The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein

Lucas, Lauren M.; Dwivedi, Vipasha; Senfeld, Jared I.; Cullum, Richard L.; Mill, Christopher; Piazza, John T.; Bryant, Ianthe; Cook, Laura J.; Miller, Sarah; Lott, James H.; Kelley, Connor M.; Knerr, Elizabeth L.; Markham, Jessica A.; Kaufmann, David P.; Jacobi, Megan A.; Shen, Jianzhong; Riese, David J.

doi:10.1124/pharmrev.121.000381

Cited by 43 publications

(50 citation statements)

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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).…”

Section: Resultssupporting

confidence: 88%

“…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 ).…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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 ).…”

Section: Introductionmentioning

confidence: 99%

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Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies

et al. 2022

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ERBB4 is a tyrosine kinase receptor reported to exert both oncogenic and tumor suppressor activities. These paradoxical effects were suggested to stem from different ERBB4 homo-/hetero-dimers and/or isoforms. By stratifying breast cancer patients for clinical and molecular subtypes and ERBB4 mRNA abundance, we here report that higher ERBB4 levels correlate with longer relapse-free survival in breast cancer patients of HER2-enriched and luminal A molecular subtypes, proposing a cancer-protecting role for this receptor in these specific subgroups. We also observed that HER2-enriched breast cancers express intermediate ERBB4 mRNA levels compared to luminal and triple-negative/basal-like subgroups, which displayed the highest and the lowest levels, respectively. Inspired by these clinical data, we tested the activation of ERBB4 by Neuregulins as a potential anticancer strategy for HER2+ breast cancers. To this end, we employed two HER2+ breast cancer cellular models (BT474 and SKBR3), which express intermediate/high and low ERBB4 levels, respectively. Cell proliferation and motility were evaluated on these cellular models following treatments with Neuregulin 1 (NRG1), which activates both ERBB3 and ERBB4, or Neuregulin 4 (NRG4), which specifically activates ERBB4. Both NRG1 and NRG4 were used alone or in combination with anti-ERBB2 neutralizing antibodies, namely trastuzumab and pertuzumab. In vitro treatment with NRG1 on BT474 cells restrained cell growth and reduced the anti-proliferative efficacy of trastuzumab. In contrast, treatment with NRG1 on SKBR3 cells increased cell proliferation and migration, and partially or completely impaired the anti-proliferative/anti-migratory action of trastuzumab and/or pertuzumab. Importantly, in both the cell lines, treatment with NRG4 robustly potentiated the anti-proliferative action of trastuzumab and pertuzumab. Collectively, our data in HER2+ breast cancer cells highlight that NRG1 may exert both pro- and anti-proliferative effects, and may reduce the efficacy of anti-HER2 agents, whereas NRG4 may boost the anti-proliferative effects of anti-ERBB2 agents. We propose a provocative paradigm shift in the field of growth factors in cancer progression, suggesting the administration of ERBB4 ligands, such as Neuregulin 4, as a strategy to improve the efficacy of anti-ERBB2 agents.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies

et al. 2022

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Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient‐derived orthotopic xenografts, cell lines and tumor entities

Creus‐Bachiller,

Fernández‐Rodríguez,

Magallón‐Lorenz

et al. 2023

Molecular Oncology

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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient‐derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments. Herein, we describe the expansion of this platform using six primary tumors clinically diagnosed as MPNSTs, from which we obtained six additional PDOX mouse models and three cell lines, thus generating three pairs of in vitro–in vivo models. We extensively characterized these tumors and derived preclinical models, including genomic, epigenomic and histological analyses. Tumors were reclassified after these analyses: three remained as MPNSTs (two being classic MPNSTs), one was a melanoma, another an Neurotrophic tyrosine receptor kinase (NTRK)‐rearranged spindle cell neoplasm, and, finally, an unclassifiable tumor bearing Neurofibromin‐2 (NF2) inactivation, an Neuroblastoma RAS Viral Oncogene Homolog (NRAS) oncogenic mutation and a SWI/SNF‐related Matrix associated Actin‐dependent Regulator of Chromatin (SMARCA4) heterozygous truncated variant. New cell lines and PDOXs faithfully recapitulated histology, marker expression and genomic characteristics of the primary tumors. The diversity in tumor identity and their specific associated genomic alterations impacted on treatment responses obtained when we used the new cell lines for testing compounds against known altered pathways in MPNSTs. In summary, we present here an extension of our MPNST precision medicine platform, with new PDOXs and cell lines, including tumor entities confounded as MPNSTs in a real clinical scenario. This platform may constitute a useful tool for obtaining correct preclinical information to guide MPNST clinical trials.

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HER4 is a high‐affinity dimerization partner for all EGFR/HER/ErbB family proteins

Singh,

Kim,

Smith

2024

Protein Science

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Human epidermal growth factor receptors (HER)—also known as EGFR or ErbB receptors—are a subfamily of receptor tyrosine kinases (RTKs) that play crucial roles in cell growth, division, and differentiation. HER4 (ErbB4) is the least studied member of this family, partly because its expression is lower in later stages of development. Recent work has suggested that HER4 can play a role in metastasis by regulating cell migration and invasiveness; however, unlike EGFR and HER2, the precise role that HER4 plays in tumorigenesis is still unresolved. Early work on HER family proteins suggested that there are direct interactions between the four members, but to date, there has been no single study of all four receptors in the same cell line with the same biophysical method. Here, we quantitatively measure the degree of association between HER4 and the other HER family proteins in live cells with a time‐resolved fluorescence technique called pulsed interleaved excitation fluorescence cross‐correlation spectroscopy (PIE‐FCCS). PIE‐FCCS is sensitive to the oligomerization state of membrane proteins in live cells, while simultaneously measuring single‐cell protein expression levels and diffusion coefficients. Our PIE‐FCCS results demonstrate that HER4 interacts directly with all HER family members in the cell plasma membrane. The interaction between HER4 and other HER family members intensified in the presence of a HER4‐specific ligand. Our work suggests that HER4 is a preferred dimerization partner for all HER family proteins, even in the absence of ligands.

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The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein

Cited by 43 publications

References 364 publications

Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies

Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies

Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient‐derived orthotopic xenografts, cell lines and tumor entities

HER4 is a high‐affinity dimerization partner for all EGFR/HER/ErbB family proteins

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