Human epidermal growth factor receptor 4 (HER4) is a favorable prognostic marker of breast cancer: a systematic review and meta-analysis

Abstract

Based on a large cohort of clinical studies involving a total of 8024 patients and reporting the effects of HER4 on breast cancer prognosis, we conducted the first meta-analysis and review of this type. We identified 26 studies published between 1985 and 2016 and assessed the prognostic value of HER4 in breast cancer by either real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR, for mRNA levels) or immunohistochemistry (IHC, for protein levels). Elevated expression of HER4 was significantly associated with longer relapse-free survival (RFS) (HR = 0.63; CI: 0.48−0.83; P = 0.001, random effects). Further subgroup analysis showed that our results were stable irrespective of subtype [Luminal: HR = 0.40, CI: 0.30−0.53, P < 0.001, fixed effects; triple negative breast cancer (TNBC): HR = 0.49, CI: 0.26−0.90, P = 0.02, fixed effects; and HER2-positive: HR = 0.53, CI: 0.40−0.71, P < 0.001, fixed effects]. Cytoplasmic HER4 was more effective than nuclear HER4 (HR = 0.74, CI: 0.60−0.92, P = 0.007, fixed effects) for predicting RFS. HER4 was also found to be a favorable prognostic marker for overall survival (OS) among patients with non-TNBC in the subgroup analysis (Luminal: HR = 0.71, CI: 0.52−0.95, P = 0.023, fixed effects; HER2-positive: HR = 0.48, CI: 0.26−0.89, P = 0.020, fixed effects).

Impact of plasma oxidation on structural features of human epidermal growth factor

“…EGFR is known to be involved in several cancer types, because an overproduction or overstimulation of EGFR has a severe impact on the cell cycle by inducing proliferation, survival, and differentiation . Furthermore, a variant of EGFR in humans is described as a favorable marker for breast cancer diagnosis . Besides EGFR, its ligand EGF is also investigated concerning its role in various cancer types .…”

Ligand-Independent Epidermal Growth Factor Receptor Overexpression Correlates with Poor Prognosis in Colorectal Cancer

“…Khelwatty et al [ 8 ] also demonstrated that the evaluation of not only EGFR expression, but also the expression of its ligands may be used to predict the effect of anti-EGFR treatments. Furthermore, some EGFR ligands including HBEGF and betacellulin interact with human epidermal growth factor receptor 4 (HER4)— another member of the EGFR family—that may have close associations with favorable features and prognosis in cancer [ 12 - 14 ]. However, the clinicopathologic impact of various EGFR ligands and underlying mechanisms in ligand-dependent EGFR signaling remains unclear.…”

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

“…Notably, loss of the C2 domain in WWP1 promotes s80 HER4 degradation, suggesting that the unique spatial distribution of WWP1 is a key factor for regulating the ErbB4/HER4 protein level . Clinically, ErbB4/HER4 is a well‐recognized prognosis marker . WWP1 promotes ErbB4/HER4 degradation, thereby blocking the anti‐proliferation and differentiation functions of ErbB4/HER4 (Figure C).…”