Micromapping (µMap) of HER2 Across Human Breast Cancers: Photocatalytic Proximity Labeling Identifies Primary Resistance Mechanisms and Functional Interactors

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.