KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer.
KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer.
复制标题
DOI：
10.1016/j.celrep.2018.02.095
复制
发表时间：
2018-03-20
期刊：
影响因子：
8.8
通讯作者：
Park M
中科院分区：
文献类型：
--
作者：
Knight JF;Sung VYC;Kuzmin E;Couzens AL;de Verteuil DA;Ratcliffe CDH;Coelho PP;Johnson RM;Samavarchi-Tehrani P;Gruosso T;Smith HW;Lee W;Saleh SM;Zuo D;Zhao H;Guiot MC;Davis RR;Gregg JP;Moraes C;Gingras AC;Park M
三阴性乳腺癌 (TNBC) 显示出一系列复杂的突变和染色体畸变。在高达 70% 的 TNBC 中检测到染色体 5q (5q) 丢失，但与此事件相关的遗传驱动因素却知之甚少。在这里，我们在 TNBC 小鼠模型中展示了与人类 5q33.2-35.3 同线区域的体细胞缺失。从机制上讲，我们认为 KIBRA 是导致 5q 缺失对肿瘤生长和转移进展影响的主要因素。 KIBRA 的重新表达会损害体内转移并抑制体外 TNBC 细胞的肿瘤球形成。 KIBRA 与蛋白酪氨酸磷酸酶 PTPN14 协同作用，触发机械转导调节信号，抑制致癌转录共激活剂 YAP/TAZ 的核定位。我们的结果表明，5q 缺失产生的选择性优势涉及减少 KIBRA 剂量，促进 TNBC 中 YAP/TAZ 的致癌功能。 KIBRA 表达减少与乳腺癌中 5q 染色体缺失相关 恢复 Kibra 表达可抑制小鼠体内的转移扩散 KIBRA 损害三阴性乳腺癌细胞的自我更新能力 KIBRA 阻断 YAP/TAZ 激活所需的机械转导信号 三阴性乳腺癌 (TNBC) 经常丢失染色体 5q。 Knight 等人使用具有同线性区域自发丢失的 TNBC 小鼠模型。确定 KIBRA 是一种转移抑制剂。从机制上讲，KIBRA 抑制 RHOA 激活，损害癌基因 YAP/TAZ 的核转位，而癌基因 YAP/TAZ 会驱动转移和癌症干细胞样行为。
Triple-negative breast cancers (TNBCs) display a complex spectrum of mutations and chromosomal aberrations. Chromosome 5q (5q) loss is detected in up to 70% of TNBCs, but little is known regarding the genetic drivers associated with this event. Here, we show somatic deletion of a region syntenic with human 5q33.2–35.3 in a mouse model of TNBC. Mechanistically, we identify KIBRA as a major factor contributing to the effects of 5q loss on tumor growth and metastatic progression. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro. KIBRA functions co-operatively with the protein tyrosine phosphatase PTPN14 to trigger mechanotransduction-regulated signals that inhibit the nuclear localization of oncogenic transcriptional co-activators YAP/TAZ. Our results argue that the selective advantage produced by 5q loss involves reduced dosage of KIBRA, promoting oncogenic functioning of YAP/TAZ in TNBC. Reduced KIBRA expression is associated with chr 5q loss in breast cancer Restoring Kibra expression inhibits metastatic dissemination in mice KIBRA impairs the self-renewal capacity of triple-negative breast cancer cells KIBRA blocks mechanotransduction signals required for YAP/TAZ activation Triple-negative breast cancers (TNBCs) frequently lose chromosome 5q. Using a TNBC mouse model with spontaneous loss of a syntenic region, Knight et al. identify KIBRA as a metastasis suppressor. Mechanistically, KIBRA suppresses RHOA activation, impairing nuclear translocation of the oncogenes YAP/TAZ, which drive metastatic and cancer stem cell-like behavior.
登录
查看更多内容
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
168.9
作者：
Denkert, Carsten;Liedtke, Cornelia;von Minckwitz, Gunter
通讯作者：
von Minckwitz, Gunter
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
11.8
作者：
Genevet A;Wehr MC;Brain R;Thompson BJ;Tapon N
通讯作者：
Tapon N
影响因子：
3.7
作者：
Lehmann BD;Jovanović B;Chen X;Estrada MV;Johnson KN;Shyr Y;Moses HL;Sanders ME;Pietenpol JA
通讯作者：
Pietenpol JA