Nevalainen Marja T, Xie Jianwu, Bubendorf Lukas, Wagner Kay-Uwe, Rui Hallgeir
United States Military Cancer Institute and Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20852, USA.
Mol Endocrinol. 2002 May;16(5):1108-24. doi: 10.1210/mend.16.5.0839.
Transcription factor Stat5 (signal transducer and activator of transcription) is essential for PRL-induced terminal differentiation of mouse mammary epithelial cells during pregnancy and lactation and has been implicated in mammary tumorigenesis. A new and sensitive immunological method to detect active, tyrosine phosphorylated Stat5 in situ revealed that Stat5 is continuously activated in luminal epithelial cells of mouse and human breast, not only during pregnancy and lactation, but also outside of pregnancy. Examination of virgin Stat5a or Stat5b null mice suggested that Stat5a was the primary isoform activated in mammary epithelial cells. Basal activation of Stat5 in mammary epithelium of virgin wild-type mice was continuous throughout estrous cycle and was also detected in 17 of 17 normal human breast tissue specimens analyzed. PRL was identified as the principal factor maintaining basal activation of Stat5 in mammary epithelium of nonpregnant mice based on several lines of evidence. First, administration of PRL, but not GH or epidermal growth factor, uniformly enhanced basal activation of Stat5 in luminal mammary epithelial cells. Second, hypophysectomy disrupted basal activation of Stat5, an effect that was completely reversed by administration of PRL, but only partially by GH. Third, knock-out of the PRL receptor gene markedly reduced basal activation of Stat5, an effect that was maintained in a normalized endocrine environment after transplanting PRL receptor null mammary epithelium into wild-type mice. Continuous activation of Stat5 indicates a role of this transcription factor in normal, nonpregnant breast epithelial cells, and may shed new light on Stat5 involvement in breast tumor promotion.
转录因子Stat5（信号转导子和转录激活子）对于妊娠和哺乳期催乳素诱导的小鼠乳腺上皮细胞终末分化至关重要，并且与乳腺肿瘤发生有关。一种新的、灵敏的免疫方法可原位检测活性酪氨酸磷酸化的Stat5，结果显示Stat5不仅在妊娠和哺乳期，而且在非妊娠期间，均在小鼠和人乳腺的腔上皮细胞中持续被激活。对未孕Stat5a或Stat5b基因敲除小鼠的研究表明，Stat5a是乳腺上皮细胞中被激活的主要异构体。未孕野生型小鼠乳腺上皮中Stat5的基础激活在整个发情周期持续存在，在分析的17份正常人乳腺组织标本中也均检测到。基于多条证据，催乳素被确定为维持未孕小鼠乳腺上皮中Stat5基础激活的主要因子。首先，给予催乳素而非生长激素或表皮生长因子，可一致增强乳腺腔上皮细胞中Stat5的基础激活。其次，垂体切除破坏了Stat5的基础激活，这种作用可通过给予催乳素完全逆转，但生长激素只能部分逆转。第三，催乳素受体基因敲除显著降低了Stat5的基础激活，将催乳素受体基因敲除的乳腺上皮移植到野生型小鼠中，在正常内分泌环境下该作用依然存在。Stat5的持续激活表明该转录因子在正常未孕乳腺上皮细胞中发挥作用，可能为Stat5参与乳腺肿瘤促进作用提供新的线索。
