P21CIP1 Attenuates Ras- and C-Myc-dependent Breast Tumor Epithelial Mesenchymal Transition and Cancer Stem Cell-like Gene Expression in Vivo

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Oct 28

PMID 19858489

Citations 106

Authors

Manran Liu

Mathew C Casimiro

Chenguang Wang

L Andrew Shirley

Xuanmao Jiao

Sanjay Katiyar

Xiaoming Ju

Zhiping Li

Zuoren Yu

Jie Zhou

Michael Johnson

Paolo Fortina

Terry Hyslop

Jolene J Windle

Richard G Pestell

Affiliations

Soon will be listed here.

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.

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