Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype lacking ER, PR, and HER2, with limited targeted therapies. EDIL3/Del-1, a secreted glycoprotein enriched in extracellular vesicles, has been detected at elevated levels in TNBC, but its mechanistic contribution remains unclear. AMPK functions as a key energy sensor, and its β subunit (AMPKβ) is often amplified in cancers. This study examines Del-1's role in regulating AMPKβ and its effects on TNBC progression and patient outcomes. Methods AMPKβ expression in TNBC patient samples (n = 100, KNUCH) was evaluated by immunohistochemistry on tissue microarrays, and its prognostic relevance was further assessed using web-based TNBC patient cohorts (n = 126, KM Plotter). For the invitro assays, expression of Del-1 and AMPK subunits in TNBC cell lines was measured by qRT-PCR and Western blot. CRISPR/Cas9 was used to generate Del-1 knockout cells. Additionally, pharmacologic activation of AMPKβ and overexpression of a phospho-mimetic AMPKβ mutant were employed. Proliferation and invasion were assessed via MTT, BrdU, and Matrigel assays. Results In our institution KNUCH TNBC patient cohorts (n = 100), elevated AMPKβ protein levels by IHC showed a trend toward shorter distant disease-free survival (p = 0.067). Consistently, in a public TNBC cohort (n = 126), high PRKAB2 mRNA levels analyzed via KM plotter were significantly associated with reduced overall survival (p = 0.0009). In parallel, Del-1 and AMPKβ were found to be upregulated in TNBC cell lines, especially within the mesenchymal stem-like subtype, while AMPKα levels remained unchanged. Functional assays demonstrated that Del-1 overexpression or pharmacological activation of AMPKβ enhanced proliferation and invasion, whereas CRISPR/Cas9-mediated Del-1 knockout reduced AMPKβ expression and abrogated these phenotypes. Mechanistically, Del-1 promoted phosphorylation of AMPKβ at Ser108, and expression of a phospho-mimetic AMPKβ mutant recapitulated the tumor-promoting effects. Conclusions High AMPKβ expression in TNBC patient samples correlates with shorter distant disease-free and overall survival, underscoring its prognostic value. Complementing these clinical data, Del-1–mediated Ser108 phosphorylation of AMPKβ in mesenchymal stem-like TNBC cells promotes aggressive phenotypes, establishing AMPKβ as a promising biomarker and therapeutic target. Citation Format: S. Jeong, L. Soo Jung, L. Jeeyeon, L. In Hee, K. Byeongju, M. Joon Suk, P. Ho Yong, P. Ji Young, P. Nora Jee-Young, K. Eun Ae, K. Jieun, Y. Jung Dug, L. Yangsoo, J. Tae-Du, C. Yee Soo. Edil3/del-1-induced phosphorylation of ampkβ facilitates progression and correlates with poor prognosis in triple-negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-12-25.
Jeong et al. (2026) studied this question.