Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Death Dis. 2012 Sep 20;3(9):e391. doi: 10.1038/cddis.2012.131.
The development of the lactating mammary gland is a complex multifactorial process occurring in mammals during pregnancy. We show here that this process requires NHERF1/EBP50 (Na/H exchanger regulatory factor 1/ERM-binding phosphoprotein 50) expression and that successful lactation depends on NHERF1 allele copy number, with rates of 50 and 20% in NHERF1(+/-) and (-/-) mice, respectively. The prolactin receptor (PRLR)-STAT5 signaling provides the central axis triggering the differentiation of secretory mammary alveolar cells. In successfully lactating glands, NHERF1 is massively upregulated and forms complexes with PRLR, but also with β-catenin, E-cadherin and ezrin at the alveolar basal membrane, establishing basal polarity. In NHERF1-deficient glands, the basal polarity is disrupted, the PRLR levels and basal membrane localization are abolished, and the downstream STAT5 activation collapses with consequent reduction of milk protein synthesis. NHERF1/EBP50, a protein deregulated in breast cancer, thus emerges as an important physiological mediator of milk secretion, by engagement of PRLR in multimeric complexes at the alveolar basal membrane with subsequent network activation leading to cell differentiation.
乳腺的发育是一个复杂的多因素过程，发生在哺乳动物的妊娠期间。我们在这里表明，这一过程需要 NHERF1/EBP50（Na/H 交换体调节因子 1/ERM 结合磷蛋白 50）的表达，并且成功的哺乳依赖于 NHERF1 等位基因拷贝数，NHERF1(+/-)和 (-/-)小鼠的成功率分别为 50%和 20%。催乳素受体（PRLR）-STAT5 信号提供了触发分泌型乳腺腺泡细胞分化的中心轴。在成功哺乳的乳腺中，NHERF1 大量上调，并与 PRLR 形成复合物，但也与 β-连环蛋白、E-钙黏蛋白和 ezrin 在腺泡基膜形成复合物，建立基底极性。在 NHERF1 缺失的乳腺中，基底极性被破坏，PRLR 水平和基膜定位被消除，下游 STAT5 激活崩溃，导致乳蛋白合成减少。NHERF1/EBP50 是乳腺癌中失调的一种蛋白质，因此作为乳汁分泌的重要生理介质出现，通过 PRLR 在腺泡基膜的多聚体复合物中的参与，并随后激活网络导致细胞分化。
