D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer.
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.
Authors' Affiliations: Department of Oncology, Tel Aviv Sourasky Medical Center; Sackler Faculty of Medicine; The Bioinformatics Unit, Goerge S. Wise Faculty of Life Sciences, Tel Aviv University; Assuta Medical Center, Tel Aviv; Kaplan Medical Center, Rehovot; Oncotest-Teva Pharmaceutical Industries; Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva, Israel; Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; and Foundation Medicine, Cambridge, Massachusetts.
Keren
K
Merenbakh-Lamin
Noa
N
Ben-Baruch
Adva
A
Yeheskel
Addie
A
Dvir
Lior
L
Soussan-Gutman
Rinath
R
Jeselsohn
Roman
R
Yelensky
Myles
M
Brown
Vincent A
VA
Miller
David
D
Sarid
Shulamith
S
Rizel
Baruch
B
Klein
Tami
T
Rubinek
Ido
I
Wolf
D019943:Amino Acid Substitution / Q000502:physiology; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D020125:Mutation, Missense / Q000502:physiology; D013629:Tamoxifen / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D001224:Aspartic Acid; D005998:Glycine