# EDIL3/Del-1-Dependent Induction of AMPKβ Phosphorylation Regulates the Progression of Mesenchymal Stem-like Triple-Negative Breast Cancer

## TL;DR

This study shows that EDIL3/Del-1 promotes aggressive triple-negative breast cancer by activating AMPKβ, suggesting AMPKβ as a potential treatment target.

## Contribution

The study identifies a novel mechanism by which Del-1 promotes TNBC through AMPKβ phosphorylation and suggests AMPKβ as a therapeutic target.

## Key findings

- Del-1 and AMPKβ are enriched in mesenchymal stem-like TNBC cells and promote tumor growth and invasion.
- Del-1 deletion reduces AMPKβ expression and suppresses tumor-promoting behaviors in TNBC cells.
- High AMPKβ expression is linked to poorer disease-free survival in early-stage TNBC patients.

## Abstract

Triple-negative breast cancer (TNBC) lacks effective targeted therapies, and the mechanisms by which developmental endothelial locus-1 (EDIL3/Del-1) promotes TNBC remain incompletely defined. We profiled Del-1 and AMPK subunits in TNBC cell lines by RT-PCR and immunoblotting, performed functional assays in CRISPR/Cas9 Del-1 knockout and AMPKβ-manipulated cells, and evaluated AMPKβ in early-stage TNBC tumors using tissue microarrays (TMA) (immunohistochemistry; n = 100) and AMPKβ2 mRNA quantification. Del-1 and AMPKβ were enriched in TNBC cells, most prominently in the mesenchymal stem-like subtype, whereas AMPKα levels were relatively stable. Increased Del-1 and activated AMPKβ enhanced proliferation and invasion, while Del-1 deletion reduced AMPKβ expression and suppressed tumor-promoting phenotypes. Mechanistically, Del-1 increased AMPKβ phosphorylation at serine 108, and a phospho-mimetic AMPKβ mutant further amplified oncogenic effects. In the pilot TMA study, high AMPKβ protein expression showed a trend toward poorer DFS in Kaplan–Meier analysis, while multivariate analysis identified high AMPKβ protein expression as an independent factor associated with poorer DFS in patients with early TNBC. These data support AMPKβ as a key mediator of Del-1-driven signaling and suggest AMPKβ could be a therapeutic target in aggressive TNBC subsets.