The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein

Abstract

ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). EGFR and ERBB2 are oncoproteins and validated targets for therapeutic intervention in a variety of solid tumors. In contrast, the role that ERBB4 plays in human malignancies is ambiguous. Thus, here we review the literature regarding ERBB4 function in human malignancies. We review the mechanisms of ERBB4 signaling with an emphasis on mechanisms of signaling specificity. In the context of this signaling specificity, we discuss the hypothesis that ERBB4 appears to function as a tumor suppressor protein and as an oncoprotein. Next, we review the literature that describes the role of ERBB4 in tumors of the bladder, liver, prostate, brain, colon, stomach, lung, bone, ovary, thyroid, hematopoietic tissues, pancreas, breast, skin, head, and neck. Whenever possible, we discuss the possibility that ERBB4 mutants function as biomarkers in these tumors. Finally, we discuss the potential roles of ERBB4 mutants in the staging of human tumors and how ERBB4 function may dictate the treatment of human tumors. Significance Statement This articles reviews ERBB4 function in the context of the mechanistic model that ERBB4 homodimers function as tumor suppressors, whereas ERBB4-EGFR or ERBB4-ERBB2 heterodimers act as oncogenes. Thus, this review serves as a mechanistic framework for clinicians and scientists to consider the role of ERBB4 and ERBB4 mutants in staging and treating human tumors.

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“…To this end, a cohort of 4929 breast cancer patients, whose data are publicly available online, has been stratified into three groups (trichotomization) according to the expression levels of ERBB4, and the relapse-free survival probability in lower tercile versus upper tercile was evaluated during a follow-up period of 250 months after tumor resection (please refer to the “Material and methods” section for further details regarding relapse-free patients’ survival analyses). In line with the majority of previous reports ( 15 – 17 ) [reviewed in ( 13 , 21 )], higher expression of ERBB4 was predictive of a better relapse-free patients’ survival, with a hazard ratio (HR) of 0.53 and p-value < 1E-16 ( Supplementary Figure S1A ). Next, we characterized the mRNA expression of ERBB4 in publicly available datasets of breast cancer specimens and normal breast tissue (technical details are provided in the “Material and methods” section).…”

“…ERBB4 is the only ERBB receptor that is not necessary for the proliferation of breast epithelial cells in puberty and early pregnancy; however, it drives cell differentiation in late pregnancy and early lactation ( 11 , 12 ) [reviewed in ( 13 , 14 )]. In line with a positive role in cell differentiation and/or apoptosis, increased ERBB4 expression was found associated with longer relapse-free survival ( 15 – 17 ), disease-free survival ( 17 , 18 ), and overall survival ( 15 , 17 – 20 ) in breast cancer patients [reviewed in ( 13 , 21 )]. Nevertheless, a few reports evidenced a correlation between increased levels of ERBB4 and an unfavorable clinical outcome, such as reduced overall survival and relapse-free survival ( 22 , 23 ).…”

“…Furthermore, an association between ERBB4 overexpression and chemoresistance to endocrine therapies and/or poorer prognosis has also been described ( 23 – 25 ) [reviewed in ( 13 , 26 , 27 )]. Based on this evidence, ERBB4 has been reported to exert both oncogenic and tumor suppressor activities [reviewed in ( 21 )]. These paradoxical effects were suggested to stem from different ERBB4 homo-/hetero-dimers and/or isoforms.…”

“…Alternative splicing of ERBB4 may produce four different isoforms, which differ in the extracellular juxtamembrane domain (JMa versus JMb) and/or in the cytoplasmic domain (CYT1 versus CYT2). JMa-CYT1 isoform is predominantly expressed and considered the canonical ERBB4 transcript [reviewed in ( 21 )]. Cleavage of JMa-CYT1 by γ-secretase determines the release of the cytoplasmic region of ERBB4 (the 4ICD) from the plasma membrane.…”

“…In contrast, breast-specific expression of the canonical CYT1 isoform of 4ICD reduces the proliferation of the ductal epithelium and induces lactogenic differentiation ( 29 ). These opposite effects triggered by the full-length ERBB4 transgene and its cytoplasmic region (4ICD-CYT1) were suggested to derive from the fact that full-length ERBB4 can heterodimerize with other ERBB family receptors, whereas the ERBB4-ICD transduces only homotypic ERBB4 signaling [reviewed in ( 21 )]. In contrast to the 4ICD-CYT1, breast-specific expression of the CYT2 isoform of the 4ICD (4ICD-CYT2) was shown to induce epithelial hyperplasia ( 29 ).…”