Cooperative signaling between Wnt1 and integrin-linked kinase induces accelerated breast tumor development.
Cooperative signaling between Wnt1 and integrin-linked kinase induces accelerated breast tumor development.
复制标题
DOI：
10.1186/bcr2592
复制
发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Dedhar S
中科院分区：
文献类型：
--
作者：
Oloumi A;Maidan M;Lock FE;Tearle H;McKinney S;Muller WJ;Aparicio SA;Dedhar S
乳腺癌在基因和临床上都是一种异质性疾病。然而，不同细胞类型和致癌突变对这种异质性的确切贡献还不是很清楚。最近，我们发现在调节细胞生长和存活的信号级联中，Wnt和整合素连接的激酶(ILK)之间存在相互作用。有趣的是，这两种蛋白中的任何一种的乳腺特异性表达都被证明促进了乳腺肿瘤的发生。根据我们最近的发现，为了研究Wnt和ILK蛋白在乳腺肿瘤形成和发展过程中的潜在相互作用，我们建立了一种在乳腺上皮细胞中同时表达Wnt和ILK的转基因小鼠模型。通过将MMTV-WNT1和MMTV-ILK两种已鉴定的小鼠模型杂交，建立了一种新的具有乳腺特异表达WNT1和ILK的转基因小鼠模型。由此产生的MMTV-WNT/ILK小鼠被密切监测肿瘤的发展和生长，以及肿瘤的发生。用生化和整体基因表达分析的方法研究了肿瘤和癌前乳腺的分子表型。在MMTV-WNT/ILK小鼠中观察到乳腺肿瘤的发病率和生长显著加速。癌前乳腺还表现为小叶肺泡增生和导管上皮细胞增多。除了Wnt/ILK靶标如β-连环蛋白和细胞周期蛋白D1的表达升高外，基因表达谱还发现FOXA1转录因子的惊人激活。FOXA1的上调与MMTV-WNT/ILK肿瘤中CD29loCD24hiCD61+细胞的扩增一致，FOXA1也被认为是分化的乳腺腔细胞的分子标志。这些结果表明，在乳腺癌发生过程中，WNT1和ILK转基因之间存在合作，导致转录网络的变化，这可能决定一种特定的乳腺癌表型，具有增强的生长动力学。MMTV-WNT/ILK可作为进一步鉴定雌激素受体β/FOXA1下游基因的模型，并可用于研究靶向扩张的腔前体细胞导致增殖和肿瘤发生的机制。
Breast cancer is genetically and clinically a heterogeneous disease. However, the exact contribution of different cell types and oncogenic mutations to this heterogeneity are not well understood. Recently, we discovered an interaction between Wnt and integrin-linked kinase (ILK) within the signaling cascade that regulates cell growth and survival. Interestingly, mammary-specific expression of either one of these proteins has been shown to promote mammary tumorigenesis. In light of our recent findings and to investigate the potential interaction between Wnt and ILK proteins during mammary tumor formation and progression, we established a transgenic mouse model that expresses both Wnt and ILK in mammary epithelial cells. A novel transgenic mouse model with mammary-specific expression of both Wnt1 and ILK was generated by crossing the two previously characterized mouse models, MMTV-Wnt1 and MMTV-ILK. The resulting MMTV-Wnt/ILK mice were closely monitored for tumor development and growth, as well as for the tumor onset. The molecular phenotypes of both tumors and premalignant mammary glands were investigated by using biochemical and global gene-expression analysis approaches. A significant acceleration in mammary tumor incidence and growth was observed in the MMTV-Wnt/ILK mice. Pre-neoplastic mammary glands also display lobuloalveolar hyperplasia and an increase in ductal epithelium proliferation. Apart from elevated expression of Wnt/ILK targets, such as β-catenin and cyclin D1, gene-expression profiling identified the surprising activation of the FOXA1 transcription factor. Upregulation of FOXA1, which is also known as the molecular marker of differentiated mammary luminal cells, was consistent with the expansion of the enriched luminal progenitor population or CD29loCD24hiCD61+ cells in MMTV-Wnt/ILK tumors. These results show cooperation between Wnt1 and ILK transgenes during mammary carcinogenesis, leading to changes in a transcriptional network, which could dictate a specific breast cancer phenotype with enhanced growth dynamics. The MMTV-Wnt/ILK can be used as a model to identify further the genes downstream of the estrogen receptor-β/FOXA1 and to investigate the mechanisms targeting the expansion of the luminal progenitor cells leading to hyperplasia and tumorigenesis.
登录
查看更多内容
影响因子：
7.8
作者：
Hinck, L;Nelson, W J;Papkoff, J
通讯作者：
Papkoff, J
影响因子：
11.4
作者：
Bauer, A;Chauvet, S;Pradel, J
通讯作者：
Pradel, J
影响因子：
64.5
作者：
Kouros-Mehr, Hosein;Slorach, Euan M.;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
23.9
作者：
Bouras, Toula;Pal, Bhupinder;Visvader, Jane E.
通讯作者：
Visvader, Jane E.
影响因子：
3.5
作者：
Goulioumis, Anastasios K.;Bravou, Vasiliki;Papadaki, Helen
通讯作者：
Papadaki, Helen