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

Abstract

Retinoic acid receptor α (RARα) is a transcription factor that plays an essential role in tumor progression. Triplenegative 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 β-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.

Keywords

• retinoic acid receptor α (rarα)
• triple-negative breast cancer (tnbc)
• epithelial-mesenchymal transition (emt)
• rarα agonist am580
• phosphorylation