Soluble N-terminal EphA2 fragment as a diagnostic biomarker and functional mediator of tumor progression in triple-negative breast cancer.
9 affiliations
- 1Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
- 2School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
- 3Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
- 4Taiwan Autoantibody Biobank Initiative, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
- 5Ph.D. Program in Innovative Medical Technology Research and Development Industry, Taipei Medical University, Taipei, Taiwan.
- 6Department of Laboratory Medicine, Lotung PohAi Hospital, Lo-Hsu Medical Foundation, Yilan, Taiwan; Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
- 7Ph.D. Program in Innovative Medical Technology Research and Development Industry, Taipei Medical University, Taipei, Taiwan; National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
- 8Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
- 9Department of Laboratory Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Abstract
Triple-negative breast cancer (TNBC) lacks reliable biomarkers for early detection and remains a highly aggressive disease. Ephrin type-A receptor 2 (EphA2), a receptor tyrosine kinase frequently overexpressed in advanced cancers, undergoes MMP14-mediated cleavage that releases soluble N-terminal fragments. Here, we investigated the diagnostic and functional significance of this fragment in TNBC. Immunohistochemical analysis of clinical specimens revealed elevated EphA2 expression in TNBC tissues, with a trend toward higher levels in tumors of advanced stage and grade. To enable non-invasive detection, we established a dual-epitope sandwich ELISA targeting spatially distinct regions of the EphA2 extracellular domain. The assay showed concentration-dependent detection of recombinant EphA2 (EC₅₀, 48 ng/mL) and detected soluble EphA2 in TNBC cell-conditioned media. Serum analysis showed significantly higher EphA2 levels in TNBC patients compared with healthy controls (median 93.3 vs 25.6 ng/mL). In this exploratory cohort, ROC analysis yielded an AUC of 0.912 (95% CI, 0.862-0.962), with a sensitivity of 95.0% (95% CI, 86.3-98.6%) and a specificity of 78.3% (95% CI, 66.4-86.9%), and higher levels were associated with lymph node metastasis and higher histological grade. Functionally, recombinant EphA2-P328 promoted TNBC-cell migration and induced cell context-dependent changes in EMT-associated markers in vitro. Collectively, these findings support the soluble N-terminal EphA2 fragment as a candidate serum biomarker and an in vitro modulator of TNBC cell migration, warranting validation in larger independent cohorts and further mechanistic investigation.
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BibTeX
@article{lin2026soluble,
title = {{Soluble N-terminal EphA2 fragment as a diagnostic biomarker and functional mediator of tumor progression in triple-negative breast cancer.}},
author = {Tsai-Yu Lin and Fu-Ling Chang and Shang-Ju Hsieh and Jia-Huei Zheng and Yen-Chen Lu and Ming-Hui Cheng and Keng-Chang Tsai and Wei-Chun HuangFu and Ching-Sheng Hung and Yu-Ching Lee},
journal = {Translational oncology},
year = {2026},
month = oct,
doi = {10.1016/j.tranon.2026.103074},
url = {https://europepmc.org/article/MED/42868712},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Soluble N-terminal EphA2 fragment as a diagnostic biomarker and functional mediator of tumor progression in triple-negative breast cancer.
AU - Tsai-Yu Lin
AU - Fu-Ling Chang
AU - Shang-Ju Hsieh
AU - Jia-Huei Zheng
AU - Yen-Chen Lu
AU - Ming-Hui Cheng
AU - Keng-Chang Tsai
AU - Wei-Chun HuangFu
AU - Ching-Sheng Hung
AU - Yu-Ching Lee
PY - 2026
DA - 2026/10/13
JO - Translational oncology
DO - 10.1016/j.tranon.2026.103074
UR - https://europepmc.org/article/MED/42868712
AB - Triple-negative breast cancer (TNBC) lacks reliable biomarkers for early detection and remains a highly aggressive disease. Ephrin type-A receptor 2 (EphA2), a receptor tyrosine kinase frequently overexpressed in advanced cancers, undergoes MMP14-mediated cleavage that releases soluble N-terminal fragments. Here, we investigated the diagnostic and functional significance of this fragment in TNBC. Immunohistochemical analysis of clinical specimens revealed elevated EphA2 expression in TNBC tissues, with a trend toward higher levels in tumors of advanced stage and grade. To enable non-invasive detection, we established a dual-epitope sandwich ELISA targeting spatially distinct regions of the EphA2 extracellular domain. The assay showed concentration-dependent detection of recombinant EphA2 (EC₅₀, 48 ng/mL) and detected soluble EphA2 in TNBC cell-conditioned media. Serum analysis showed significantly higher EphA2 levels in TNBC patients compared with healthy controls (median 93.3 vs 25.6 ng/mL). In this exploratory cohort, ROC analysis yielded an AUC of 0.912 (95% CI, 0.862-0.962), with a sensitivity of 95.0% (95% CI, 86.3-98.6%) and a specificity of 78.3% (95% CI, 66.4-86.9%), and higher levels were associated with lymph node metastasis and higher histological grade. Functionally, recombinant EphA2-P328 promoted TNBC-cell migration and induced cell context-dependent changes in EMT-associated markers in vitro. Collectively, these findings support the soluble N-terminal EphA2 fragment as a candidate serum biomarker and an in vitro modulator of TNBC cell migration, warranting validation in larger independent cohorts and further mechanistic investigation.
SN - 1936-5233
ER -