Hypophosphorylation of retinoic acid receptor alpha inhibits triple-negative breast cancer cell migration and invasion

Authors

  • Jiajia Ying School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China
  • Fanli Zheng School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China
  • Yanan Zheng School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China
  • Hongtao Hu School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China
  • Siyue Lou School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China https://orcid.org/0000-0002-5119-9799

DOI:

https://doi.org/10.2298/ABS220531025Y

Keywords:

retinoic acid receptor α (RARα), triple-negative breast cancer (TNBC), epithelial-mesenchymal transition (EMT), RARα agonist AM580, phosphorylation

Abstract

Paper description:

  • Retinoic acid receptor alpha (RARα) is a critical transcription factor whose phosphorylation regulation is ill-defined in triple-negative breast cancer (TNBC) progression.
  • We overexpressed a phosphorylation-defective mutant RARαS77A to reduce RARα phosphorylation and monitored its effect on TNBC cell migration and invasion.
  • RARαS77A inhibited cell motility in vitro and in vivo via suppression of epithelial-mesenchymal transition (EMT), whereas wild-type RARα in the presence of the RARα agonist AM580 failed to suppress cell migration.
  • Hypophosphorylated RARαS77 directly mimics activated RARα to inhibit EMT and TNBC migration/invasion, thus providing a novel target in the therapeutic intervention in TNBC.

Abstract: Retinoic acid receptor α (RARα) is a transcription factor that plays an essential role in tumor progression. Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma with a poor prognosis due to early therapeutic escape from conventional treatments and aggressive metastatic relapse by the occurrence of an epithelial-mesenchymal transition (EMT). However, as the expression level of RARα does not correlate with the overall survival of TNBC patients, we speculate that post-translational modification such as phosphorylation of RARα may be involved in EMT and TNBC metastasis. After overexpressing a phosphorylation-defective mutant of RARα at serine 77 residue (RARαS77A), we found that RARα hypophosphorylation inhibited MDA-MB-231 cell motility and migration in vitro while reducing the lung metastatic potential in vivo. This was accompanied by increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers b-catenin and zinc finger E-box-binding homeobox 1 (ZEB1) in agreement with the suppression of EMT. Interestingly, the overexpression of wild-type RARα in the presence of the RARα agonist AM580 failed to suppress EMT and cell migration. These results indicate that hypophosphorylated RARαS77 can directly mimic activated RARα to inhibit EMT and migration/invasion of cells, thus providing a novel target in the therapeutic intervention of TNBC.

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Published

2022-10-05

How to Cite

1.
Ying J, Zheng F, Zheng Y, Hu H, Lou S. Hypophosphorylation of retinoic acid receptor alpha inhibits triple-negative breast cancer cell migration and invasion. Arch Biol Sci [Internet]. 2022Oct.5 [cited 2024Nov.27];74(3):263-70. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/7818

Issue

Vol. 74 No. 3 (2022)

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Articles

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Copyright (c) 2022 Jiajia Ying, Fanli Zheng, Yanan Zheng, Hongtao Hu, Siyue Lou

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