Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
Stem Cell Reports. 2018 Jan 9;10(1):257-271. doi: 10.1016/j.stemcr.2017.11.021. Epub 2017 Dec 28.
Mammary stem and progenitor cells are essential for mammary gland homeostasis and are also candidates for cells of origin of mammary tumors. Here, we have investigated the function of the protein kinase p38α in the mammary gland using mice that delete this protein in the luminal epithelial cells. We show that p38α regulates the fate of luminal progenitor cells through modulation of the transcription factor RUNX1, an important controller of the estrogen receptor-positive cell lineage. We also provide evidence that the regulation of RUNX1 by p38α probably involves the kinase MSK1, which phosphorylates histone H3 at the RUNX1 promoter. Moreover, using a mouse model for breast cancer initiated by luminal cells, we show that p38α downregulation in mammary epithelial cells reduces tumor burden, which correlates with decreased numbers of tumor-initiating cells. Collectively, our results define a key role for p38α in luminal progenitor cell fate that affects mammary tumor formation.
乳腺干/祖细胞对于乳腺稳态至关重要，也是乳腺肿瘤起始细胞的候选细胞。在这里，我们利用细胞中缺失蛋白激酶 p38α 的小鼠，研究了该蛋白在乳腺中的功能。我们发现，p38α 通过调节转录因子 RUNX1 来调控腔上皮祖细胞的命运，RUNX1 是雌激素受体阳性细胞谱系的重要调控因子。我们还提供了证据表明，p38α 对 RUNX1 的调节可能涉及激酶 MSK1，后者在 RUNX1 启动子处磷酸化组蛋白 H3。此外，我们利用由腔上皮细胞引发的乳腺癌小鼠模型表明，乳腺上皮细胞中 p38α 的下调可降低肿瘤负担，这与肿瘤起始细胞数量的减少相关。总的来说，我们的研究结果定义了 p38α 在影响乳腺肿瘤形成的腔上皮祖细胞命运中的关键作用。
