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

Retinoic acid receptor ? (RAR?) 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 RAR? does not correlate with the overall survival of TNBC patients, we speculate that post-translational modification such as phosphorylation of RAR? may be involved in EMT and TNBC metastasis. After overexpressing a phosphorylation-defective mutant of RAR? at serine 77 residue (RAR?S77A), we found that RAR? 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 ?-catenin and zinc finger E-box-binding homeobox 1 (ZEB1) in agreement with the suppression of EMT. Interestingly, the overexpression of wild-type RAR? in the presence of the RAR? agonist AM580 failed to suppress EMT and cell migration. These results indicate that hypophosphorylated RAR?S77 can directly mimic activated RAR? to inhibit EMT and migration/invasion of cells, thus providing a novel target in the therapeutic intervention of TNBC.