Membrane-bound mucins belong to a heterogeneous family of large O-glycoproteins involved in numerous cancers and inflammatory diseases of the epithelium. Some of them are also involved in protein-protein interactions (PPI), with receptor tyrosine kinase (RTK) ErbB2, and fundamental and clinical data showed that these complexes have a detrimental impact on cancer outcome thus raising interest for therapeutic targeting. This paper aims at demonstrating that MUC3, MUC4, MUC12, MUC13 and MUC17 came from a common evolutionary origin and share a common structural organization with EGF-like and SEA domains. Theoretical structure-function relationship analysis of the conserved domains were performed indicating that the studied membrane-bound mucins share common biological properties along with potential specific functions. Finally, the potential druggability of these complexes were discussed revealing ErbB2-related pathways of cell signaling to be targeted.