Cdc42 overexpression induces hyperbranching in the developing mammary gland by enhancing cell migration.
Cdc42 overexpression induces hyperbranching in the developing mammary gland by enhancing cell migration.
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DOI：
10.1186/bcr3487
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Vargo-Gogola T
中科院分区：
文献类型：
--
作者：
Bray K;Gillette M;Young J;Loughran E;Hwang M;Sears JC;Vargo-Gogola T
与正常乳腺组织相比，Rho GTdR Cdc 42在乳腺肿瘤中过表达和过度活化。cdc 42调节对乳腺形态发生至关重要的关键过程，并在乳腺癌的发展、进展和转移过程中被破坏。然而，Cdc 42在体内对正常和肿瘤性乳腺发育的贡献仍然知之甚少。因此，我们有兴趣研究Cdc 42过表达对乳腺形态发生的影响，作为了解其过表达如何促进乳腺肿瘤发生的第一步。我们开发了一种四环素可调控的Cdc 42过表达小鼠模型，其中Cdc 42可以在发育中的乳腺中诱导过表达。Cdc 42过表达在出生后乳腺发育过程中的影响进行了研究，在体内和体外的方法，包括形态分析的wholemounted乳腺，定量的组织学标志物，和初级乳腺上皮细胞（MEC）的功能和生化测定。Cdc 42过表达乳腺的分析显示异常的末端芽（TEB）形态，其特征在于超芽和三叉，并增加导管树内的侧支。增殖和凋亡标记物的定量表明，这些表型不是由于细胞增殖或存活增加。相反，Cdc 42过表达MEC更迁移和收缩，并形成畸形，侵入性腺泡在三维文化。Cdc 42和RhoA活性，磷酸化肌球蛋白轻链，MAPK信号，这有助于迁移和侵袭，在Cdc 42过表达MEC显着升高。有趣的是，Cdc 42过表达的乳腺显示出与改变的上皮-基质相互作用相关的几个特征，这是已知的调节分支形态发生。这些包括增加的基质厚度和胶原沉积，从Cdc 42过表达乳腺中分离的基质细胞表现出细胞外基质蛋白和重塑酶的mRNA表达升高。这些数据表明，Cdc 42过表达通过改变Rho GT3和MAPK信号转导破坏乳腺分支形态发生，导致MEC收缩性和迁移增加与基质改变。我们的研究提供了深入了解如何异常Cdc 42表达可能有助于乳腺肿瘤的发生。
The Rho GTPase Cdc42 is overexpressed and hyperactivated in breast tumors compared to normal breast tissue. Cdc42 regulates key processes that are critical for mammary gland morphogenesis and become disrupted during the development, progression, and metastasis of breast cancer. However, the contribution of Cdc42 to normal and neoplastic mammary gland development in vivo remains poorly understood. We were therefore interested in investigating the effects of Cdc42 overexpression on mammary gland morphogenesis as a first step toward understanding how its overexpression may contribute to mammary tumorigenesis. We developed a tetracycline-regulatable Cdc42 overexpression mouse model in which Cdc42 can be inducibly overexpressed in the developing mammary gland. The effects of Cdc42 overexpression during postnatal mammary gland development were investigated using in vivo and in vitro approaches, including morphometric analysis of wholemounted mammary glands, quantification of histological markers, and primary mammary epithelial cell (MEC) functional and biochemical assays. Analysis of Cdc42-overexpressing mammary glands revealed abnormal terminal end bud (TEB) morphologies, characterized by hyperbudding and trifurcation, and increased side branching within the ductal tree. Quantification of markers of proliferation and apoptosis suggested that these phenotypes were not due to increased cell proliferation or survival. Rather, Cdc42 overexpressing MECs were more migratory and contractile and formed dysmorphic, invasive acini in three-dimensional cultures. Cdc42 and RhoA activities, phosphorylated myosin light chain, and MAPK signaling, which contribute to migration and invasion, were markedly elevated in Cdc42 overexpressing MECs. Interestingly, Cdc42 overexpressing mammary glands displayed several features associated with altered epithelial-stromal interactions, which are known to regulate branching morphogenesis. These included increased stromal thickness and collagen deposition, and stromal cells isolated from Cdc42 overexpressing mammary glands exhibited elevated mRNA expression of extracellular matrix proteins and remodeling enzymes. These data suggest that Cdc42 overexpression disrupts mammary gland branching morphogenesis by altering Rho GTPase and MAPK signaling, leading to increased MEC contractility and migration in association with stromal alterations. Our studies provide insight into how aberrant Cdc42 expression may contribute to mammary tumorigenesis.
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DOI：
10.1083/jcb.200601059
发表时间：
2006-06-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Akhtar N;Streuli CH
通讯作者：
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影响因子：
7.8
作者：
Nobes, C D;Hall, A
通讯作者：
Hall, A
影响因子：
4.8
作者：
Gunther, EJ;Belka, GK;Chodosh, LA
通讯作者：
Chodosh, LA
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
4.8
作者：
Fowler, AM;Solodin, N;Alarid, ET
通讯作者：
Alarid, ET