PAK1 hyperactivation is sufficient for mammary gland tumor formation
PAK1 hyperactivation is sufficient for mammary gland tumor formation
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DOI：
10.1038/sj.onc.1209309
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发表时间：
2006-05-01
期刊：
影响因子：
8
通讯作者：
Kumar, R.
中科院分区：
文献类型：
--
作者：
Wang, R-A;Zhang, H.;Kumar, R.
新数据表明，p21 激活激酶 1 (Pak1)（小 GTP 酶、生长因子和脂质信号传导的下游信号分子）在人类乳腺癌中上调或过度激活。然而到目前为止，尚未发现 Pak1 在乳腺肿瘤形成中的直接致病作用。因此，我们试图确定 Pak1 在乳腺肿瘤发生中所起的作用。我们的结果表明，在转基因小鼠模型中，催化活性 Pak1 的过度表达会导致恶性乳腺肿瘤和各种其他乳腺病变的发展，包括局灶性实性结节、导管增生以及小型导管内肿瘤和腺瘤。我们还发现 Pak1 过度激活会增加乳腺肿瘤上皮细胞中下游增殖信号效应器 MEK1/2 和 p38-MAPK 的刺激。此外，在我们的研究中，我们在病变早期检测到雌激素受体-α表达和孕激素受体表达，但它们的表达在细胞转变为恶性侵袭性肿瘤期间丢失。最后，我们发现，在广泛使用的多步多瘤中T抗原转基因小鼠中，从导管增生到导管原位癌再到腺癌的转变过程中，Pak1表达及其核积累逐渐增加，这与乳腺肿瘤进展中的作用一致。总之，这些发现提供了第一个直接证据，表明 Pak1 失调可能足以形成乳腺肿瘤。
Emerging data suggest that p21- activated kinase 1 ( Pak1), a downstream signaling molecule of the small GTPases, growth factors, and lipid signaling, is upregulated or hyperactivated in human breast cancer. Until now, however, no direct causative role had been found for Pak1 in mammary tumor formation. We therefore sought to identify the role that Pak1 plays in mammary gland tumorigenesis. Our results showed that in a transgenic mouse model, overexpression of catalytically active Pak1 leads to the development of malignant mammary tumors and to a variety of other breast lesions, including focal solid nodules, ductal hyperplasia, and mini- intraductal neoplasm and adenoma. We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/ 2 and p38- MAPK in mammary tumor epithelial cells. Moreover, in our study, we detected expression of estrogen receptor- alpha expression and progesterone receptor expression during early stages of the lesions, but their expression was lost during the cells' transition to malignant invasive tumors. Finally, we found that consistent with a role in breast tumor progression, Pak1 expression and its nuclear accumulation was increased progressively during the transition from ductal hyperplasia to ductal carcinoma in situ to adenocarcinoma in widely used multistep polyoma- middle T- antigen transgenic mice. Together, these findings provide the first direct evidence that Pak1 deregulation may be sufficient for the formation of mammary gland tumors.