Janus kinase 2 is required for the initiation but not maintenance of prolactin-induced mammary cancer.
Janus kinase 2 is required for the initiation but not maintenance of prolactin-induced mammary cancer.
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DOI：
10.1038/onc.2010.274
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发表时间：
2010-09-30
期刊：
影响因子：
8
通讯作者：
Wagner, K-U
中科院分区：
文献类型：
--
作者：
Sakamoto, K.;Triplett, A. A.;Schuler, L. A.;Wagner, K-U
催乳素受体(PRLR)及其相关的蛋白激酶JAK2和Stat5是正常乳腺发育所必需的。由于肿瘤细胞中PRLR的上调及其配体的局部合成，已有研究表明PRL在乳腺癌中可作为一种局部生长因子。这一观点得到了转基因小鼠的实验证据的支持，这些证据表明，PRL的乳房特异性表达有助于体内的癌症发生。为了评估JAK2/Stat5信号在乳腺癌发生和发展中的重要性，我们建立了一个PRL诱导的乳腺癌模型，该模型允许在肿瘤转化之前和之后功能性地消融乳腺上皮中的JAK2基因。总之，这项研究的结果表明，功能消融JAK2可以预防PRL诱导的乳腺肿瘤的发生，这表明靶向这种Janus激酶是预防乳腺癌的一种相关策略。令人惊讶的是，JAK2缺乏并没有影响PRL诱导的乳腺癌细胞在培养和体内的生长和存活。因此，JAK2不能成为治疗这种既定疾病的唯一治疗目标。PRL诱导的乳腺癌表现出ErbB2和其他ErbB受体酪氨酸激酶的上调，这可能取代了通过JAK2的PRLR信号的功能。
The prolactin receptor (PRLR), its associated kinase Jak2, and Stat5 are essential for normal mammary gland development. Due to the upregulation of the PRLR and the local synthesis of its ligand in neoplastic cells, it has been proposed that PRL can act as a local growth factor in human breast cancers. This notion is supported by experimental evidence in transgenic mice that demonstrated that the mammary-specific expression of PRL contributes to carcinogenesis in vivo. To assess the importance of Jak2/Stat5 signaling during mammary cancer initiation and progression, we generated a PRL-induced mammary cancer model that allows the functional ablation of the Jak2 gene in the mammary epithelium prior to and after neoplastic transformation. Collectively, the results of this study show that the functional ablation of Jak2 protects against the onset of PRL-induced mammary tumorigenesis, suggesting that targeting this Janus kinase is a relevant strategy for mammary cancer prevention. Surprisingly, Jak2 deficiency did not affect the growth and survival of PRL-induced mammary cancer cells in culture and in vivo. Consequently, Jak2 cannot be a sole therapeutic target to treat the established disease. PRL-induced mammary cancers exhibited an upregulation of ErbB2 and other ErbB receptor tyrosine kinases that may supersede the functionality of PRLR signaling through Jak2.
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