PDIA4-NF-κB 信号介导可溶性 E-cadherin 驱动的炎性乳腺癌进展

Background: Inflammatory breast cancer (IBC) is an aggressive form of primary breast cancer marked by rapid progression and a high propensity for metastasis. Despite its severity, no specific FDA-approved targeted therapies exist for IBC, highlighting the need for novel therapeutic strategies. Through analysis of metastatic xenograft-derived IBC sublines, we identified soluble E-cadherin (sEcad), a proteolytic extracellular fragment of full-length E-cadherin, as a protein associated with tumor aggressiveness and metastasis. Mass spectrometry-based proteomics further identified Protein Disulfide Isomerase A4 (PDIA4) as a novel sEcad-binding partner. We hypothesize that sEcad promotes IBC tumor progression via PDIA4-dependent mechanisms. Methods: sEcad was stably overexpresed in MDA-IBC3 and SUM149 IBC cells via lentiviral transduction, and PDIA4 was silenced using lentiviral shRNAs. Modified cells were injected into cleared mammary fat pads of SCID/Beige mice to assess tumor growth and progression. Protein-protein interactions were validated by co-immunoprecipitation. RNA-seq and GSEA were used to identify enriched pathways. Serum sEcad levels from IBC patients (n=301) and healthy donors (n=20) were measured by ELISA. Results: Serum sEcad levels were significantly higher in IBC patients than in healthy donors (P<0.0001). Elevated sEcad levels were associated with metastatic disease (p=0.0036), reduced overall survival (p=0.04), and increased risk of metastasis (0.004). Functionally, sEcad overexpression enhanced cell survival and colony formation in vitro, and mice injected with sEcad-overexpressing SUM149 or MDA-IBC3 cells exhibited accelerated tumor growth compared with controls (SUM149: p=0.007; MDA-IBC3: p=0.006). Mechanistically, endogenous and exogenous co-immunoprecipitation confirmed the interaction between sEcad and PDIA4. RNA-seq and GSEA revealed significant enrichment of NF-κB signaling in sEcad high cells. sEcad overexpression increased PDIA4 expression and NF-kB activation, whereas PDIA4 knockdown suppressed NF-κB activation and increased cell death. PDIA4 overexpression also enhanced NF-κB activation in IBC cells. In vivo, PDIA4 knockdown markedly reduced tumor incidence and tumor burden in sEcad-high IBC mouse models. Conclusions: Our study identifies sEcad functions as a clinically relevant biomarker and a driver of IBC progression via activation of PDIA4-dependent NF-kB signaling. These findings support sEcad and PDIA4 as mechanistically linked contributors to IBC and highlight this pathway as a potential therapeutic target.