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Review Open Access

Soluble isoforms of EGFR family in breast cancer: Advances and clinical relevance (Review)

  • Authors:
    • Peng Yang
    • Xinnong Jiang
    • Fangguo He
  • View Affiliations / Copyright

    Affiliations: Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Key Laboratory of Molecular Biophysics of The Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China, Department of Applied Mathematics, College of Mathematics and Statistics, Huanggang Normal University, Huanggang, Hubei 438000, P.R. China
    Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 235
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    Published online on: April 14, 2026
       https://doi.org/10.3892/ol.2026.15590
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Abstract

Breast cancer (BrCa) is the leading cause of cancer death among women worldwide. The epidermal growth factor receptor (EGFR) family, consisting of EGFR/erythroblastic leukemia viral (v‑erbB) oncogene homolog (ErbB)1, human epidermal growth factor receptor (HER)2/ErbB2, HER3/ErbB3 and HER4/ErbB4, serves a pivotal role in BrCa pathogenesis. In addition to the membrane‑bound forms, soluble isoforms of these receptors have emerged as biologically and clinically significant players in BrCa. These soluble variants are produced either through alternative splicing or proteolytic cleavage of the extracellular domain. Functionally, soluble EGFR family members can act as decoy receptors or interfere with receptor homo‑ or heterodimerization, ultimately disrupting downstream signaling cascades and contributing to the dysregulated growth and survival of BrCa cells. Notably, soluble EGFR and HER2 are detectable in the serum of patients with BrCa, and their serum levels fluctuate during disease progression and treatment. These dynamic serum fluctuations possess strong prognostic and predictive potential. This review summarized the current understanding of soluble EGFR family members in BrCa, including their mechanisms of generation and biological functions. The clinical relevance of soluble EGFR and the shed extracellular domain of HER2 in BrCa is addressed, with an emphasis on their emerging roles as diagnostic biomarkers and promising therapeutic targets.
View Figures

Figure 1

The structure and ligands of the EGFR
family. The extracellular domains consist of subdomains I, II, III
and IV. The ligand-binding domain of HER2 and the tyrosine kinase
domain of HER3 are defective. HER4 has two alternative splicing
sites, the JM splicing site results in isoforms JMa and JMb, and
the Cyt splicing site results in isoforms Cyt1 and Cyt2. The amino
acid sequence differences among HER4 isoforms are indicated on the
right. The numbers indicate the initial amino acid residue of each
(sub)domain except for the last residues of the receptors (3,6). The
red cross symbols indicate functional deficient domains. AREG,
amphiregulin; BTC, betacellulin; EPG, epigen; EREG, epiregulin;
HB-EGF, heparin-binding EGF-like growth factor; NRG, neuregulin;
JM, juxtamembrane; Cyt, C-terminal region; EGFR, epidermal growth
factor receptor;

Figure 2

Soluble isoforms of EGFR family. (A)
sEGFR isoforms. Alternative splicing produces p110 sEGFR with a
novel 78 C-terminal amino acid residues. (B) Soluble HER2 isoforms.
Retention of I8 during alternative splicing results in herstatin,
which contains a unique 79 C-terminal residues encoded by I8.
Retention of I12 results in HER2-I12 with a unique 73 C-terminal
residues. (C) sHER3 isoforms produced via alternative splicing. p23
sHER3 contains a unique 43 C-terminal residues. Retention of I9
results in p50 sHER3 with a novel C-terminal region (30 residues),
retention of I8 and I9 results in p45 sHER3 with two unique
C-terminal glycine residues, retention of I13 results in p85 sHER3
with a unique 23 C-terminal residues and retention of I12 and I13
results in p76 sHER3 with a unique 41 C-terminal residues. (D)
Soluble HER4 isoform produced by proteolytic cleavage. The numbers
indicate the initial amino acid residue of each (sub)domain except
for the last residues of the proteins (23,51,54,55,57,67,95,96,108).
The red cross symbols indicate functional deficient domains. I,
intron; EGFR, epidermal growth factor receptor; JM, juxtamembrane;
sEGFR, soluble EGFR; ECD, extracellular domain; ICD, intracellular
domain; HER, human epidermal growth factor receptor; sHER3, soluble
HER3.
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Yang P, Jiang X and He F: Soluble isoforms of EGFR family in breast cancer: Advances and clinical relevance (Review). Oncol Lett 31: 235, 2026.
APA
Yang, P., Jiang, X., & He, F. (2026). Soluble isoforms of EGFR family in breast cancer: Advances and clinical relevance (Review). Oncology Letters, 31, 235. https://doi.org/10.3892/ol.2026.15590
MLA
Yang, P., Jiang, X., He, F."Soluble isoforms of EGFR family in breast cancer: Advances and clinical relevance (Review)". Oncology Letters 31.6 (2026): 235.
Chicago
Yang, P., Jiang, X., He, F."Soluble isoforms of EGFR family in breast cancer: Advances and clinical relevance (Review)". Oncology Letters 31, no. 6 (2026): 235. https://doi.org/10.3892/ol.2026.15590
Copy and paste a formatted citation
x
Spandidos Publications style
Yang P, Jiang X and He F: Soluble isoforms of EGFR family in breast cancer: Advances and clinical relevance (Review). Oncol Lett 31: 235, 2026.
APA
Yang, P., Jiang, X., & He, F. (2026). Soluble isoforms of EGFR family in breast cancer: Advances and clinical relevance (Review). Oncology Letters, 31, 235. https://doi.org/10.3892/ol.2026.15590
MLA
Yang, P., Jiang, X., He, F."Soluble isoforms of EGFR family in breast cancer: Advances and clinical relevance (Review)". Oncology Letters 31.6 (2026): 235.
Chicago
Yang, P., Jiang, X., He, F."Soluble isoforms of EGFR family in breast cancer: Advances and clinical relevance (Review)". Oncology Letters 31, no. 6 (2026): 235. https://doi.org/10.3892/ol.2026.15590
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