The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein
Lauren M Lucas1, Vipasha Dwivedi1, Jared I Senfeld1
1Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.).
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.
Insights
The ERBB4 (HER4) receptor tyrosine kinase can act as both a tumor suppressor and an oncoprotein in human cancers. Its dual role depends on dimerization partners, influencing cancer staging and treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- ERBB4 (HER4) is a receptor tyrosine kinase in the ERBB family, alongside EGFR, ERBB2, and ERBB3.
- While EGFR and ERBB2 are established oncoproteins and therapeutic targets, ERBB4's role in malignancies remains unclear.
- Understanding ERBB4's function is crucial for advancing cancer diagnostics and therapeutics.
Purpose of the Study:
- To review existing literature on ERBB4 function in various human malignancies.
- To explore the mechanistic basis of ERBB4 signaling specificity.
- To evaluate ERBB4's potential as a tumor suppressor and oncoprotein.
Main Methods:
- Literature review of ERBB4 signaling mechanisms and its role in different cancer types.
- Analysis of ERBB4 dimerization (homodimers vs. heterodimers with EGFR/ERBB2).
- Examination of ERBB4 mutants as potential biomarkers for cancer staging and treatment.
Main Results:
- ERBB4 signaling specificity is influenced by its dimerization partners.
- ERBB4 homodimers may function as tumor suppressors, while ERBB4-EGFR or ERBB4-ERBB2 heterodimers can act as oncogenes.
- ERBB4 and its mutants have roles in numerous cancers, including bladder, liver, prostate, brain, and breast.
Conclusions:
- ERBB4 exhibits context-dependent roles in human malignancies, acting as both a tumor suppressor and an oncoprotein.
- ERBB4 mutants may serve as valuable biomarkers for cancer staging.
- Understanding ERBB4 dimerization is key for developing targeted cancer therapies.
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