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.

Metastatic skin cutaneous melanomas remain a significant clinical problem. In particular, those melanomas that do not contain a gain-of-function BRAF allele remain challenging to treat because of the paucity of targets for therapeutic intervention. Thus, here we investigate the role of the ERBB4 receptor tyrosine kinase in skin cutaneous melanomas that contain wild-type BRAF alleles (“BRAF WT melanomas”). We have performed in silico analyses of a public repository (The Cancer Genome Atlas - TCGA) of skin cutaneous melanoma gene expression and mutation data (TCGA-SKCM data set). These analyses demonstrate that ERBB4 overexpression strongly correlates with RAS gene or NF1 mutations that stimulate RAS signaling. Thus, these results have led us to hypothesize that elevated ERBB4 signaling promotes PI3K signaling, which cooperates with elevated RAS signaling to drive BRAF WT melanomas. We have tested this hypothesis using commercially available BRAF WT melanoma cell lines. Overexpression of wild-type ERBB4 stimulates clonogenic proliferation of the MEL-JUSO, MEWO, and IPC-298 BRAF WT melanoma cell lines. Moreover, overexpression of a dominant-negative ERBB4 (K751M) mutant inhibits clonogenic proliferation of the MEL-JUSO and MEWO cell lines. We discuss how these results may impact strategies for treating metastatic BRAF WT skin cutaneous melanomas.