INHIBITION OF MAMMARY DUCT DEVELOPMENT BUT NOT ALVEOLAR OUTGROWTH DURING PREGNANCY IN TRANSGENIC MICE EXPRESSING ACTIVE TGF-BETA-1
INHIBITION OF MAMMARY DUCT DEVELOPMENT BUT NOT ALVEOLAR OUTGROWTH DURING PREGNANCY IN TRANSGENIC MICE EXPRESSING ACTIVE TGF-BETA-1
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DOI：
10.1101/gad.7.12a.2308
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发表时间：
1993-12-01
影响因子：
10.5
通讯作者：
MOSES, HL
中科院分区：
文献类型：
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作者：
PIERCE, DF;JOHNSON, MD;MOSES, HL
转化生长因子β(TGFs-β)是一种有效的细胞增殖抑制因子，通常以潜伏的形式分泌。在发育中的小鼠乳腺中，转化生长因子-β1、转化生长因子-β2和转化生长因子-β3以不同但重叠的模式表达。为了研究转化生长因子-β1在正常乳腺发育和乳腺肿瘤中的作用，我们构建了三个表达猴转化生长因子-β1S223/225的转基因小鼠系，并在MMTV增强子/启动子的控制下产生了一个结构性的活性产物。原位杂交、免疫组织化学和Northern印迹分析证实，转基因基因的表达与女性转基因患者乳腺导管树正常发育模式的显著抑制有关。随着正常乳腺导管生长的下降，总的导管体积在发情后不久的7周时被观察到，并在13周时最为明显。这一效应在所有三条线路上都能看到。然而，在怀孕期间，肺泡从发育不良的导管树发育而来，并发生哺乳，因此，所有转基因雌性动物都可以喂养完整的幼崽。与许多其他转基因小鼠模型不同的是，在MMTV启动子控制下的生长因子或癌基因的表达会导致乳腺上皮细胞增生和肿瘤形成增加，而MMTV-TGF-beta1S223/225转基因动物会导致乳腺导管树的条件性发育不良，并且在MMTV-TGF-beta1S223/225转基因动物中没有检测到自发性肿瘤。
The transforming growth factors beta (TGFs-beta) are potent inhibitors of cell proliferation and are usually secreted in a latent form. TGF-beta1, TGF-beta2, and TGF-beta3 are expressed in distinct but overlapping patterns in the developing mouse mammary gland. To study the role of transforming growth factor-beta1 (TGF-beta1) in normal mammary development and in mammary neoplasia, we have constructed three transgenic mouse lines that express a simian TGF-beta1S223/225 mutated to produce a constitutively active product under the control of the MMTV enhancer/promoter. Expression of the transgene, as confirmed by in situ hybridization, immunohistochemistry, and Northern blot analysis, was associated with marked suppression of the normal pattern of mammary ductal tree development in female transgenics. Reduction in total ductal tree volume was observed at 7 weeks, soon after estrous begins, and was most apparent at 13 weeks, as ductal growth in the normal mammary gland declines. This effect was seen in all three lines. However, during pregnancy, alveolar outgrowths developed from the hypoplastic ductal tree, and lactation occurred, therefore, all transgenic females could feed full litters. Unlike many other transgenic mouse models in which expression of growth factors or oncogenes under control of the MMTV promoter leads to mammary epithelial hyperplasia and increased tumor formation, the MMTV-TGF-beta1S223/225 transgene causes conditional hypoplasia of the mammary ductal tree and no spontaneous tumors have been detected in the MMTV-TGF-beta1S223/225 transgenic animals.