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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Breast Cancer | Research

Inhibition of retinoic acid receptor α phosphorylation represses the progression of triple-negative breast cancer via transactivating miR-3074-5p to target DHRS3

Authors: Siyue Lou, Hang Gao, Huanwu Hong, Zhihui Zhu, Huajun Zhao

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Retinoids are promising agents in the treatment of different types of neoplasia including estrogen receptor-positive breast cancers, whereas refractoriness/low sensitivity is observed in triple-negative breast cancer (TNBC) subtype. However, the reason for these diverse retinoid-sensitivity remains elusive.

Methods

Determinants of retinoid sensitivity were investigated using immunohistochemistry of primary patient samples, and identified retinoic acid receptor α (RARα) as a putative factor. The anti-tumor activity of hypo-phosphorylated RARα was investigated in TNBC cell models and a xenograft mouse model. Next, miRNA sequencing analysis was performed to identify the target miRNA of RARα, and luciferase reporter was used to confirm the direct target gene of miR-3074-5p.

Results

We discovered that serine-77 residue of RARα was constantly phosphorylated, which correlated with TNBC’s resistance to retinoids. Overexpression of a phosphorylation-defective mutant RARαS77A mimicked activated RARα and repressed TNBC cell progression both in vitro and in vivo, via activating cell cycle arrest, apoptosis, and cytotoxic autophagy, independent of RARα agonists. We further revealed that the anti-tumor action of RARαS77A was, at least in part, mediated by the up-regulation of miR-3074-5p, which directly targeted DHRS3, a reductase negatively associated with TNBC patient survival. Our results suggest that the inhibition of RARαS77 phosphorylation by either expressing RARαS77A or inhibiting RARα’s phosphokinase CDK7, can bypass RA stimuli to transactivate tumor-suppressive miR-3074-5p and reduce oncogenic DHRS3, thus overcoming the RA-resistance of TNBC.

Conclusion

The novel regulatory network, involving RARαS77 phosphorylation, miR-3074-5p, and DHRS3, emerges as a new target for TNBC treatment.

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Title: Inhibition of retinoic acid receptor α phosphorylation represses the progression of triple-negative breast cancer via transactivating miR-3074-5p to target DHRS3
Authors: Siyue Lou
Hang Gao
Huanwu Hong
Zhihui Zhu
Huajun Zhao
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Breast Cancer
Breast Cancer
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01941-7

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