EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice

• Published in: PLoS genetics 2012-05, Vol.8 (5), p.e1002723
• Main Authors: Morel, Anne-Pierre, Hinkal, George W, Thomas, Clémence, Fauvet, Frédérique, Courtois-Cox, Stéphanie, Wierinckx, Anne, Devouassoux-Shisheboran, Mojgan, Treilleux, Isabelle, Tissier, Agnès, Gras, Baptiste, Pourchet, Julie, Puisieux, Isabelle, Browne, Gareth J, Spicer, Douglas B, Lachuer, Joël, Ansieau, Stéphane, Puisieux, Alain
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cell Differentiation; Cell Line; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Claudins - genetics; Claudins - metabolism; Colonies & territories; Development and progression; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelial-Mesenchymal Transition - genetics; Experiments; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes, ras; Genetic aspects; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Life Sciences; Mammary Glands, Animal - cytology; Mammary Glands, Animal - metabolism; Mammary Glands, Human - cytology; Mammary Glands, Human - metabolism; Medicine; Mice; Mice, Transgenic; Physiological aspects; Protein Phosphatase 2 - antagonists & inhibitors; Protein Phosphatase 2 - metabolism; Proteins; Retinoblastoma Protein - metabolism; Risk factors; Rodents; Telomerase - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - metabolism; Tumors; Twist-Related Protein 1 - genetics; Twist-Related Protein 1 - metabolism; Zinc Finger E-box-Binding Homeobox 1
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1002723

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