We would like to call your attention to a publication by promotes an aggressive phenotype in human breast cancer cells") 1 in Tissue Barriers. The authors show that high claudin-20 expression correlates with the aggressiveness of breast cancer and poor survival rates for affected patients. They discuss a connection between the sensitivity of cancer cells to Gefitinib and claudin-20 content and suggest that claudin-20 might serve as a biomarker for Gefitinib resistance. However, this conclusion is based on a misconception on the part of the authors. They claim that claudin-20 is the same protein as epithelial membrane protein 1 (EMP-1), and to substantiate this claim, they misleadingly refer to a prior publication demonstrating that EMP-1 is a biomarker for Gefitinib-resistance in an adenocarcinoma model. However, Claudin-20 and EMP-1 are 2 distinct proteins. EMP-1 (NCBI reference sequence accession number NP_001414.1) has been described as a tight junction protein in the blood-brain barrier 3 as well as in the human airway epithelium, where it regulates tight junction formation. 4 To our knowledge, the paper of Martin et al. 1 is the first publication that presents functional data regarding human claudin-20 (NP_001001346.1). Their paper will be immediately found (and likely cited) by other scientists working with either of the 2 proteins. Therefore, it is crucial to avoid misrepresentations through a careful review of the existing literature.According to Price et al. 5 (also cited by Martin and colleagues 1 ) both claudin-20 and EMP-1 belong to the Pfam00822 superfamily, which includes claudins, peripheral myelin protein 22 (PMP-22), lens intrinsic membrane protein (LIM-2/MP20), EMP-1, ¡2, ¡3 and voltage dependent calcium channel gamma subunits (CACNGs). The study places claudin-20 within the claudin family (where it is most closely related to the classic claudins 2 and 14), while EMP-1 is placed in the LIM2/PMP22/EMP family.5 This classification was confirmed in an independent investigation, which came to the same results and confirmed the separate identities of claudin-20 and EMP-1. 6 Nevertheless, the phylogeny of the Pfam00822 family has not yet been completely resolved. TMEM114 and TMEM235 were first assigned to the claudin family using PMP-22 as an outgroup.7 Later, these TMEMs were renamed claudin-26 and ¡27, respectively. 8 Subsequent work that also included CACNGs, EMPs and LIM-2 and used clarin-1 as an outgroup revealed that TMEM114 and TMEM235 were more closely related to the CACNG family than with the claudin family. 6 Thus, Pfam00822 superfamily nomenclature has not yet been conclusively determined.The members of this superfamily are tetraspanning membrane proteins and share a WX 9-44 GLWXXC(X 9-26 C) signature motif in the first extracellular loop (whereas the second cysteine is not conserved in the LIM2/PMP22/EMP family). To illustrate the differences between EMP-1 and claudin-20, we modeled their structures using I-TASSER. 9 The recently published crystal structure of claudin-15 10 was applied a...