at the beginning of exon 8 in the COOH-terminal portion of the hormone-binding domain of the ER, to which dimerization and transcription activation functions have also been ascribed. It has been identified as a phosphorylation site implicated in hormone binding, dimerization, and hormone-dependent transcriptional activity. Our results suggest that the Tyr537Asn substitution induces conformational changes in the ER that might mimic hormone binding, not affecting the ability of the receptor to dimerize, but conferring a constitutive transactivation function to the receptor. If present in other metastatic breast tumors, this naturally occurring ER mutant may contribute to breast cancer progression and/or hormone resistance.

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author
; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast Neoplasms/genetics, Estradiol/pharmacology, Female, HeLa Cells, Humans, Models, Genetic, Mutation, Neoplasm Metastasis, Polymorphism, Single-Stranded Conformational, Receptors, Estrogen/agonists, Tamoxifen/analogs & derivatives, Transcription, Genetic, Transfection
in
Cancer Research
volume
57
issue
7
pages
6 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • pmid:9102207
  • scopus:0030940071
ISSN
0008-5472
language
English
LU publication?
no
id
b23fc172-bb9a-4db5-804f-cf0ac645714e
date added to LUP
2019-05-27 22:53:42
date last changed
2024-05-29 12:28:30
@article{b23fc172-bb9a-4db5-804f-cf0ac645714e,
  abstract     = {{<p>Thirty tumors from metastatic breast cancer patients were screened for mutations in the estrogen receptor (ER) gene using single-strand conformation polymorphism and sequence analysis. Three missense mutations, Ser47Thr, Lys531Glu, and Tyr537Asn, were identified in these lesions. To investigate these mutated ERs or altered transcriptional activation function, expression vectors containing wild-type (wt) and mutant ERs were constructed and cotransfected with different estrogen response element reporter gene constructs into HeLa cells and MDA-MB-231 human breast cancer cells. The first two ER mutants were similar to wt ER. However, the Tyr537Asn ER mutant possessed a potent, estradiol-independent transcriptional activity, as compared to wt ER. Moreover, the constitutive activity of the Tyr537Asn ER mutant was virtually unaffected by estradiol, tamoxifen, or the pure antiestrogen ICI 164,384. Tyr537 is located at the beginning of exon 8 in the COOH-terminal portion of the hormone-binding domain of the ER, to which dimerization and transcription activation functions have also been ascribed. It has been identified as a phosphorylation site implicated in hormone binding, dimerization, and hormone-dependent transcriptional activity. Our results suggest that the Tyr537Asn substitution induces conformational changes in the ER that might mimic hormone binding, not affecting the ability of the receptor to dimerize, but conferring a constitutive transactivation function to the receptor. If present in other metastatic breast tumors, this naturally occurring ER mutant may contribute to breast cancer progression and/or hormone resistance.</p>}},
  author       = {{Zhang, Q X and Borg, A and Wolf, D M and Oesterreich, S and Fuqua, S A}},
  issn         = {{0008-5472}},
  keywords     = {{Breast Neoplasms/genetics; Estradiol/pharmacology; Female; HeLa Cells; Humans; Models, Genetic; Mutation; Neoplasm Metastasis; Polymorphism, Single-Stranded Conformational; Receptors, Estrogen/agonists; Tamoxifen/analogs & derivatives; Transcription, Genetic; Transfection}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{7}},
  pages        = {{9--1244}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer}},
  volume       = {{57}},
  year         = {{1997}},
}