Suppression of NGALR impedes TNBC cell survival, proliferation, invasion, and migration through Akt/mTOR and JAK/STAT3 pathway inhibition.

[PURPOSE] Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype lacking estrogen, progesterone, and HER2 receptors, thereby limiting targeted therapeutic options. The present study aimed to elucidate the functional significance of neutrophil gelatinase-associated lipocalin receptor (NGALR) in TNBC progression and evaluate its potential as a therapeutic target.

[METHODS] Expression levels of NGALR were analyzed in TNBC cell lines and tissue samples. Functional assays were performed following siRNA-mediated silencing of NGALR to assess effects on cell proliferation, survival, migration, and invasion. Changes in cell cycle distribution, autophagy induction, and expression of associated regulatory proteins were examined using flow cytometry and immunoblotting. The modulation of key signaling pathways, including Akt/mTOR and JAK/STAT3, was also investigated.

[RESULTS] NGALR was markedly upregulated in TNBC cells and tissues compared with controls. NGALR knockdown significantly reduced cell proliferation and survival, induced S-phase arrest, and enhanced autophagic activity. Silencing NGALR decreased the expression of Bcl-2, Cox-2, Cyclin A2, and survivin while increasing p21 levels. Additionally, NGALR suppression diminished migratory and invasive capabilities, accompanied by reduced expression of N-cadherin, Vimentin, Snail, Twist-1, VEGF-A, and CXCR-4, and enhanced E-cadherin levels. Inhibition of NGALR also downregulated the Akt/mTOR and JAK/STAT3 signaling cascades, both integral to TNBC progression.

[CONCLUSIONS] The study demonstrates that NGALR promotes TNBC cell growth, invasion, and survival through modulation of cell cycle, autophagy, and oncogenic signaling pathways. NGALR represents a promising therapeutic target warranting further preclinical and clinical validation.