Introduction: Desmocollin-1 (DSC1) is a desmosomal protein playing a role in cell-cell adhesion and tight cell junctions. Recently [1] we identified increased levels of DSC1 in lymph node positive vs. negative primary luminal A tumors. Therefore, we focused on the DSC1 role in molecular mechanisms of lymph node metastasis in luminal A breast cancer and its possible therapeutic modulation. Methods: A stably transduced, DSC1 overexpressing luminal A breast cancer cell line (MCF7-DSC1-GFP) was generated. Transwell assay and atomic force microscopy were used to study effect of DSC1 overexpression on MCF7 cell migration, invasion, and morphology. Effect of potential DSC1 inhibitors selected in Gene Set Enrichment Analysis (GSEA) of mRNA microarray data set of 341 luminal A tumors was analyzed using western blots and flow cytometry. Quantitative total proteome analysis and pull-down assays were performed in direct data independent acquisition mode on Orbitrap Fusion Lumos mass spectrometer with data analysis in Spectronaut and GSEA. Results: DSC1 overexpression increased migration and invasion capacity, decreased height of MCF7 cells and led to enrichment of proteins involved in cell cycle regulation, including CDK2, MCM2-7, IBP5 and LACRT in the total proteome analysis (p<0.05). Parthenolide, the best performing inhibitor, decreased DSC1 protein levels in MCF7-DSC1-GFP cells, directed them to apoptosis and decreased levels of cell cycle-associated proteins. DSC1 interaction partners included cadherins, protocadherins and tyrosine kinases ERBB2 and ERBB3. Of these, DSC1-ERBB3 interaction was affected by parthenolide (p<0.05). Conclusions: Our systems biology data indicate that DSC1 is connected to cell migration, invasion and cell cycle regulation in luminal A breast cancer cells, and can be effectively modulated by parthenolide, directing the cells to apoptosis. This work was supported by the Ministry of Health of the Czech Republic, grant No. NV19-08-00250. References: 1. Faktor, J. et al., Proteomics 2019, 19, 1900073.