BACKGROUND: This study investigates the role of DNA Damage Inducible Transcript 3 (DDIT3) in luminal A subtype breast cancer (LABC). DDIT3, a transcription factor linked to various stress responses, has been implicated in tumorigenesis, yet its specific contributions to LABC biology remain poorly understood. METHODS: To elucidate these functions, we utilized bioinformatics analyses, including data from TCGA and Kaplan-Meier databases. Furthermore, we performed siRNA-mediated knockdown and overexpression experiments in MCF-7 and T47D cells to assess DDIT3's functional impact on cell proliferation, drug resistance, etc. RNA sequencing analysis identified differentially expressed genes (DEGs) associated with DDIT3 manipulation, and pinpointing the crucial downstream target with rescue experiment. RESULTS: Compared to normal breast tissue, DDIT3 is lowly expressed in LABC, and LABC patients with low DDIT3 expression have a lower survival rate, indicating relatively poor prognosis. Furthermore, DDIT3 negatively regulates the proliferation of LABC cells, also negatively correlated with the sensitivity of TAM. RNA-seq result and rescue experiment identified the interferon regulatory factor 1 (IRF1) as a crucial downstream target of DDIT3 to regulating LABC cell proliferation and tamoxifen (TAM) resistance. CONCLUSIONS: DDIT3 is negatively correlated with poor prognosis in LABC patients. And DDIT3 may negatively regulate the proliferation and TAM sensitivity in LABC cells through the DDIT3-IRF1 axis.