Triple-negative breast cancer (TNBC) is a subtype of breast cancer which has the poorest prognosis, with high recurrence and metastasis rates. ZNF503 (Zinc finger elbow-related proline domain protein 2) was a transcriptional factor involved in the aggressive breast cancer development through the down-regulation of GATA3 expression. However, the precise role of the ZNF503/GATA3 axis in TNBC progression and metastasis remains unclear.

RT-qPCR and Western blotting were used to investigate the expression profiles of ZNF503 and GATA3 in breast cancer cell lines. Stable cell lines with either gene knockdown or overexpression were subsequently established for mechanistic investigations in vitro and in vivo functional studies. Chromatin immunoprecipitation (ChIP), RT-qPCR, Western blotting, CCK-8, Transwell and immunofluorescence experiments were performed to reveal the molecular mechanisms of CXCL12/ZNF503/GATA3 on TNBC progression. Bioinformatic prediction using UCSC Genome Browser and JASPAR database identified NF-κB as a potential regulator of ZNF503, which was subsequently validated through dual luciferase reporter assays and ChIP experiments. RNA-seq and GO analysis were conducted to screen MMP1 as the downstream molecule. The prognostic value of CXCL12/ZNF503/GATA3/MMP1 was assessed by Kaplan-Meier survival curves and ROC curves analyses.

In this study, we observed that ZNF503 was highly expressed in TNBC and contributed to TNBC proliferation and metastasis by suppressing GATA3 expression. We further identified that CXCL12 regulated ZNF503/GATA3 expression via the PI3K/Akt/NF-κB signaling pathway, thereby driving TNBC proliferation and metastasis. Additionally, the CXCL12/ZNF503/GATA3 axis promoted TNBC progression by regulating the downstream molecule MMP1. Meanwhile, we suggested that the CXCL12/ZNF503/GATA3/MMP1 signature has the potential to serve as a valuable biomarker for TNBC prognosis.

Our findings underscored that the CXCL12/ZNF503/GATA3/MMP1 axis facilitated tumor progression and metastasis of TNBC, thus providing a novel therapeutic strategy for TNBC treatment.