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Single Molecule and Single Cell Analysis of HER2 Receptors in Breast Cancer Cells Using Liquid Phase Scanning Transmission Electron Microscopy

HER2 positive breast cancer is an aggressive form of cancer, diagnosed in about 20% of breast cancer patients [1]. HER2-targeted antibody drugs trastuzumab [2] and pertuzumab are the standard of care in combination with chemotherapy in the metastatic setting. These targeted drugs prevent activation of HER2 via dimerization and subsequent activation of growth signaling. In early and metastatic stages of the disease this treatment strategy significantly improves survival. However, many patients do not respond at all, and by far most patients have developed so-called acquired resistance by about a year of initial treatment [3]. But despite extensive research, effective remedies against drug resistance development are lacking. Our research is based on the hypothesis that particular subpopulations of cancer cells at the tumor site play a critical role in the development of drug resistance. These cells are characterized by different morphology and receptor expression levels. The problem of drug resistance development should thus be tackled by taking cancer cell heterogeneity into account [4]. However, this has been challenging until now due to limitations of the available analytical methods. Biochemical methods generally used to study the cellular responses to drugs are not capable of examining proteins in intact single cells and use pooled cellular material. Information is thus obtained only from average responses across a cell population, insufficient for studies including cell heterogeneity. A range of microscopy techniques exist but none of these provides the required localized stoichiometric information for endogenously expressed proteins.