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Updated: Feb 14, 2026
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy
Konstantinos V Floros1, Timothy L Lochmann1, Bin Hu2
1Department of Oral and Craniofacial Molecular Biology, Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298.
Abstract:
HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes.
Insights
HER2-amplified breast cancer shows limited response to HER2 inhibitors due to low NOXA levels. A HER2-intronic micro-RNA (miR-4728) suppresses Estrogen Receptor α (ERα), reducing NOXA and apoptosis, a resistance overcome by MCL-1 inhibition.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- HER2 (ERBB2) amplification drives breast cancer, with HER2 inhibitors (HER2i) showing clinical benefit.
- However, HER2i efficacy as single agents is limited, unlike EGFR inhibitors in EGFR-mutant lung cancer, despite effective intracellular signaling shutdown.
Purpose of the Study:
- To investigate intrinsic causes for the limited efficacy of HER2 inhibitors in HER2-amplified breast cancer.
- To identify mechanisms underlying depressed NOXA levels and explore strategies to overcome resistance.
Main Methods:
- Analysis of NOXA levels in HER2-amplified breast cancer.
- Identification and characterization of miR-4728 encoded within the HER2 gene.
- Investigation of miR-4728's targeting of Estrogen Receptor α (ESR1) mRNA.
- Assessment of ERα-mediated NOXA transcription and apoptosis.
- Evaluation of MCL-1 inhibition to overcome resistance.
Main Results:
- HER2-amplified breast cancer exhibits significantly depressed levels of NOXA, an inhibitor of antiapoptotic MCL-1.
- A novel micro-RNA, miR-4728, encoded in a HER2 intron, targets ESR1 mRNA.
- Reduced ESR1 expression impairs ERα-mediated NOXA transcription, mitigating apoptosis upon HER2i treatment (lapatinib).
- Pharmacological inhibition of MCL-1 effectively overcomes this resistance mechanism.
Conclusions:
- Targeted therapies against oncogenes driven by focal amplification may be limited by coamplified genes.
- The HER2/miR-4728/ESR1/NOXA axis represents a novel mechanism of resistance to HER2 inhibitors in breast cancer.
- MCL-1 inhibition offers a promising strategy to re-sensitize HER2-amplified breast cancer to HER2-targeted therapies.
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