Data from Loss of <i>Trop2</i> Promotes Carcinogenesis and Features of Epithelial to Mesenchymal Transition in Squamous Cell Carcinoma

Abstract

<div>Abstract<p>Trop2, an oncogenic cell surface protein under investigation as a therapeutic target, is commonly overexpressed in several epithelial tumor types yet its function in tumor biology remains relatively unexplored. To investigate the role of Trop2 in epithelial carcinogenesis, we generated <i>Trop2<sup>−/−</sup></i> mice, which are viable and possess a normal lifespan. Contrary to expectations, Trop2 loss fails to suppress keratinocyte transformation. Instead, <i>ras</i>-transformed <i>Trop2<sup>−/−</sup></i> keratinocytes preferentially pass through an epithelial to mesenchymal transition (EMT) and form tumors with spindle cell histology. Furthermore, <i>Trop2</i> loss renders <i>Arf</i>-null mice susceptible to the formation of biphasic sarcomatoid carcinomas containing both squamous and spindle cell components upon carcinogen exposure in an otherwise skin cancer–resistant strain (C57BL/6). Immortalized keratinocytes derived from <i>Trop2<sup>−/−</sup>Arf<sup>−/−</sup></i> mice exhibit enhanced proliferative and migratory capacity as well as increased activation of mitogen-activated protein kinase and Src prior to transformation. The clinical relevance of these findings was supported by studying the molecular epidemiology of Trop2 in primary head and neck squamous cell carcinomas. This analysis revealed that Trop2 mRNA levels are decreased in a subset of tumors with features of EMT, and total loss of Trop2 protein expression is observed in the spindle cell component of sarcomatoid carcinomas. Therefore, while previous studies have emphasized the potential importance of Trop2 gain of function, these results uncover a role for <i>Trop2</i> loss in tumorigenesis and the mesenchymal transdifferentiation observed in a subset of squamous cell carcinomas. <i>Mol Cancer Res; 9(12); 1686–95. ©2011 AACR</i>.</p></div>