D538G Mutation in Estrogen Receptor-α: A Novel Mechanism for Acquired Endocrine Resistance in Breast Cancer

Abstract

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, acquired mutations of the ERa 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 ERa, 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-ERa among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity. Cancer Res; 73(23); 6856-64. Ó2013 AACR.

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

“…This finding is consistent with the known concept of tumor heterogeneity within a primary tumor and metastatic sites (25). These findings are also in accord with recent data demonstrating that acquired ER mutations can be found in liver metastatic lesions, but not pulmonary metastases within the same patient (15), and additional studies revealing that ER mutations are relatively rare in primary breast cancers but are more common after acquired resistance to endocrine therapies (12)(13)(14)16). Gene expression qRT-PCR data from the prior analysis in Fig. 1B correlated with IHC results for the metastatic sites queried in these five patients.…”

“…In part, this is due to the heterogeneous nature of breast cancers, resulting in multiple mechanisms of resistance. For example, past studies have demonstrated that tamoxifen resistance is mediated by differential expression of nuclear hormone receptor coregulators (2, 3), growth factor signaling crosstalk (4-7), regulation of microRNAs (8), cyclin dependent kinases (CKDs) (9), CDK inhibitors (10,11), and more recently, acquired somatic mutations and alterations in ER (12)(13)(14)(15)(16)(17). Further insight into the molecular mediators of tamoxifen and hormone therapy resistance would have great impact on the ability to target genes and pathways that could overcome drug resistance and lead to improved clinical outcomes.…”

WITHDRAWN: Prognostic value of circulating tumor DNA in breast cancers

“…Previous studies have reported that TP53 mutations are found in more than 80% of ctDNA samples. Mutations in the ESR1 gene are acquired in approximately 20% of breast cancers patients treated with endocrine agents and constitute a mechanism of resistance to aromatase inhibitors [38][39][40].…”

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…More recently, several studies have reported the identification of mutations in the ERα LBD in metastases of patients having undergone at least one line of endocrine treatment (Li et al . 2013, Merenbakh-Lamin et al . 2013, Robinson et al .…”