EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice.
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.
Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Anne-Pierre
AP
Morel
George W
GW
Hinkal
Clémence
C
Thomas
Frédérique
F
Fauvet
Stéphanie
S
Courtois-Cox
Anne
A
Wierinckx
Mojgan
M
Devouassoux-Shisheboran
Isabelle
I
Treilleux
Agnès
A
Tissier
Baptiste
B
Gras
Julie
J
Pourchet
Isabelle
I
Puisieux
Gareth J
GJ
Browne
Douglas B
DB
Spicer
Joël
J
Lachuer
Stéphane
S
Ansieau
Alain
A
Puisieux
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
D057167:Claudins; D018398:Homeodomain Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C509186:TERT protein, human; D019098:Telomerase; D054648:Protein Phosphatase 2