RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini
RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini
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DOI：
10.1128/mcb.01298-06
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发表时间：
2007-02-01
影响因子：
5.3
通讯作者：
Dougall, William C.
中科院分区：
文献类型：
--
作者：
Gonzalez-Suarez, Eva;Branstetter, Daniel;Dougall, William C.
RANK和RANKL是破骨细胞分化和活化的关键调节因子，在妊娠期间乳腺上皮细胞增殖和分化的控制中也发挥重要作用。在这里，我们表明，RANK蛋白的表达在乳腺发育过程中的空间和时间的方式严格调节。在转基因小鼠模型中，小鼠乳腺肿瘤病毒（MMTV）启动子控制下的RANK过表达导致妊娠期间乳腺上皮细胞增殖增加、小叶-肺泡结构分化受损、乳蛋白β-酪蛋白和乳清酸性蛋白表达降低以及泌乳不足。我们还表明，用RANKL处理来自MMTV-RANK小鼠的原代乳腺细胞的三维体外培养物，导致管腔区域的增殖增加和凋亡减少，导致具有填充管腔的更大腺泡。综上所述，这些结果表明，通过RANK的信号不仅促进增殖，而且抑制乳腺上皮细胞的终末分化。此外，在三维培养系统中观察到的增殖和存活增加表明RANK信号传导异常在乳腺肿瘤发生过程中的作用。
RANK and RANKL, the key regulators of osteoclast differentiation and activation, also play an important role in the control of proliferation and differentiation of mammary epithelial cells during pregnancy. Here, we show that RANK protein expression is strictly regulated in a spatial and temporal manner during mammary gland development. RANK overexpression under the control of the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model results in increased mammary epithelial cell proliferation during pregnancy, impaired differentiation of lobulo-alveolar structures, decreased expression of the milk proteins beta-casein and whey acidic protein, and deficient lactation. We also show that treatment of three-dimensional in vitro cultures of primary mammary cells from MMTV-RANK mice with RANKL results in increased proliferation and decreased apoptosis in the luminal area, resulting in bigger acini with filled lumens. Taken together, these results suggest that signaling through RANK not only promotes proliferation but also inhibits the terminal differentiation of mammary epithelial cells. Moreover, the increased proliferation and survival observed in a three-dimensional culture system suggests a role for aberrant RANK signaling during breast tumorigenesis.