Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, Sichuan, 646000, P. R. China.
Department of Pathophysiology, Mudanjiang Medical University, Heilongjiang, 157011, P. R. China.
Cell Death Dis. 2023 Aug 26;14(8):569. doi: 10.1038/s41419-023-06098-z.
Luminal breast cancer (BC) is the predominant subtype of breast cancer with a sustained risk of late recurrence and death. Understanding the molecular mechanisms for the oncogenesis of luminal BC would improve the prognosis for this large subset of patients. SPDEF was reported to be dysregulated in breast cancers. However, the biological functions and underlying molecular mechanism of SPDEF in luminal BC remains largely unknown. The aim of the present study was to elucidate the potential roles of SPDEF underlying subtype-specific functions in BC, especially in luminal subtypes.
The expressions and clinicopathological characteristics of SPDEF in luminal BC patients were evaluated bioinformatically. In vitro and in vivo assays were performed to investigate the oncogenic function and stemness maintenance of SPDEF in luminal BC. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were conducted to determine the transcription regulation of GALNT7 by SPDEF. GALNT7 levels in serum from luminal BC patients were further detected by enzyme-linked immunosorbent assay (ELISA).
SPDEF is markedly upregulated in luminal BC and positively associated with tumor progression and poor prognosis. Furthermore, we confirmed that SPDEF enhanced the proliferation, migration, invasion and stemness of luminal BC cells in vitro as well the tumorigenicity in vivo. Mechanistically, we demonstrated the stimulative effect of SPDEF on the progression and stemness of luminal BC, which is mediated by its directly transcriptional target GALNT7. Clinically, we verified that the GALNT7 can be used as a noninvasive diagnostic marker. Noteworthy, the combined detection of serum GALNT7 and traditional tumor markers can enhance diagnostic accuracy thus is of vital importance in the early diagnosis of luminal BC.
Our study reveals a novel mechanism by which SPDEF transcriptionally activates GALNT7 via directly binding to its promoter to promote cell proliferation, motility and stemness, and led to luminal BC tumorigenesis and poor prognosis.
腔面乳腺癌（BC）是乳腺癌的主要亚型，其复发和死亡的风险持续存在。了解腔面 BC 发生的分子机制将改善这一大部分患者的预后。SPDEF 已被报道在乳腺癌中失调。然而，SPDEF 在腔面 BC 中的生物学功能和潜在分子机制在很大程度上仍然未知。本研究旨在阐明 SPDEF 在 BC 特别是腔面亚型中具有亚组特异性功能的潜在作用。
通过生物信息学方法评估了 SPDEF 在腔面 BC 患者中的表达和临床病理特征。进行体外和体内实验，以研究 SPDEF 在腔面 BC 中的致癌功能和干性维持作用。进行染色质免疫沉淀（ChIP）和双荧光素酶报告基因检测，以确定 SPDEF 对 GALNT7 的转录调控。通过酶联免疫吸附测定（ELISA）检测腔面 BC 患者血清中的 GALNT7 水平。
SPDEF 在腔面 BC 中明显上调，与肿瘤进展和不良预后呈正相关。此外，我们证实 SPDEF 增强了腔面 BC 细胞在体外的增殖、迁移、侵袭和干性，以及体内的致瘤性。机制上，我们证明了 SPDEF 通过其直接转录靶标 GALNT7 对腔面 BC 的进展和干性的刺激作用。临床上，我们验证了 GALNT7 可以作为一种非侵入性的诊断标志物。值得注意的是，血清 GALNT7 与传统肿瘤标志物的联合检测可以提高诊断准确性，因此对腔面 BC 的早期诊断具有重要意义。
我们的研究揭示了一种新的机制，即 SPDEF 通过直接结合其启动子转录激活 GALNT7，从而促进细胞增殖、迁移和干性，导致腔面 BC 肿瘤发生和不良预后。
