HER2-driven breast cancer suppression by the JNK signaling pathway.
HER2-driven breast cancer suppression by the JNK signaling pathway.
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DOI：
10.1073/pnas.2218373120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
Davis, Roger J.
中科院分区：
文献类型：
--
作者：
Itah, Zeynep;Chaudhry, Shanzah;Ponny, Sithara Raju;Aydemir, Ozkan;Lee, Alexandra;Cavanagh-Kyros, Julie;Tournier, Cathy;Muller, William J.;Davis, Roger J.
The cJun NH2-terminal kinase (JNK) signaling pathway has been implicated in the etiology of breast cancer because mutations in the JNK pathway have been identified in tumors. To test the role of the JNK pathway, we studied an in vitro CRISPR-based model of HER2+ cancer using human mammary epithelial cells and an in vivo mouse genetic model of HER2+ breast cancer. The data obtained demonstrated that JNK deficiency and HER2 signaling caused similar changes in gene expression in 3D cultures of human mammary epithelial cells in vitro. Moreover, JNK deficiency caused accelerated development of mouse breast cancer in vivo. These observations establish a tumor suppression function for the JNK signaling pathway in HER2+ breast cancer. The HER2+ subtype of human breast cancer is associated with the malignant transformation of luminal ductal cells of the mammary epithelium. The sequence analysis of tumor DNA identifies loss of function mutations and deletions of the MAP2K4 and MAP2K7 genes that encode direct activators of the JUN NH2-terminal kinase (JNK). We report that in vitro studies of human mammary epithelial cells with CRISPR-induced mutations in the MAPK and MAP2K components of the JNK pathway caused no change in growth in 2D culture, but these mutations promoted epithelial cell proliferation in 3D culture. Analysis of gene expression signatures in 3D culture demonstrated similar changes caused by HER2 activation and JNK pathway loss. The mechanism of signal transduction cross-talk may be mediated, in part, by JNK-suppressed expression of integrin α6β4 that binds HER2 and amplifies HER2 signaling. These data suggest that HER2 activation and JNK pathway loss may synergize to promote breast cancer. To test this hypothesis, we performed in vivo studies using a mouse model of HER2+ breast cancer with Cre/loxP-mediated ablation of genes encoding JNK (Mapk8 and Mapk9) and the MAP2K (Map2k4 and Map2k7) that activate JNK in mammary epithelial cells. Kaplan–Meier analysis of tumor development demonstrated that JNK pathway deficiency promotes HER2+-driven breast cancer. Collectively, these data identify JNK pathway genes as potential suppressors for HER2+ breast cancer.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
基于截短和基序的泛伴侣分析揭示了肿瘤抑制的激酶。
影响因子：
7.3
作者：
Hudson AM;Stephenson NL;Li C;Trotter E;Fletcher AJ;Katona G;Bieniasz-Krzywiec P;Howell M;Wirth C;Furney S;Miller CJ;Brognard J
通讯作者：
Brognard J
影响因子：
16.6
作者：
Lessard SJ;MacDonald TL;Pathak P;Han MS;Coffey VG;Edge J;Rivas DA;Hirshman MF;Davis RJ;Goodyear LJ
通讯作者：
Goodyear LJ
影响因子：
64.5
作者：
Ciriello G;Gatza ML;Beck AH;Wilkerson MD;Rhie SK;Pastore A;Zhang H;McLellan M;Yau C;Kandoth C;Bowlby R;Shen H;Hayat S;Fieldhouse R;Lester SC;Tse GM;Factor RE;Collins LC;Allison KH;Chen YY;Jensen K;Johnson NB;Oesterreich S;Mills GB;Cherniack AD;Robertson G;Benz C;Sander C;Laird PW;Hoadley KA;King TA;TCGA Research Network;Perou CM
通讯作者：
Perou CM