Wnt5a suppresses tumor formation and redirects tumor phenotype in MMTV-Wnt1 tumors.
Wnt5a suppresses tumor formation and redirects tumor phenotype in MMTV-Wnt1 tumors.
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DOI：
10.1371/journal.pone.0113247
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Serra R
中科院分区：
文献类型：
--
作者：
Easter SL;Mitchell EH;Baxley SE;Desmond R;Frost AR;Serra R
Wnt5a 是一种非经典信号传导 Wnt，与肿瘤抑制有关。我们之前表明，MMTV-PyVmT 肿瘤中 Wnt5a 的缺失会导致肿瘤表型的转变，从而导致肿瘤基础表型增加和 Wnt/β-catenin 信号传导增强。本研究的目的是检验 Wnt5a 可以抑制由 Wnt/β-catenin 信号传导激活形成的肿瘤的假设。为此，我们对 MMTV-Wnt1 和双转基因 MMTV-Wnt1;MMTV-Wnt5a 小鼠的肿瘤和非肿瘤乳腺组织进行了表征。与 MMTV-Wnt1 对照相比，含有 Wnt5a 的小鼠肿瘤较少，潜伏期较长。在 Wnt5a 存在的情况下形成的肿瘤中，基底样肿瘤标记物的表达下调，表明表型转换。在双转基因肿瘤中检测到典型 Wnt 信号传导减少，表现为活性 β-catenin 蛋白的减少和 Axin2 mRNA 转录水平的减少。在非肿瘤组织中，MMTV-Wnt1 乳腺中 Wnt5a 的过度表达导致 MMTV-Wnt1 腺体中通常观察到的表型减弱，包括超分支以及祖细胞和基底细胞群增加。尽管 Wnt5a 可以拮抗培养的原代乳腺上皮细胞中的 Wnt/β-catenin 信号传导，但在体内非肿瘤 MMTV-Wnt1;Wnt5a 组织中未检测到 Wnt/β-catenin 信号传导减少。数据表明，Wnt5a 抑制肿瘤形成并促进 MMTV-Wnt1 肿瘤的表型转变。
Wnt5a is a non-canonical signaling Wnt that has been implicated in tumor suppression. We previously showed that loss of Wnt5a in MMTV-PyVmT tumors resulted in a switch in tumor phenotype resulting in tumors with increased basal phenotype and high Wnt/β-catenin signaling. The object of this study was to test the hypothesis that Wnt5a can act to inhibit tumors formed by activation of Wnt/β-catenin signaling. To this end, we characterized tumor and non-tumor mammary tissue from MMTV-Wnt1 and double transgenic MMTV-Wnt1;MMTV-Wnt5a mice. Wnt5a containing mice demonstrated fewer tumors with increased latency when compared to MMTV-Wnt1 controls. Expression of markers for basal-like tumors was down-regulated in the tumors that formed in the presence of Wnt5a indicating a phenotypic switch. Reduced canonical Wnt signaling was detected in double transgenic tumors as a decrease in active β-catenin protein and a decrease in Axin2 mRNA transcript levels. In non-tumor tissues, over-expression of Wnt5a in MMTV-Wnt1 mammary glands resulted in attenuation of phenotypes normally observed in MMTV-Wnt1 glands including hyperbranching and increased progenitor and basal cell populations. Even though Wnt5a could antagonize Wnt/β-catenin signaling in primary mammary epithelial cells in culture, reduced Wnt/β-catenin signaling was not detected in non-tumor MMTV-Wnt1;Wnt5a tissue in vivo. The data demonstrate that Wnt5a suppresses tumor formation and promotes a phenotypic shift in MMTV-Wnt1 tumors.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
3.8
作者：
Ghebeh H;Sleiman GM;Manogaran PS;Al-Mazrou A;Barhoush E;Al-Mohanna FH;Tulbah A;Al-Faqeeh K;Adra CN
通讯作者：
Adra CN
影响因子：
3.6
作者：
Baxley, Sarah E.;Jiang, Wen;Serra, Rosa
通讯作者：
Serra, Rosa
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
DOI：
10.1023/b:jomg.0000037157.94207.33
发表时间：
2004-04-01
影响因子：
2.5
作者：
Brennan, KR;Brown, AMC
通讯作者：
Brown, AMC