SPDEF enhances cancer stem cell-like properties and tumorigenesis through directly promoting GALNT7 transcription in luminal breast cancer

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.