p21CIP¹ attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 45; pp. 19035 - 19039
• Main Authors: Liu, Manran, Casimiro, Mathew C, Wang, Chenguang, Shirley, L. Andrew, Jiao, Xuanmao, Katiyar, Sanjay, Ju, Xiaoming, Li, Zhiping, Yu, Zuoren, Zhou, Jie, Johnson, Michael, Fortina, Paolo, Hyslop, Terry, Windle, Jolene J, Pestell, Richard G
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 2009
• Subjects: breast neoplasms; carcinogenesis; cell culture; cell proliferation; cyclin-dependent kinase; epithelium; gene expression; humans; immunohistochemistry; mice; stem cells; therapeutics; transgenic animals
• ISSN: 0027-8424; 1091-6490

p21CIP¹/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 p21CIP¹ in regulating features of tumor stem cells in vivo is unknown. Herein, deletion of p21CIP¹, 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 p21CIP¹ enhanced, and expression of p21CIP¹ repressed, features of EMT in transformed immortal human MEC lines. p21CIP¹ 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 p21CIP¹ and the acquisition of breast cancer EMT and stem cell properties in vivo.