Details

Autor(en) / Beteiligte

• Li, Yuing
• Fischler, Thomas
• Xu, Xiaoling
• Wang, Rui-Hong
• Kim, Hyun-Seok
• Sengupta, Kundan
• Vassilopoulos, Athanassios
• Lahusen, Tyler
• Liu, Qinghua
• Elledge, Steve
• Ried, Thomas
• Deng, Chuxia

Titel

Abstract 1964: Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1

Ist Teil von

• Cancer research (Chicago, Ill.), 2010-04, Vol.70 (8_Supplement), p.1964-1964

Erscheinungsjahr

2010

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract Chk1 is a key element in the DNA damage response pathway that is required for maintaining genomic stability. To study the potential role of Chk1 in mammary tumorigenesis, we disrupted it using a Cre/loxP system. We showed that although Chk1 haploinsufficiency caused abnormal development of the mammary gland, it was not sufficient to induce tumorigenesis. Simultaneous deletion of one copy of p53 failed to rescue the developmental defects; however, it synergistically induced mammary tumor formation in Chk1+/-;MMTV-Cre animals with a median time to tumor latency of about 10 months. Chk1 deficiency caused a preponderance of abnormalities, including prolongation, multipolarity, misalignment, mitotic catastrophe and loss of spindle checkpoint that is accompanied by reduced expression of several cell cycle regulators, including Mad2. On the other hand, we also showed that Chk1 deficiency inhibited mammary tumor formation in mice carrying a homozygous deletion of p53, uncovering a complex relationship between Chk1 and p53. Furthermore, inhibition of Chk1 with a specific inhibitor, SB-218078, or acute deletion of Chk1 using shRNA killed mammary tumor cells effectively. These data demonstrate that Chk1 is critical for maintaining genome integrity and serves as a double-edged sword for cancer: while its inhibition kills cancer cells, it also triggers tumorigenesis when avorable mutations are accumulated for cell growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1964.