Dynorphin A Inhibits the Proliferation, Migration, Invasion, and Stemness of Triple Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is an aggressive subtype that is characterized by a high metastatic capacity, limited therapeutic options, and a poor prognosis, largely because of its stemness properties and aberrant signaling. Dynorphin A, an endogenous opioid peptide, has been identified as a potential modulator of cancer progression, although its role in TNBC remains unclear. This study demonstrates that the Dynorphin/κ-opioid receptor (KOR) signaling axis is markedly diminished in TNBC patients and TNBC cell lines, suggesting its tumor-suppressive function. Functional assays revealed that Dynorphin A suppresses TNBC cell proliferation, migration, invasion, and stemness while inducing apoptosis. Cell cycle analysis showed Dynorphin A induced G1/S phase arrest. Mechanistically, Dynorphin A blocked epithelial-mesenchymal transition (EMT) by restoring E-cadherin and reducing N-cadherin, Vimentin, and Snail. Morphological analysis confirmed a reversion from mesenchymal to epithelial phenotype. Furthermore, it attenuated stem cell-like properties as indicated by lower levels of CD44, CD133, and Octamer-binding transcription factor 4 (OCT4). Notably, Dynorphin A disrupted zinc finger E-box binding homeobox 1 (ZEB1)-mediated Wnt/β-catenin signaling, and forced expression of ZEB1 partially rescued β-catenin levels, confirming that ZEB1 is a downstream mediator. These findings identify Dynorphin A as a promising endogenous inhibitor of TNBC progression that targets both malignancy and stemness via the ZEB1/β-catenin axis.