Deregulation of STAT5 expression and activation causes mammary tumors in transgenic mice
Deregulation of STAT5 expression and activation causes mammary tumors in transgenic mice
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DOI：
10.1002/ijc.20484
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发表时间：
2004-11-20
影响因子：
6.4
通讯作者：
Barash, I
中科院分区：
文献类型：
--
作者：
Iavnilovitch, E;Cardiff, RD;Barash, I
信号转导子和转录激活子（Stat）家族的成员调节正常细胞中的基本细胞生长和存活功能，并且还与肿瘤发生有关。我们研究了Stat 5在乳腺肿瘤发生中的潜在作用，通过使用β-乳球蛋白基因的调控序列将Stat 5变体靶向转基因小鼠的乳腺。野生型Stat 5、组成性激活Stat 5和羧基末端截短显性阴性Stat 5形式的乳腺定向表达导致乳腺肿瘤的发病率高达22%，潜伏期为8-12个月。未分化癌最常发生在表达羧基末端截短的Stat 5的小鼠中。分化程度更高的乳头状和微乳头状腺癌主要发现于过表达天然和组成型活性转基因的小鼠中。与表达野生型或截短形式的小鼠相比，在表达组成型活性Stat 5的小鼠肿瘤中发现更高水平的翻译起始因子4 E（elF 4 E）和细胞周期蛋白D1表达，但更低水平的活化Stat 3。与其他表型相比，在癌中观察到雌激素受体（ER α）的更高表达。两种形式的Stat 5，反式激活形式和显性负性形式，参与肿瘤发生的能力表明，有一个以上的机制，Stat 5有助于这一过程。Stat 5的反式激活功能参与确定具有更分化表型的肿瘤。(C)2004 Wiley-Liss，Inc.
Members of the signal transducers and activators of transcription (Stat) family regulate essential cellular growth and survival functions in normal cells and have also been implicated in tumorigenesis. We have studied the potential role of Stat5 in mammary tumorigenesis by targeting Stat5 variants to the mammary gland of transgenic mice using regulatory sequences of the beta-lactoglobulin gene. Mammary-directed expression of the wild-type Stat5, constitutively activated Stat5 and carboxyl-terminally truncated dominant negative Stat5 forms resulted in mammary tumors with incidence rates of up to 22% and latency periods of 8-12 months. Undifferentiated carcinomas most frequently occurred in mice expressing the carboxyl-terminally truncated Stat5. The more differentiated papillary and micropapillary adenocarcinomas were primarily found in mice overexpressing the native and constitutively active transgenes. Higher levels of translation initiation factor 4E (elF4E) and cyclin D1 expression but lower levels of activated Stat3 were found in tumors of mice expressing the constitutively active Stat5 when compared to mice expressing the wild-type or truncated forms. A higher expression of the estrogen receptor (ERalpha) was observed in carcinomas compared to other phenotypes. The ability of both forms of Stat5, the transactivating form and the dominant negative form, to participate in oncogenesis indicates that there is more than one mechanism by which Stat5 contributes to this process. The transactivation function of Stat5 is involved in the determination of tumors with a more differentiated phenotype. (C) 2004 Wiley-Liss, Inc.