SPDEF, known as the prostate-derived ETS factor, is a member of the ETS transcription factor family. It plays important roles in normal organs' cell development and survival, and is involved in multiple biological processes [1,2]. It has been associated with various pathways, and its dysregulation is related to cancer development [1-10]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In luminal breast cancer, SPDEF is upregulated, enhancing cancer stem-cell-like properties and tumorigenesis by directly promoting GALNT7 transcription, which is associated with tumor progression and poor prognosis [3]. In prostate cancer, the role of SPDEF is controversial. Some studies show its upregulation is associated with aggressive behavior and poor prognosis, especially in ERG-negative prostate cancer [6]. However, in advanced prostate cancer, hypermethylation leads to a decrease in SPDEF expression, and loss of its expression is related to increased cell migration and invasion [4]. In head and neck squamous cell carcinoma (HNSCC), SPDEF is downregulated, and restoring it suppresses HNSCC cell viability and tumor growth by transcriptionally activating NR4A1 [5]. In colorectal cancer, SPDEF can induce a quiescent state in cancer cells by disrupting β-catenin's binding to TCF1 and TCF3, thus inhibiting tumorigenesis [7].

In conclusion, SPDEF has dual roles in cancer, acting as both an oncogene and a tumor-suppressor depending on the cancer type. Studies using KO/CKO mouse models and other functional assays have revealed its significant functions in breast, prostate, head and neck, and colorectal cancers, providing insights into tumor biology and potential therapeutic targets.