HotspotESR1Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis

Abstract

Constitutively active estrogen receptor α (ER/ESR1) mutations have been identified in approximately one-third of ER+ metastatic breast cancers. Although these mutations are known as mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1-mutant tumors, genome-edited ESR1 Y537S and D538G-mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell–cell contacts while decreasing cell-extracellular matrix adhesion. In vivo studies showed ESR1-mutant cells were associated with larger multicellular circulating tumor cell (CTC) clusters with increased compactness compared with ESR1 wild-type CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, context-dependent migratory phenotypes revealed cotargeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited noncanonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation–modulated metastasis and suggest future therapeutic strategies for targeting ESR1-mutant breast cancer. Significance: Context- and allele-dependent transcriptome and cistrome reprogramming in mutant ESR1 cell models elicit diverse metastatic phenotypes related to cell adhesion and migration, which can be pharmacologically targeted in metastatic breast cancer.

Estrogen receptor alpha mutations regulate gene expression and cell growth in breast cancer through microRNAs

“…The frequent occurrence of ER mutations in hormone therapy-resistant ER-positive metastatic breast cancer has led to intense research efforts to elucidate the molecular and phenotypic effects of ER mutations and to identify vulnerabilities in ER mutant cancers that could be exploited to develop effective therapies for hormone therapy-resistant tumors (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). In a previous study, we used isogenic T-47D models expressing the Y537S or D538G ER mutations from the endogenous ER locus to show that ER mutations regulated the differential expression of thousands of genes and that these transcriptional changes were accompanied by phenotypic changes, including increased migration, invasion, and proliferation (16,17).…”

“…Structural changes in ER's LBD as a result of ER LBD mutations confer an active conformation and ligand-independent activity to unliganded mutant ER, which drives large transcriptional changes in the absence of estrogens (5,7,9,(11)(12)(13)(14)(15)(16). Several studies have shown that this dramatic change in gene expression can drive increased cellular proliferation, invasion, and metastasis in breast cancer cells expressing mutant ER (4,5,9,13,14,(16)(17)(18). Recently, we showed that over half of these gene expression changes are driven directly by the constitutive activity of ER (16).…”

“…Activating mutations in the ligand binding domain (LBD) of ER have been observed in approximately 30% of hormone therapy-resistant ER-positive breast cancers (4)(5)(6). Over the last decade, several studies have improved our understanding of ER mutations and the mechanisms by which these mutations lead to breast cancer recurrence (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Structural changes in ER's LBD as a result of ER LBD mutations confer an active conformation and ligand-independent activity to unliganded mutant ER, which drives large transcriptional changes in the absence of estrogens (5,7,9,(11)(12)(13)(14)(15)(16).…”

Detection of circulating tumor cells: opportunities and challenges

“…Many studies have identified genes that can be used as prognostic markers by CTC detection, including HER2, ESR1, PI3KCA, PSMA, MYC, TP53 and so on [173][174][175][176]. Several studies have demonstrated the feasibility of evaluating HER2 status of CTCs in BC using CellSearch ® [136,177,178].…”

Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role

“…In ESR1-mut breast cancer, research demonstrates further genomic dysregulation and downstream signaling modulation that could be leveraged, including aberrant DNA bindings cofactors FOXA1 and CTCF, 41 NOTCH signaling, 41 and Wnt signaling. 135 …”