Mammary epithelial-specific disruption of c-Src impairs cell cycle progression and tumorigenesis
Mammary epithelial-specific disruption of c-Src impairs cell cycle progression and tumorigenesis
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DOI：
10.1073/pnas.1018861108
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发表时间：
2012-02-21
影响因子：
11.1
通讯作者：
Muller, William J.
中科院分区：
文献类型：
--
作者：
Marcotte, Richard;Smith, Harvey W.;Muller, William J.
酪氨酸激酶 c-Src 在大部分乳腺癌中被激活，它被认为在促进恶性表型中发挥关键作用。 c-Src 活性在乳腺癌转基因小鼠模型中也有所升高，包括广泛使用的多瘤病毒中 T 抗原 (PyVmT) 模型，这为研究 c-Src 在乳腺肿瘤发生中的重要性提供了机会。然而，由于乳腺发育的严重缺陷，乳腺上皮和基质区室中种系 c-Src 缺失使体内肿瘤发生研究的解释变得复杂。因此，我们设计了一种小鼠品系，其中 c-Src 的删除可以针对乳腺上皮。我们证明，c-Src 的乳腺上皮破坏会损害体内 PyVmT 驱动的增殖和肿瘤进展。尽管相关激酶在 PyVmT 信号传导中取代了 c-Src，但 c-Src 消除会导致细胞周期蛋白表达降低和细胞周期蛋白依赖性激酶抑制剂表达升高，从而损害细胞周期进程。我们的数据表明，c-Src 在该小鼠模型中的增殖和肿瘤进展中具有重要且独特的功能，这在某些人类乳腺癌的某些情况下也可能很重要。
The tyrosine kinase c-Src is activated in a large proportion of breast cancers, in which it is thought to play a key role in promoting the malignant phenotype. c-Src activity is also elevated in transgenic mouse models of breast cancer, including the widely used polyomavirus middle-T antigen (PyVmT) model, which provides an opportunity to study the importance of c-Src in mammary tumorigenesis. However, germline c-Src deletion in mammary epithelial and stromal compartments complicates the interpretation of in vivo tumorigenesis studies as a result of severe defects in mammary gland development. We have therefore engineered a mouse strain in which deletion of c-Src can be targeted to the mammary epithelium. We demonstrate that mammary epithelial disruption of c-Src impairs proliferation and tumor progression driven by PyVmT in vivo. Whereas related kinases substitute for c-Src in PyVmT signaling, c-Src ablation impairs cell cycle progression with decreased cyclin expression and elevated expression of cyclin-dependent kinase inhibitors. Our data indicate that c-Src has essential and unique functions in proliferation and tumor progression in this mouse model that may also be important in certain contexts in some human breast cancers.