p21CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo
p21CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo
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DOI：
10.1073/pnas.0910009106
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发表时间：
2009-11-10
影响因子：
11.1
通讯作者：
Pestell, Richard G.
中科院分区：
文献类型：
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作者：
Liu, Manran;Casimiro, Mathew C.;Pestell, Richard G.
p21（CIP 1/WAF 1）是肿瘤抑制因子的下游效应子，并且作为细胞周期蛋白依赖性激酶抑制剂发挥作用以阻断细胞增殖。乳腺肿瘤可能来源于自我更新的肿瘤起始细胞（BT-IC），这有助于肿瘤进展、复发和治疗抵抗。p21（CIP 1）在体内调节肿瘤干细胞特征中的作用尚不清楚。在本文中，p21（CIP 1）的缺失增强了由乳腺靶向Ha-Ras或c-Myc诱导的肿瘤发生的速率，增强了上皮间质转化（EMT）和推定的癌症干细胞在体内的基因表达谱和免疫组织化学特征。沉默p21（CIP 1）增强，和表达p21（CIP 1）抑制，EMT的功能，在转化的不朽的人MEC线。p21（CIP 1）减弱癌基因诱导的BT-IC和乳腺球形成。因此，体外细胞培养试验反映了转基因小鼠体内观察到的变化。这些发现建立了p21（CIP 1）的损失和乳腺癌EMT和干细胞特性在体内的收购之间的联系。
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.