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Updated: Sep 15, 2025
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Micromapping (μMap) of HER2 Across Human Breast Cancers: Photocatalytic Proximity Labeling Identifies Primary
Steve D Knutson1,2, Jacob A Boyer2,3,4, Danielle C Morgan1,2
1Merck Center for Catalysis at Princeton University, Princeton, New Jersey, 08544, USA.
Abstract:
Interactions among receptor tyrosine kinases (RTKs), particularly HER2, are critical in driving the growth of certain breast cancer subtypes. However, the mechanisms of HER2 dependency and resistance to targeted therapies remain unclear. Using photocatalytic micromapping (μMap) proximity labeling, we profiled the HER2 interactome across human breast cancer lines. We identify galectin family proteins as uniquely enriched in trastuzumab-resistant models, and show that genetic and pharmacological inhibition of galectins restores trastuzumab sensitivity. Mechanistically, galectin inhibition destabilized HER2 and other RTKs and enhanced antibody-mediated receptor degradation. Galectin inhibition in combination with trastuzumab triggered mitochondrial and endoplasmic reticulum stress pathways, revealing new mechanisms underlying HER2 signaling, dependency, and resistance in breast cancer. We also identified protein tyrosine phosphatase F (PTPRF) as a pan-cancer HER2 interactor, which is broadly upregulated and whose knockdown suppresses proliferation in HER2-low cancers. This work provides an extensive new interactomic resource and underscores the utility of proximity labeling for mapping complex cancer networks and identifying new therapeutic targets.
Insights
Researchers discovered that inhibiting galectin proteins can restore sensitivity to trastuzumab in HER2-positive breast cancer. This approach destabilizes HER2 and enhances receptor degradation, offering new therapeutic strategies for resistant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Receptor tyrosine kinases (RTKs), especially HER2, drive growth in specific breast cancer subtypes.
- Mechanisms of HER2 dependency and resistance to targeted therapies are not fully understood.
Purpose of the Study:
- To profile the HER2 interactome in human breast cancer cell lines using photocatalytic micromapping (μMap) proximity labeling.
- To identify novel therapeutic targets and understand resistance mechanisms in HER2-driven breast cancer.
Main Methods:
- Utilized photocatalytic micromapping (μMap) proximity labeling to map the HER2 interactome.
- Employed genetic and pharmacological inhibition of identified proteins.
- Analyzed downstream effects on receptor stability, degradation, and cellular stress pathways.
Main Results:
- Galectin family proteins were uniquely enriched in trastuzumab-resistant breast cancer models.
- Inhibition of galectins restored trastuzumab sensitivity by destabilizing HER2 and enhancing receptor degradation.
- Combined galectin inhibition and trastuzumab triggered mitochondrial and endoplasmic reticulum stress.
- Identified protein tyrosine phosphatase F (PTPRF) as a pan-cancer HER2 interactor upregulated in HER2-low cancers.
Conclusions:
- Galectin inhibition represents a promising strategy to overcome trastuzumab resistance in HER2-driven breast cancer.
- Proximity labeling is a powerful tool for mapping complex cancer signaling networks.
- PTPRF is a potential therapeutic target for HER2-low cancers.
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