Journal Article
. 2013 Nov; 73(23):6856-64.
doi: 10.1158/0008-5472.CAN-13-1197.

D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer

Keren Merenbakh-Lamin 1 Noa Ben-Baruch  Adva Yeheskel  Addie Dvir  Lior Soussan-Gutman  Rinath Jeselsohn  Roman Yelensky  Myles Brown  Vincent A Miller  David Sarid  Shulamith Rizel  Baruch Klein  Tami Rubinek  Ido Wolf  
  • PMID: 24217577
  •     149 citations


Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor α (ERα)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERα expression, altered activity of coregulators, and cross-talk between the ERα and growth factor signaling pathways. To our knowledge, acquired mutations of the ERα have not been described as mediating endocrine resistance. Samples of 13 patients with metastatic breast cancer were analyzed for mutations in cancer-related genes. In five patients who developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment. Structural modeling indicated that D538G substitution leads to a conformational change in the ligand-binding domain, which mimics the conformation of activated ligand-bound receptor and alters binding of tamoxifen. Indeed, experiments in breast cancer cells indicated constitutive, ligand-independent transcriptional activity of the D538G receptor, and overexpression of it enhanced proliferation and conferred resistance to tamoxifen. These data indicate a novel mechanism of acquired endocrine resistance in breast cancer. Further studies are needed to assess the frequency of D538G-ERα among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity.

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ESR1 Gene Mutation in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Patients: Concordance Between Tumor Tissue and Circulating Tumor DNA Analysis.
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