Elevated ERβ expression driven by low ASB8-mediated ubiquitination in lung adenocarcinoma promotes lymph node metastasis via tumor-associated neutrophils

This study investigated the role of estrogen receptor beta (ERβ) in the lymph node metastasis of lung adenocarcinoma (LUAD), focusing on its interaction with tumor-associated neutrophils (TANs) and its regulation of lymphangiogenesis. Clinical analysis of LUAD patient samples revealed that high ERβ expression was correlated with positive lymph node metastasis and increased lymphatic vessel density. In vitro experiments showed that ERβ promotes neutrophil chemotaxis by regulating CCL15 transcription, whereas TANs secrete VEGF-C, enhancing lymphangiogenesis. Using an orthotopic lung cancer model, we confirmed that ERβ facilitates LUAD lymph node metastasis through TAN recruitment, and inhibiting neutrophils with anti-Ly6G antibodies or CCR1 antagonists reduced this effect. Additionally, the study found that ASB8, an E3 ubiquitin ligase, degrades ERβ through K48-linked polyubiquitination. Low ASB8 expression results in increased ERβ stability and promotes LUAD metastasis. These findings suggest that ERβ, by recruiting TANs through the CCL15-CCR1 axis, plays a key role in LUAD lymph node metastasis, with ASB8 acting as a crucial regulator of ERβ stability. Targeting ERβ and ASB8 could offer new therapeutic strategies for LUAD metastasis, warranting further investigation of their clinical applications.