Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers.
Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers.
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DOI：
10.18632/oncotarget.8988
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Dey N
中科院分区：
文献类型：
--
作者：
De P;Carlson JH;Wu H;Marcus A;Leyland-Jones B;Dey N
肿瘤细胞在基因改变后获得转移相关（MA）表型，从而导致不同信号通路的失调。早些时候，我们报道了 Wnt-β-连环蛋白通路（WP）的上调是三阴性乳腺癌（TNBC）的遗传显着特征之一，并且 WP 信号传导与 TNBC 的转移相关。使用 cBioPortal，我们发现乳腺浸润性癌中 WP 基因、CTNNB1、APC 和 DVL1 的集体改变百分比为 21%，而 PAM50 Basal 中的改变百分比为 56%。为了了解 WP 在异质/转移 TNBC 细胞生物学中的功能相关性，我们使用 15 个细胞系进行了这项综合研究，其中我们检查了 WP 在整合素依赖性 MA 表型背景下的作用。通过共焦免疫荧光显微镜和定量共焦视频显微镜观察肿瘤细胞的定向运动，同时通过 MMP7 特异性酪蛋白酶谱研究基质胶侵袭。 WntC59、XAV939、舒林酸硫化物和 β-连环蛋白 siRNA (1) 抑制纤连蛋白定向迁移，(2) 减少足参数和运动描述符，(3) 改变丝状肌动蛋白，(4) 减少基质胶侵袭，(5) 抑制细胞增殖以及 3D 克隆生长。舒林酸硫化物和 β-连环蛋白 siRNA 降低了 β-连环蛋白/活性-β-连环蛋白和 MMP7。 LWnt3ACM 刺激的增殖、克隆形成、纤维连接定向迁移和基质胶侵袭受到 WP 调节剂、舒林酸硫化物和 GDC-0941 的干扰。我们通过刺激脑转移特异性 MDA-MB231BR 细胞来研究 WP 在转移中的直接参与，以证明 LWnt3ACM 刺激的增殖、克隆形成和迁移在舒林酸硫化物、GDC-0941 和 β-连环蛋白敲低后被阻断。我们提出了第一个证据，表明 WP 激活和整合素依赖性 MA 表型之间存在直接功能关系。通过证明 WP 激活和 MA 表型之间的功能关系，我们的数据机械地解释了（1）为什么 WP 的不同成分在 TNBC 中上调，（2）WP 激活如何与转移相关，以及（3）如何通过减轻 WP 来调节整合素依赖性 MA 表型。
Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronection-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.
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影响因子：
8.8
作者：
Lawrence RT;Perez EM;Hernández D;Miller CP;Haas KM;Irie HY;Lee SI;Blau CA;Villén J
通讯作者：
Villén J
影响因子：
4.7
作者：
Lague, Marie-Noelle;Paquet, Marilene;Boerboom, Derek
通讯作者：
Boerboom, Derek
Wnt-β-catenin途径在三阴性乳腺癌中的差异激活以PTEN依赖性方式增加了MMP7。
影响因子：
3.7
作者：
Dey N;Young B;Abramovitz M;Bouzyk M;Barwick B;De P;Leyland-Jones B
通讯作者：
Leyland-Jones B
DOI：
10.1158/1078-0432.ccr-13-0790
发表时间：
2013-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Lin NU;Amiri-Kordestani L;Palmieri D;Liewehr DJ;Steeg PS
通讯作者：
Steeg PS
影响因子：
7.5
作者：
Geyer, Felipe C.;Lacroix-Triki, Magali;Reis-Filho, Jorge S.
通讯作者：
Reis-Filho, Jorge S.