Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER+ breast cancer

Abstract

Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less understood. We recently discovered that the Hippo pathway is required for the proper expression of ESR1. YAP/TAZ are transcription coactivators that are phosphorylated and inhibited by the Hippo pathway kinase LATS. Here we delineated the molecular mechanisms underlying ESR1 transcription repression by the Hippo pathway. Mechanistically, YAP binds to TEAD to increase local chromatin accessibility to stimulate transcription of nearby genes. Among the YAP target genes, Vestigial-Like Protein 3 (VGLL3) competes with YAP/TAZ for binding to TEAD transcription factor and recruits the NCOR2/SMRT repressor to the super-enhancer of ESR1 gene, leading to epigenetic alteration and transcriptional silencing. We developed a potent LATS inhibitor VT02956. Targeting the Hippo pathway by VT02956 represses ESR1 expression and inhibits the growth of ER+ breast cancer cells as well as patient-derived tumour organoids. Moreover, histone deacetylase inhibitors, such as Entinostat, induce VGLL3 expression to inhibit ER+ breast cancer cells. Our study suggests LATS as unexpected cancer therapeutic targets, especially for endocrine-resistant breast cancers.

Pharmacological blockade of TEAD–YAP reveals its therapeutic limitation in cancer cells

“…Previously, VGLL3 has been shown to enhance breast cancer cell proliferation and drive systemic autoimmunity 62 , 63 . Recently, VGLL3 has been shown to bind to TEAD and suppress ESR1 gene expression 64 . Here we show that VGLL3 functions as a transcription co-activator to induce the expression of YAP-suppressed genes, suggesting complexed and context dependent functions of VGLL family of proteins.…”

ENDORSE: a prognostic model for endocrine therapy in estrogen‐receptor‐positive breast cancers

“…In the METABRIC cohort, tumors with early mortality (within 5 years of sample collection) showed consistent enrichment of pathways that are known to contribute to epithelial to mesenchymal transition, angiogenesis, and stemness. Enriched pathways, including TGF‐beta (Band & Laiho, 2011 ) and YAP (Ma et al , 2022 ), have been suggested to directly crosstalk and repress the estrogen receptor signaling pathway. Concurrently, MEK (Fujii et al , 2011 ) and PI3K/AKT/MTOR (Ciruelos Gil, 2014 ) have been implicated as key primary resistance mechanisms in endocrine‐resistant ER + breast cancers.…”

Robust ERα-Targeted Near-Infrared Fluorescence Probe for Selective Hydrazine Imaging in Breast Cancer

“…Among these patients, nearly 79% cases are estrogen receptor α (ERα)-positive, which is a hormone receptor that mediates estrogen effect and regulates transcription and expression of estrogen-sensitive genes. Aberrant ERα activity has been observed in a variety of diseases, − including breast cancer. Meanwhile, several pieces of accumulated evidence have suggested that ERα plays an important role in the development and progression of breast cancer .…”