Rädler Patrick D, Wehde Barbara L, Wagner Kay-Uwe
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA; Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA.
Mol Cell Endocrinol. 2017 Aug 15;451:31-39. doi: 10.1016/j.mce.2017.04.025. Epub 2017 May 8.
Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to function downstream of several peptide hormones and cytokines that are required for postnatal development and secretory function of the mammary gland. As part of an extended network, these signal transducers can engage in crosstalk with other pathways to facilitate synergistic, and sometimes antagonistic, actions of different growth factors. Specifically, signaling through the JAK2/STAT5 cascade has been demonstrated to be indispensable for the specification, proliferation, differentiation, and survival of secretory mammary epithelial cells. Following a concise description of major cellular programs in mammary gland development and the role of growth factors that rely on JAK/STAT signaling to orchestrate these programs, this review highlights the significance of active STAT5 and its crosstalk with the PI3 kinase and AKT1 for mediating the proliferation of alveolar progenitors and survival of their functionally differentiated descendants in the mammary gland. Based on its ability to provide self-sufficiency in growth signals that are also capable of overriding intrinsic cell death programs, persistently active STAT5 can serve as a potent oncoprotein that contributes to the genesis of breast cancer. Recent experimental evidence demonstrated that, similar to normal developmental programs, oncogenic functions of STAT5 rely on molecular crosstalk with PI3K/AKT signaling for the initiation, and in some instances the progression, of breast cancer. The multitude by which STATs can interact with individual mediators of the PI3K/AKT signaling cascade may provide novel avenues for targeting signaling nodes within molecular networks that are crucial for the survival of cancer cells.
Janus激酶（JAKs）和信号转导及转录激活因子（STATs）已被证明在几种肽类激素和细胞因子的下游发挥作用，这些肽类激素和细胞因子是乳腺产后发育和分泌功能所必需的。作为扩展网络的一部分，这些信号转导因子可与其他途径发生串扰，以促进不同生长因子的协同作用，有时是拮抗作用。具体而言，通过JAK2/STAT5级联的信号传导已被证明对于分泌性乳腺上皮细胞的特化、增殖、分化和存活是不可或缺的。在简要描述乳腺发育中的主要细胞程序以及依赖JAK/STAT信号传导来协调这些程序的生长因子的作用之后，本综述强调了活性STAT5及其与PI3激酶和AKT1的串扰对于介导乳腺中肺泡祖细胞的增殖及其功能分化后代的存活的重要性。基于其在生长信号中提供自给自足的能力，这种生长信号也能够超越内在的细胞死亡程序，持续活跃的STAT5可以作为一种有效的癌蛋白，促进乳腺癌的发生。最近的实验证据表明，与正常发育程序类似，STAT5的致癌功能依赖于与PI3K/AKT信号传导的分子串扰来启动乳腺癌，在某些情况下还促进其进展。STATs与PI3K/AKT信号级联的各个介质相互作用的多种方式可能为靶向分子网络中的信号节点提供新途径，这些信号节点对癌细胞的存活至关重要。
