Bone Marrow Stromal Cells Transcriptionally Repress ESR1 but Cannot Overcome Constitutive ESR1 Mutant Activity. Endocrinology 2019 Oct 01;160(10):2427-2440
Date
09/11/2019Pubmed ID
31504407Pubmed Central ID
PMC6760314DOI
10.1210/en.2019-00299Scopus ID
2-s2.0-85072628742 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Estrogen receptor α (ER) is the target of endocrine therapies in ER-positive breast cancer (BC), but their therapeutic effectiveness diminishes with disease progression. Most metastatic BCs retain an ER-positive status, but ER expression levels are reduced. We asked how the bone tumor microenvironment (TME) regulates ER expression. We observed ESR1 mRNA and ER protein downregulation in BC cells treated with conditioned media (CM) from patient-derived, cancer-activated bone marrow stromal cells (BMSCs) and the BMSC cell line HS5. Decreases in ESR1 mRNA were attributed to decreases in nascent transcripts as well as decreased RNA polymerase II occupancy and H3K27Ac levels on the ESR1 promoter and/or distal enhancer (ENH1). Repression extended to neighboring genes of ESR1, including ARMT1 and SYNE1. Although ERK/MAPK signaling pathway can repress ER expression by other TME cell types, MAPK inhibition did not reverse decreases in ER expression by BMSC-CM. ESR1 mRNA and ER protein half-lives in MCF7 cells were unchanged by BMSC-CM treatment. Whereas ER phosphorylation was induced, ER activity was repressed by BMSC-CM as neither ER occupancy at known binding sites nor estrogen response element-luciferase activity was detected. BMSC-CM also repressed expression of ER target genes. In cells expressing the Y537S and D538G ESR1 mutations, BMSC-CM reduced ESR1, but expression of target genes PGR and TFF1 remained significantly elevated compared with that of control wild-type cells. These studies demonstrate that BMSCs can transcriptionally corepress ESR1 with neighboring genes and inhibit receptor activity, but the functional consequences of the BMSC TME can be limited by metastasis-associated ESR1 mutations.
Author List
Lung DK, Warrick JW, Hematti P, Callander NS, Mark CJ, Miyamoto S, Alarid ETAuthor
Peiman Hematti MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Estrogen Receptor alphaGene Expression Regulation
Humans
MCF-7 Cells
Mitogen-Activated Protein Kinase Kinases
Mutation
Protein Processing, Post-Translational
RNA, Messenger
Transcription, Genetic