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Updated: Aug 19, 2026

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Cleavable ErbB4 isoform in estrogen receptor-regulated growth of breast cancer cells
Teemu T Junttila1, Maria Sundvall, Mikael Lundin
1Medicity Research Laboratory, Departments of Medical Biochemistry and Molecular Biology, and Turku Postgraduate School of Biomedical Sciences, University of Turku, Finland.
Abstract:
ErbB1 and ErbB2 receptors are well-characterized targets for anticancer drugs, but the clinical relevance of the related ErbB4 receptor is unknown. Here, we have assessed the clinical significance of the proteolytically cleavable ErbB4 isoforms in breast cancer patients and investigated their functions in vitro. The expression of transcripts encoding the cleavable ErbB4 isoforms associated with estrogen receptor-alpha (ER) expression (P < 0.001) and a high histologic grade of differentiation (P = 0.002) in real-time reverse transcription-PCR analysis of 62 breast cancer samples. Despite high ErbB4 mRNA expression levels in a subset of samples, ErbB4 gene amplification was not observed. High ErbB4 protein expression levels, as assessed by immunohistochemistry, associated with a favorable outcome in ER-positive cases from a series of 458 breast cancer patients (P = 0.01), whereas no association between ErbB4 expression and survival was found among women with ER-negative cancer (P = 0.86). However, nuclear ErbB4 immunoreactivity was associated with poor survival as compared with women whose cancer had membranous ErbB4 staining (P = 0.04). In vitro, overexpression of a cleavable ErbB4 isoform in ER-positive breast cancer cells resulted in translocation of a proteolytically released intracellular ErbB4 receptor fragment into the nucleus, as well as, enhanced proliferation, anchorage-independent growth, and estrogen response element-mediated transcriptional activity. These results suggest that the association of ErbB4 expression with clinical outcome is dependent on the subcellular localization of ErbB4 and that a proteinase-cleavable ErbB4 isoform promotes growth of ER-positive breast cancer and enhances ER-mediated gene transcription.
Insights
The ErbB4 receptor
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- ErbB1 and ErbB2 receptors are established anticancer targets.
- The clinical role of the ErbB4 receptor in breast cancer remains unclear.
Purpose of the Study:
- To investigate the clinical significance of proteolytically cleavable ErbB4 isoforms in breast cancer.
- To explore the in vitro functions of ErbB4 in breast cancer cells.
Main Methods:
- Real-time reverse transcription-PCR analysis of 62 breast cancer samples.
- Immunohistochemistry on 458 breast cancer patients.
- In vitro overexpression studies in ER-positive breast cancer cells.
Main Results:
- Cleavable ErbB4 isoforms correlate with estrogen receptor-alpha (ER) expression and high histologic grade.
- High ErbB4 protein expression is linked to favorable outcomes in ER-positive breast cancer.
- Nuclear ErbB4 immunoreactivity is associated with poor survival, unlike membranous staining.
- In vitro, ErbB4 promoted proliferation and transcriptional activity in ER-positive cells.
Conclusions:
- ErbB4's clinical impact in breast cancer depends on its subcellular localization.
- A cleavable ErbB4 isoform promotes ER-positive breast cancer growth and enhances ER-mediated transcription.
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