D538GMutation in EstrogenReceptor-a: ANovelMechanism for Acquired Endocrine Resistance in Breast Cancer

Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor a (ERa)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERa expression, altered activity of coregulators, and cross-talk between the ERa and growth factor signaling pathways. To our knowledge, acquiredmutations of the ERa have not been described asmediating endocrine resistance. Samples of 13 patients withmetastatic breast cancerwere analyzed formutations in cancer-related genes. Infive patientswho developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERa, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, themutation 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-ERa among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity. Cancer Res; 73(23); 6856–64. 2013 AACR.