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HERO ID
7476644
Reference Type
Journal Article
Title
The lncRNA MIR2052HG regulates ER alpha levels and aromatase inhibitor resistance through LMTK3 by recruiting EGR1
Author(s)
Cairns, J; Ingle, JN; Kalari, KR; Shepherd, LE; Kubo, M; Goetz, MP; Weinshilboum, RM; Wang, L
Year
2019
Is Peer Reviewed?
1
Journal
Breast Cancer Research
ISSN:
1465-5411
EISSN:
1465-542X
Volume
21
Issue
1
Page Numbers
47
Language
English
PMID
30944027
DOI
10.1186/s13058-019-1130-3
Web of Science Id
WOS:000463749200001
URL
https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-019-1130-3
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Abstract
Background: Our previous genome-wide association study using the MA.27 aromatase inhibitors adjuvant trial identified SNPs in the long noncoding RNA MIR2052HG associated with breast cancer-free interval. MIR2052HG maintained ER alpha both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated ER alpha degradation. Our goal was to further elucidate MIR2052HG's mechanism of action. Methods: RNA-binding protein immunoprecipitation assays were performed to demonstrate that the transcription factor, early growth response protein 1 (EGR1), worked together with MIR2052HG to regulate that lemur tyrosine kinase-3 (LMTK3) transcription in MCF7/AC1 and CAMA-1 cells. The location of EGR1 on the LMTK3 gene locus was mapped using chromatin immunoprecipitation assays. The co-localization of MIR2052HG RNA and the LMTK3 gene locus was determined using RNA-DNA dual fluorescent in situ hybridization. Single-nucleotide polymorphisms (SNP) effects were evaluated using a panel of human lymphoblastoid cell lines. Results: MIR2052HG depletion in breast cancer cells results in a decrease in LMTK3 expression and cell growth. Mechanistically, MIR2052HG interacts with EGR1 and facilitates its recruitment to the LMTK3 promoter. LMTK3 sustains ER levels by reducing protein kinase C (PKC) activity, resulting in increased ESR1 transcription mediated through AKT/FOXO3 and reduced ER alpha degradation mediated by the PKC/MEK/ERK/RSK1 pathway. MIR2052HG regulated LMTK3 in a SNP- and aromatase inhibitor-dependent fashion: the variant SNP increased EGR1 binding to LMTK3 promoter in response to androstenedione, relative to wild-type genotype, a pattern that can be reversed by aromatase inhibitor treatment. Finally, LMTK3 overexpression abolished the effect of MIR2052HG on PKC activity and ER alpha levels. Conclusions: Our findings support a model in which the MIR2052HG regulates LMTK3 via EGR1, and LMTK3 regulates ER alpha stability via the PKC/MEK/ERK/RSK1 axis. These results reveal a direct role of MIR2052HG in LMTK3 regulation and raise the possibilities of targeting MIR2052HG or LMTK3 in ER alpha-positive breast cancer.
Keywords
Lon noncoding RNA; MIR2052HG; EGR1; LMTK3; PKC; ER alpha; Aromatase inhibitor
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