Background/Objectives: Breast cancer is a heterogeneous disease, and the role of the transcription factor SPDEF remains controversial. We aimed to clarify the prognostic value of SPDEF, explore demographic and molecular correlates of its expression, and investigate potential regulatory mechanisms underlying its dysregulation. Methods: Genomic and clinical data for 1218 breast cancer tumors were obtained from The Cancer Genome Atlas (TCGA). SPDEF mRNA expression was compared across intrinsic subtypes, age, and race, and prognostic significance was evaluated by Kaplan–Meier analysis. Promoter methylation patterns and DNA methyltransferase (DNMT) expression were examined as potential regulatory drivers. Co-expression analysis was performed using gene panels representing luminal differentiation, basal identity, EMT, proliferation, DNA repair, and immune signaling. Results: Low SPDEF expression was significantly associated with worse overall, relapse-free, and metastasis-free survival across all breast cancers. Expression was lowest in Basal tumors, as well as among younger and Black or African American patients. Promoter methylation at six CpG islands correlated with both reduced SPDEF expression and inferior survival, and DNMT1, DNMT3A, and DNMT3B overexpression also aligned with poor prognosis and Basal enrichment. Co-expression analysis revealed that SPDEF downregulation coincided with loss of luminal markers and increased EMT, proliferation, DNA repair, and immune pathways. Conclusions: SPDEF functions as a tumor suppressor in breast cancer, with reduced expression linked to poor outcomes, aggressive molecular features, and epigenetic regulation. These findings highlight SPDEF and DNMT-driven methylation as potential prognostic biomarkers for enhanced risk stratification and targets for novel therapies, particularly in Basal breast cancers.
**背景/目的：** 乳腺癌是一种异质性疾病，转录因子SPDEF的作用仍存在争议。本研究旨在阐明SPDEF的预后价值，探讨其表达与人口统计学及分子特征的相关性，并研究其表达失调的潜在调控机制。 **方法：** 从癌症基因组图谱（TCGA）数据库获取1218例乳腺癌肿瘤的基因组和临床数据。比较了SPDEF mRNA表达在不同内在亚型、年龄和种族间的差异，并通过Kaplan-Meier分析评估其预后意义。研究了启动子甲基化模式和DNA甲基转移酶（DNMT）表达作为潜在的调控驱动因素。使用代表管腔分化、基底特征、上皮间质转化（EMT）、增殖、DNA修复和免疫信号通路的基因集进行了共表达分析。 **结果：** 在所有乳腺癌中，低SPDEF表达与较差的总生存期、无复发生存期和无转移生存期显著相关。SPDEF表达在基底样肿瘤以及年轻患者、黑人或非裔美国患者中最低。六个CpG岛的启动子甲基化与SPDEF表达降低和生存期较差相关，并且DNMT1、DNMT3A和DNMT3B的过表达也与不良预后和基底样富集相关。共表达分析显示，SPDEF下调与管腔标志物丢失以及EMT、增殖、DNA修复和免疫通路激活同时发生。 **结论：** SPDEF在乳腺癌中发挥肿瘤抑制因子的作用，其表达降低与不良预后、侵袭性分子特征和表观遗传调控相关。这些发现强调了SPDEF和DNMT驱动的甲基化作为潜在的预后生物标志物，可用于增强风险分层，并作为新型疗法的靶点，特别是在基底样乳腺癌中。
肿瘤(癌症)患者之家