Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
BMC Biol. 2009 Sep 28;7:63. doi: 10.1186/1741-7007-7-63.
The oncoprotein c-Myc has been intensely studied in breast cancer and mouse mammary tumor models, but relatively little is known about the normal physiological role of c-Myc in the mammary gland. Here we investigated functions of c-Myc during mouse mammary gland development using a conditional knockout approach.
Generation of c-mycfl/fl mice carrying the mammary gland-specific WAPiCre transgene resulted in c-Myc loss in alveolar epithelial cells starting in mid-pregnancy. Three major phenotypes were observed in glands of mutant mice. First, c-Myc-deficient alveolar cells had a slower proliferative response at the start of pregnancy, causing a delay but not a block of alveolar development. Second, while milk composition was comparable between wild type and mutant animals, milk production was reduced in mutant glands, leading to slower pup weight-gain. Electron microscopy and polysome fractionation revealed a general decrease in translational efficiency. Furthermore, analysis of mRNA distribution along the polysome gradient demonstrated that this effect was specific for mRNAs whose protein products are involved in milk synthesis. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed decreased levels of ribosomal RNAs and ribosomal protein-encoding mRNAs in mutant glands. Third, using the mammary transplantation technique to functionally identify alveolar progenitor cells, we observed that the mutant epithelium has a reduced ability to repopulate the gland when transplanted into NOD/SCID recipients.
We have demonstrated that c-Myc plays multiple roles in the mouse mammary gland during pregnancy and lactation. c-Myc loss delayed, but did not block proliferation and differentiation in pregnancy. During lactation, lower levels of ribosomal RNAs and proteins were present and translation was generally decreased in mutant glands. Finally, the transplantation studies suggest a role for c-Myc in progenitor cell proliferation and/or survival.
癌蛋白 c-Myc 在乳腺癌和小鼠乳腺肿瘤模型中已被深入研究，但关于 c-Myc 在乳腺中的正常生理功能相对知之甚少。在这里，我们使用条件性敲除方法研究了 c-Myc 在小鼠乳腺发育过程中的作用。
携带乳腺特异性 WAPiCre 转基因的 c-mycfl/fl 小鼠的生成导致 c-Myc 在妊娠中期开始从肺泡上皮细胞中丢失。在突变小鼠的腺体中观察到三种主要表型。首先，c-Myc 缺失的肺泡细胞在妊娠开始时增殖反应较慢，导致肺泡发育延迟但不被阻断。其次，尽管野生型和突变型动物的乳汁成分相当，但突变型腺体中的乳汁产量减少，导致幼鼠体重增加较慢。电子显微镜和多核糖体分级分离显示翻译效率普遍降低。此外，分析 mRNA 沿多核糖体梯度的分布表明，这种效应是特定于其蛋白质产物参与乳汁合成的 mRNA。此外，定量逆转录聚合酶链反应分析显示突变型腺体中的核糖体 RNA 和核糖体蛋白编码 mRNA 水平降低。第三，使用乳腺移植技术对肺泡祖细胞进行功能鉴定，我们观察到突变上皮细胞在移植到 NOD/SCID 受体中时，重新填充腺体的能力降低。
我们已经证明 c-Myc 在妊娠和哺乳期的小鼠乳腺中发挥多种作用。c-Myc 缺失延迟但不阻止妊娠期间的增殖和分化。在哺乳期，突变型腺体中核糖体 RNA 和蛋白质水平较低，翻译普遍减少。最后，移植研究表明 c-Myc 在祖细胞增殖和/或存活中起作用。
