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

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.