DCTPP1 is Transcriptionally Activated by FOXA1 to Affect Cisplatin Sensitivity in Triple-Negative Breast Cancer via Suppression of Ferroptosis.

Triple negative breast cancer (TNBC) leads to significant global death due to the therapeutic failure such as the development of chemoresistance. The objective of this study was to discover the potential targets inhibiting cancer progression and enhancing cisplatin sensitivity in TNBC. Forkhead Box Protein A1 (FOXA1) and deoxycytidine triphosphate pyrophosphatase 1 (DCTPP1) expression was detected via real-time quantification PCR and western blotting. Cell proliferation and death were examined using EdU and flow cytometry. Transwell migration/invasion assays were performed to assess cell metastasis. Associated indicators were determined to evaluate ferroptosis. Half inhibitory concentration of cisplatin was tested via cell counting kit-8 assay. In vivo assays were implemented using xenograft models in mice. FOXA1 and DCTPP1 binding was validated through chromatin immunoprecipitation and dual-luciferase reporter assays. DCTPP1 was highly expressed in TNBC tissues and cells, and DCTPP1 was related to poor prognosis. Silencing DCTPP1 impeded TNBC cell malignant phenotypes (reduced proliferation, inhibited migration/invasion, and enhanced cell death) in vitro and tumor growth in vivo. DCTPP1 knockdown increased cisplatin sensitivity of TNBC cells via inducing ferroptosis. FOXA1 activated transcription of DCTPP1 and then promoted DCTPP1 expression. FOXA1 overexpression contributed to TNBC cell development, while inhibited ferroptosis and cisplatin sensitivity. FOXA1 knockdown facilitated ferroptosis and cisplatin sensitivity by targeting DCTPP1 in TNBC cells. Animal model also showed that FOXA1/DCTPP1 mediated cisplatin sensitivity through ferroptosis in vivo. The above evidence elucidated the role of FOXA1-mediated DCTPP1 in regulating TNBC development and cisplatin sensitivity by mediating ferroptosis.