WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer.
WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer.
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DOI：
10.1002/emmm.201201320
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发表时间：
2013-02
影响因子：
11.1
通讯作者：
Miranda-Carboni, Gustavo A.
中科院分区：
文献类型：
--
作者：
Wend, Peter;Runke, Stephanie;Wend, Korinna;Anchondo, Brenda;Yesayan, Maria;Jardon, Meghan;Hardie, Natalie;Loddenkemper, Christoph;Ulasov, Ilya;Lesniak, Maciej S.;Wolsky, Rebecca;Bentolila, Laurent A.;Grant, Stephen G.;Elashoff, David;Lehr, Stephan;Latimer, Jean J.;Bose, Shikha;Sattar, Husain;Krum, Susan A.;Miranda-Carboni, Gustavo A.
Wnt/β-连环蛋白信号在基底细胞样乳腺癌中被认为是活跃的。然而，在高侵袭性转移性三阴性乳腺癌中，β-连环蛋白的作用和侵袭性的潜在机制(S)仍不清楚。我们说明了WNT10B在转录水平上诱导了人肿瘤细胞中β-连环蛋白的活性，并预测了肿瘤细胞和基底细胞样肿瘤患者的生存结果。我们提供的证据表明，转基因小鼠WNT10b驱动的肿瘤缺乏ER、α、PR和HER2的表达，可以模拟人的肿瘤。重要的是，HMGA2在胚胎乳房发生的早期阶段特异性表达，当WNT10B表达丢失时缺失，这表明一种发育保守的作用模式。从机制上讲，芯片分析发现WNT10B激活了典型的β-连环蛋白信号转导，导致HMGA2的上调。用两种WNT/β-连环蛋白途径调节剂或针对HMGA2的siRNA治疗小鼠和人类三阴性肿瘤细胞可降低HMGA2水平和增殖。我们证明了WNT10B对HMGA2具有上位性活性，这对TNBC细胞的增殖是必要的和充分的。此外，HMGA2的表达可以预测TNBC患者的无复发生存和转移。
Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients.
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影响因子：
5.3
作者：
Lustig, B;Jerchow, B;Behrens, J
通讯作者：
Behrens, J
影响因子：
--
作者：
Krum, Susan A.;Miranda-Carboni, Gustavo A.;Brown, Myles
通讯作者：
Brown, Myles
影响因子：
11.2
作者：
De Martino, Ivana;Visone, Rosa;Fusco, Alfredo
通讯作者：
Fusco, Alfredo
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
3.8
作者：
Pal, Sumanta Kumar;Childs, Barrett H.;Pegram, Mark
通讯作者：
Pegram, Mark