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Tumor Cell JAGGED-1 Promotes Lymph Node Metastasis and Predicts Recurrence in Lymph Node Positive Breast Cancer Patients [hdLEC_JAG1_TLA]

ABSTRACT: Purpose: Lymph node invasion is a hallmark of breast cancer disease progression, but current treatment strategies lack guidance from lymph node biomarkers. We investigated JAGGED1 (JAG1) as a promoter of lymph node metastasis and a prognostic biomarker in metastatic lymph node specimens. Experimental Design: We used mouse models to assess the role of JAG1 expression in human and mouse breast cancer cells on lymphovascular invasion, lymph node metastatic potential, transcriptional profiles, and tumor interactions with lymphatic endothelium. We examined breast and lymph node samples from 284 breast cancer patients to determine the correlative and prognostic value of tumoral JAG1 expression in the lymph node. Results: In matched human breast tumor and lymph node samples, tumor cells that invaded lymph nodes showed higher JAG1 expression than their associated primary tumors (P value < 0.0001). In multiple models, breast cancer cells with high JAG1 expression showed increased lymphovascular invasion, lymph node metastasis, lymph node metastatic outgrowth, and migration through lymphatic endothelium. Transcriptomic analysis indicated that tumoral JAG1 regulates both juxtacrine and paracrine signaling pathways that induce inflammatory and pro-metastatic genes in lymphatic endothelium. When examining patients with identical surgical treatments, patients with lymph node JAG1 H-scorelow showed increased 5-year recurrence free survival rates than patients with lymph node JAG1 H-scorehi (87% vs 70%, P=0.016). Conclusions: JAG1 expression promotes lymphovascular invasion and lymph node metastasis in murine models. In patients, high expression of JAG1 in tumor cells in lymph node metastases predicts reduced recurrence free survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252953 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:Background Breast cancer patients who present in the early stage of disease are affected by metastasis to the axillary group of lymph nodes. The first among this group that is affected is called as sentinel lymph node, and metastasis to this lymph node is crucial for the staging of cancer and the quality of surgical intervention. Sentinel Lymph Node Biopsy (SLNB) that is currently used to assess lymph node metastasis is neither sensitive, nor specific, is time-consuming, thereby necessitating the identification of novel biomarkers that can flag sentinel lymph node metastasis. Methods Breast cancer patients were screened, and those with early stage were recruited in the study. Surgical resection of the breast was followed by identification of sentinel lymph nodes by methylene fluorescent technique. Histo-pathology of fresh frozen section biopsy was used as the gold standard to assign the clinical phenotypes of metastatic (SLNM+) and non-metastatic sentinel lymph nodes (SLNM-). Discovery phase of the experiment included isobaric Tags for Relative and Absolute Quantitation (iTRAQ) technique comprising of six comparative experiments coupled with mass spectrometric analysis on Orbitrap Fusion to identify differentially expressed proteins on Proteome Discoverer 2.4. Functional enrichment and pathway analyses of differentially regulated genes was carried out in DAVID functional annotation tool. Validation was done by ELISA and protein concentrations were used to estimate the ROC for computing diagnostic parameters. Results Based on MS/MS spectra there were 2396 unique protein groups and 81 differentially expressed proteins comparing SLNB + and SLNB -. Nineteen proteins up-regulated, and eight proteins that were down regulated in SLNB+ as compared to SLNB-. Bioinformatic analysis showed the implication of extra cellular matrix proteins and ECM-receptor interaction pathways to be implicated in lymph node metastasis. ELISA confirmed the up-regulation of caveolin 1, collagen α-1, desmin, fibrillin-1, and microfibrillar associated glycoprotein 4 in metastatic, as compared to non-metastatic lymph nodes. These proteins are known to be integral in tumorogenesis, cell proliferation, invasion, cell survival and anti-apoptosis. These proteins have 80%-100%, of sensitivity and specificity to differentiate the two clinical phenotypes. Conclusion Identified extra cellular matrix protein biomarkers have requisite diagnostic parameters to be developed as a translational tool to assess the status of sentinel lymph nodes during mastectomy procedure to guide surgical therapy of axillary lymph nodes in early breast oncology.

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Tumor Cell JAGGED-1 Promotes Lymph Node Metastasis and Predicts Recurrence in Lymph Node Positive Breast Cancer Patients [hdLEC_JAG1_TLA]

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