The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein.

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.

Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics.

Whereas recent clinical studies report metastatic melanoma survival rates high as 30-50%, many tumors remain nonresponsive or become resistant to current therapeutic strategies. Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of melanomas potentially harbor gain-of-function mutations in the gene that encodes for the ErbB4 receptor tyrosine kinase. In this work, a drug discovery strategy was developed that is based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist Neuregulin-2beta (NRG2ß) functions as a partial agonist at ErbB4. NRG2ß/Q43L stimulates tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation. Compounds that exhibit these characteristics likely function as ErbB4 partial agonists, and as such hold promise as therapies for ErbB4-dependent melanomas. Consequently, three highly sensitive and reproducible (Z' > 0.5) screening assays were developed and deployed for the identification of small-molecule ErbB4 partial agonists. Six compounds were identified that stimulate ErbB4 phosphorylation, fail to stimulate ErbB4-dependent cell proliferation, and appear to selectively inhibit ErbB4-dependent cell proliferation. Whereas further characterization is needed to evaluate the full therapeutic potential of these molecules, this drug discovery platform establishes reliable and scalable approaches for the discovery of ErbB4 inhibitors.

Development and Implementation of an Effective Blind Proficiency Testing Program.

Blind proficiency testing is ideal for testing crime laboratory personnel because the elements of analyst bias and anticipation are removed. However, sending proficiency tests through the laboratory system as real casework is difficult. The substantial challenges with preparing and administering blind tests may prevent laboratory managers from initiating blind testing. In 2015, the Harris County Institute of Forensic Sciences committed to improving its crime laboratory's proficiency testing program by adding blind tests. The goal was to test the whole system, from evidence receipt to report release. With careful planning, trial-and-error, and ongoing assessment of available resources, not only was the program proven to be feasible, but there was also clear understanding of how to optimize our program. In this article, we share our experiences, lessons learned, and program details to assist other forensic service providers with developing their own blind testing programs, which would ultimately lead to improved quality assurance.

Temporal abundance and activity trends of vinyl chloride (VC)-degrading bacteria in a dilute VC plume at Naval Air Station Oceana.

Assessment and monitoring of microbial community dynamics is useful when tracking the progress of vinyl chloride (VC) bioremediation strategies, particularly in dilute plumes where apparent VC attenuation rates are low. In a long-term field study, the abundance and the activity of microbial VC degraders were tracked in three monitoring wells (MW05, MW25, and MW19) along a dilute VC plume at Naval Air Station (NAS) Oceana. High-throughput sequencing of partial 16S ribosomal RNA (rRNA) genes and transcripts revealed diverse groundwater microbial communities and showed that methanotrophs and anaerobic respirers (e.g., methanogens, sulfate reducers, and iron reducers) were among the most active and abundant guilds. Quantitative PCR analysis showed that among bacterial guilds with a potential to contribute to VC biodegradation, methanotrophs were the most abundant and active microbial group. Ethene-oxidizing bacterial populations were less abundant and relatively inactive compared to methanotrophs. In MW19, expression of functional genes associated with both aerobic VC oxidation and anaerobic VC reduction was observed. Overall, our results reveal that the groundwater community contains various active bacterial guilds previously associated with metabolic and cometabolic VC degradation processes either under aerobic and anaerobic conditions that might have contributed to the slowly decreasing VC concentrations at the NAS Oceana site over the 6-year study period.