ArticleMolecular and cellular biology2009
ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert opposing effects on the mammary epithelium in vivo.
Article in Molecular and cellular biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 77 citations in OpenAlex.
- Recurrent cancer-associated ERBB4 mutations are transforming and confer resistance to targeted therapies.Molecular oncology · 2026Article
- Genome-Wide Insights into Intermittent Milking Behavior of Pandharpuri Buffalo.Current issues in molecular biology · 2026Article
- Mechanisms and therapeutic targets of ErbB family receptors in hepatocellular carcinoma: a narrative review.Translational cancer research · 2024Review
- ERBB Receptors and Their Ligands in the Developing Mammary Glands of Different Species: Fifteen Characters in Search of an Author.Journal of mammary gland biology and neoplasia · 2023Review
- The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein.Pharmacological reviews · 2022Review
- Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies.Frontiers in oncology · 2022Article
- Biasing human epidermal growth factor receptor 4 (HER4) tyrosine kinase signaling with antibodies: Induction of cell death by antibody-dependent HER4 intracellular domain trafficking.Cancer science · 2020Article
- The role of ErbB4 in cancer.Cellular oncology (Dordrecht, Netherlands) · 2020Review
- Functional role of WW domain-containing proteins in tumor biology and diseases: Insight into the role in ubiquitin-proteasome system.FASEB bioAdvances · 2020Article
- HER4 expression in estrogen receptor-positive breast cancer is associated with decreased sensitivity to tamoxifen treatment and reduced overall survival of postmenopausal women.Breast cancer research : BCR · 2018Article
- Activation of ERBB4 in Glioblastoma Can Contribute to Increased Tumorigenicity and Influence Therapeutic Response.Cancers · 2018Article
- HER4 isoform CYT2 and its ligand NRG1III are expressed at high levels in human colorectal cancer.Oncology letters · 2018Article
- SUMOylation regulates nuclear accumulation and signaling activity of the soluble intracellular domain of the ErbB4 receptor tyrosine kinase.The Journal of biological chemistry · 2017Article
- ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation.Breast cancer research : BCR · 2017Article
- Immunocompetent mouse allograft models for development of therapies to target breast cancer metastasis.Oncotarget · 2017Article
- Parallel microarray profiling identifies ErbB4 as a determinant of cyst growth in ADPKD and a prognostic biomarker for disease progression.American journal of physiology. Renal physiology · 2017Article
- Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- ERBB4 Expression in Ovarian Serous Carcinoma Resistant to Platinum-Based Therapy.Cancer control : journal of the Moffitt Cancer Center · 2017Article
- Direct coupling of the HER4 intracellular domain (4ICD) and STAT5A signaling is required to induce mammary epithelial cell differentiation.Biochemistry and biophysics reports · 2016Article
- Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake.Science signaling · 2015Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Data concerning the prognostic value of ErbB4 in breast cancer and effects on cell growth have varied in published reports, perhaps due to the unknown signaling consequences of expression of the intracellular proteolytic ErbB4 s80(HER4) fragment or due to differing signaling capabilities of alternatively spliced ErbB4 isoforms. One isoform (Cyt1) contains a 16-residue intracellular sequence that is absent from the other (Cyt2). We expressed s80(Cyt1) and s80(Cyt2) in HC11 mammary epithelial cells, finding diametrically opposed effects on the growth and organization of colonies in three-dimensional matrices. Whereas expression of s80(Cyt1) decreased growth and increased the rate of three-dimensional lumen formation, that of s80(Cyt2) increased proliferation without promoting lumen formation. These results were recapitulated in vivo, using doxycycline-inducible, mouse breast-transgenic expression of s80(Cyt1) amd s80(Cyt2). Expression of s80(Cyt1) decreased growth of the mammary ductal epithelium, caused precocious STAT5a activation and lactogenic differentiation, and increased cell surface E-cadherin levels. Remarkably, ductal growth inhibition by s80(Cyt1) occurred simultaneously with lobuloalveolar growth that was unimpeded by s80(Cyt1), suggesting that the response to ErbB4 may be influenced by the epithelial subtype. In contrast, expression of s80(Cyt2) caused epithelial hyperplasia, increased Wnt and nuclear beta-catenin expression, and elevated expression of c-myc and cyclin D1 in the mammary epithelium. These results demonstrate that the Cyt1 and Cyt2 ErbB4 isoforms, differing by only 16 amino acids, exhibit markedly opposing effects on mammary epithelium growth and differentiation.
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