EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

• DOI: 10.1371/journal.pgen.1002723
• Publication Date: 2012-05-24T21:06:21Z
• Authors: Anne-Pierre Morel; George W. Hinkal; Clémence Thomas; Frédérique Fauvet; Stéphanie Courtoi...; Anne Wierinckx; Mojgan Devouassou...; Isabelle Treilleux; Agnès Tissier; Baptiste Gras; Julie Pourchet; Isabelle Puisieux; Gareth J. Browne; Douglas B. Spicer; Joël Lachuer; Stéphane Ansieau; Alain Puisieux
• Keywords: Transdifferentiation; Adherens junction; Malignant Transformation

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and known favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, TWIST ZEB proteins can prevent from undergoing oncogene-induced senescence apoptosis by abolishing both p53- RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase efficiently cooperate with version H-RAS malignant transformation human mammary cells. Thus, down-regulating crucial suppressor functions, EMT inducers make particularly prone conversion. Importantly, analyzing transformed generated vitro characterizing novel transgenic mouse models, further demonstrate cooperation between inducer active form RAS sufficient trigger into exhibiting all characteristic features claudin-low tumors, including low expression tight adherens junction genes, traits, stem cell–like characteristics. Claudin-low tumors believed be most primitive breast malignancies, having arisen through early precursor inherent stemness properties metaplastic features. Challenging this prevailing view, propose these aggressive arise committed luminal differentiation, a driven combining transdifferentiation.