p21 CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo

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Abstract
P21 CIP1/WAF1 is a downstream effector of tumor suppressors and functions as a cyclin-dependent kinase inhibitor to block cellular proliferation. Breast tumors may derive from self-renewing tumor-initiating cells (BT-ICs), which contribute to tumor progression, recurrence, and therapy resistance. The role of p21 CIP1 in regulating features of tumor stem cells in vivo is unknown. Herein, deletion of p21 CIP1 , which enhanced the rate of tumorigenesis induced by mammary-targeted Ha-Ras or c-Myc, enhanced gene expression profiles and immunohistochemical features of epithelial mesenchymal transition (EMT) and putative cancer stem cells in vivo. Silencing of p21 CIP1 enhanced, and expression of p21 CIP1 repressed, features of EMT in transformed immortal human MEC lines. p21 CIP1 attenuated oncogene-induced BT-IC and mammosphere formation. Thus, the in vitro cell culture assays reflect the changes observed in vivo in transgenic mice. These findings establish a link between the loss of p21 CIP1 and the acquisition of breast cancer EMT and stem cell properties in vivo.