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

Citation metadata

Date: Apr. 26, 2021
Publisher: BioMed Central Ltd.
Document Type: Article
Length: 5,857 words
Lexile Measure: 1670L

Document controls

Main content

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 [alpha] (RAR[alpha]) as a putative factor. The anti-tumor activity of hypo-phosphorylated RAR[alpha] was investigated in TNBC cell models and a xenograft mouse model. Next, miRNA sequencing analysis was performed to identify the target miRNA of RAR[alpha], and luciferase reporter was used to confirm the direct target gene of miR-3074-5p. Results We discovered that serine-77 residue of RAR[alpha] was constantly phosphorylated, which correlated with TNBC's resistance to retinoids. Overexpression of a phosphorylation-defective mutant RAR[alpha]S77A mimicked activated RAR[alpha] and repressed TNBC cell progression both in vitro and in vivo, via activating cell cycle arrest, apoptosis, and cytotoxic autophagy, independent of RAR[alpha] agonists. We further revealed that the anti-tumor action of RAR[alpha]S77A 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 RAR[alpha]S77 phosphorylation by either expressing RAR[alpha]S77A or inhibiting RAR[alpha]'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 RAR[alpha]S77 phosphorylation, miR-3074-5p, and DHRS3, emerges as a new target for TNBC treatment. Keywords: RAR[alpha], Triple-negative breast cancer, Phosphorylation, miR-3074-5p, DHRS3

Source Citation

Source Citation   

Gale Document Number: GALE|A661418763