EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors [human]

The newly identified claudin-low subtype of cancer is believed to represent the most primitive breast malignancies, having arisen from transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this hypothesis, we show both in vitro and in vivo that transcription factors inducing epithelial-mesenchymal transition can drive the development of claudin-low tumors from differentiated mammary epithelial cells, by playing a dual role in cell transformation and dedifferentiation. Human mammary epithelial cells (HMEC) were sequentially immortalized by hTert (HMEC-hTert), transduced with Twist1 or Zeb2 or Zeb1 and then with H-RasG12V. The gene expression profiles of the resulting HMEC-hTert-Twist1+Ras, HMEC-hTert-Zeb1+Ras and HMEC-hTert-Zeb2+Ras cell lines were defined. HMEC-hTert-Twist1+Ras and HMEC-hTert-Zeb2+Ras cell lines were additionally cultured in presence of TGFÃ? and their gene expression profiles were determined. The parental HMEC-hTert, the luminal MCF7 and the basal B MDMB157cell lines were used as controls.