The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Åke Borg

Åke Borg

Principal investigator

Åke Borg

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

Author

  • Q X Zhang
  • A Borg
  • D M Wolf
  • S Oesterreich
  • S A Fuqua

Summary, in English

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.

Publishing year

1997-04-01

Language

English

Pages

9-1244

Publication/Series

Cancer Research

Volume

57

Issue

7

Document type

Journal article

Publisher

American Association for Cancer Research Inc.

Topic

  • Cancer and Oncology

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

Status

Published

ISBN/ISSN/Other

  • ISSN: 0008-5472