Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le promoteur du gène ZEB1 favorise l'induction d'un état de cellule souche cancéreuse dans des cellules de cancer du sein de type basal
The recent discovery that normal and neoplastic epithelial cells re-enter the stem cell state raised the intriguing possibility that the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs) but from their proclivity to generate new CSCs from non-CSC populations. Here, we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC state. The observed cell plasticity is dependent on ZEB1, a key regulator of the epithelial-mesenchymal transition. We find that plastic non-CSCs maintain the ZEB1 promoter in a bivalent chromatin configuration, enabling them to respond readily to microenvironmental signals, such as TGF². In response, the ZEB1 promoter converts from a bivalent to active chromatin configuration, ZEB1 transcription increases, and non-CSCs subsequently enter the CSC state. Our findings support a dynamic model in which interconversions between low and high tumorigenic states occur frequently, thereby increasing tumorigenic and malignant potential. "Basal breast cancer non-CSCs are plastic populations that can generate CSCs de novo "ZEB1 drives non-CSC to CSC plasticity "Basal non-CSCs maintain ZEB1 in poised (bivalent) chromatin configuration "Poised ZEB1 promoter more readily responds to the microenvironment Nonaggressive cells in basal, but not lumenal, breast cancers exist in a poised state, ready to switch to an aggressive cancer stem cell state in response to appropriate microenvironmental stimuli, a plasticity that may promote tumorigenicity in basal compared to lumenal breast cancers.