Abstract
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.
Highlights
While the disruption of embryonic processes has been acknowledged as a cause of the outgrowth of paediatric neoplasms, more recent observations suggest that the aberrant reactivation of developmental regulatory programs might contribute to progression in the advanced stages of cancers in adults [1]
Supporting an oncogenic activity within primary lesions, we recently demonstrated that the TWIST proteins were able to prevent cells from undergoing oncogeneinduced senescence and apoptosis by abrogating both p53- and RB-dependent pathways [10,11]
MMTV-Cre;KrasG12D;Twist1 mice invariably developed aggressive multifocal squamous cell carcinomas (SCC) at very young ages necessitating euthanasia at the significantly earlier median age of 35 days (n = 12, p,0.0001, Figure 1). These observations demonstrated for the first time the oncogenic properties of TWIST1 in vivo and underscored the cooperative effect between K-RAS and TWIST1 in promoting malignant conversion
Summary
While the disruption of embryonic processes has been acknowledged as a cause of the outgrowth of paediatric neoplasms, more recent observations suggest that the aberrant reactivation of developmental regulatory programs might contribute to progression in the advanced stages of cancers in adults [1]. EMT plays critical roles in the formation of the body plan and in the differentiation of most of the tissues and organs derived from the mesoderm and the endoderm [3]. This process is tightly regulated through a delicate interplay between environmental signals from WNT, TGFb, FGF family members, and a complex network of signaling pathways that converge on the activation of transcription factors that induce EMT through repression of CDH1 (encoding for the E-cadherin) and activation of mesenchymal genes. EMT-inducing transcription factors include several zinc finger proteins
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