Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation.
Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation.
复制标题
DOI：
10.1016/j.molonc.2013.10.005
复制
发表时间：
2014-03
影响因子：
6.6
通讯作者：
Venkitaraman AR
中科院分区：
文献类型：
--
作者：
Cassidy LD;Liau SS;Venkitaraman AR
染色体不稳定是人类癌细胞的一个标志，但它在癌症发生中的作用仍然没有得到很好的解决。对这种作用的认识来自对肿瘤抑制基因BRCA2的研究，在人类癌症中，BRCA2蛋白的失活通过丧失BRCA2蛋白的基本功能而导致染色体不稳定，而BRCA2蛋白是负责细胞分裂期间DNA复制、修复和分离的正常机制。携带BRCA2基因杂合胚系突变的人类极易患乳腺癌、卵巢癌、胰腺癌、前列腺癌和其他组织癌。在这里，我们回顾了最近的研究，描述了与BRCA2突变相关的胰腺癌的基因工程小鼠模型(GEMM)。这些研究不仅令人惊讶地表明BRCA2并不遵循经典的Knudson“两次打击”肿瘤抑制范例，而且还强调了在BRCA2缺乏的情况下TP53失活与癌症发生之间的相互作用的特征。因此，这些模型揭示了BRCA2胚系突变携带者癌症进化的新方面，为BRCA2的肿瘤抑制作用提供了新的见解，并为测试胰腺癌治疗方法建立了有价值的新的临床前环境；总之，这些特征强调了GEMM在癌症研究中的价值。生殖系BRCA2突变携带者发生胰腺癌的机制尚不清楚。最近对转基因小鼠模型的研究令人惊讶地表明，即使是杂合的BRCA2突变也会促进胰腺癌。他们还揭示了在BRCA2缺乏的背景下，TP53失活和胰腺癌发生之间的相互作用。我们回顾了由这些模型引起的对肿瘤进化的见解，并强调了它们在测试新疗法方面的价值。
Chromosomal instability is a hallmark of human cancer cells, but its role in carcinogenesis remains poorly resolved. Insights into this role have emerged from studies on the tumour suppressor BRCA2, whose inactivation in human cancers causes chromosomal instability through the loss of essential functions of the BRCA2 protein in the normal mechanisms responsible for the replication, repair and segregation of DNA during cell division. Humans who carry heterozygous germline mutations in the BRCA2 gene are highly predisposed to cancers of the breast, ovary, pancreas, prostate and other tissues. Here, we review recent studies that describe genetically engineered mouse models (GEMMs) for pancreatic cancer associated with BRCA2 mutations. These studies not only surprisingly show that BRCA2 does not follow the classical Knudson “two hit” paradigm for tumour suppression, but also highlight features of the interplay between TP53 inactivation and carcinogenesis in the context of BRCA2 deficiency. Thus, the models reveal novel aspects of cancer evolution in carriers of germline BRCA2 mutations, provide new insights into the tumour suppressive role of BRCA2, and establish valuable new preclinical settings for testing approaches to pancreatic cancer therapy; together, these features emphasize the value of GEMMs in cancer research. The mechanisms underlying pancreatic carcinogenesis in germline BRCA2 mutation carriers remain unclear. Recent studies on transgenic mouse models surprisingly show that even heterozygous BRCA2 mutations promote pancreatic cancer. They also reveal the interplay between TP53 inactivation and pancreatic carcinogenesis in the context of BRCA2 deficiency. We review insights into tumour evolution arising from these models, and highlight their value in testing new therapies.
登录
查看更多内容
影响因子：
30.8
作者：
Connor, F;Bertwistle, D;Ashworth, A
通讯作者：
Ashworth, A
影响因子：
11.8
作者：
Choi, Eunhee;Park, Pil-Gu;Lee, Hyunsook
通讯作者：
Lee, Hyunsook
DOI：
10.1016/j.cub.2009.05.057
发表时间：
2009-07-14
期刊：
Current biology : CB
影响因子：
--
作者：
Ayoub N;Rajendra E;Su X;Jeyasekharan AD;Mahen R;Venkitaraman AR
通讯作者：
Venkitaraman AR
影响因子：
56.9
作者：
Daniels, MJ;Wang, YM;Venkitaraman, AR
通讯作者：
Venkitaraman, AR
影响因子：
64.8
作者：
Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.