University of Minnesota, Departments of Medicine and Pharmacology, Division of Hematology, Oncology, and Transplantation, Women's Cancer Program, Masonic Cancer Center, Minneapolis, MN 55455, United States.
Mol Cell Endocrinol. 2012 Jun 24;357(1-2):43-9. doi: 10.1016/j.mce.2011.09.017. Epub 2011 Sep 16.
Progesterone receptors (PR), in concert with peptide growth factor-initiated signaling pathways, initiate massive expansion of the epithelial cell compartment associated with the process of alveologenesis in the developing mammary gland. PR-dependent signaling events also contribute to inappropriate proliferation observed in breast cancer. Notably, PR-B isoform-specific cross talk with growth factor-driven pathways is required for the proliferative actions of progesterone. Indeed, PRs act as heavily phosphorylated transcription factor "sensors" for mitogenic protein kinases that are often elevated and/or constitutively activated in invasive breast cancers. In addition, phospho-PR-target genes frequently include the components of mitogenic signaling pathways, revealing a mechanism for feed-forward signaling that confers increased responsiveness of, PR +mammary epithelial cells to these same mitogenic stimuli. Understanding the mechanisms and isoform selectivity of PR/kinase interactions may yield further insight into targeting altered signaling networks in breast and other hormonally responsive cancers (i.e. lung, uterine and ovarian) in the clinic. This review focuses on PR phosphorylation by mitogenic protein kinases and mechanisms of PR-target gene selection that lead to increased cell proliferation.
孕激素受体（PR）与肽生长因子启动的信号通路协同作用，启动与乳腺发育过程中肺泡发生相关的上皮细胞区室的大规模扩张。PR 依赖性信号事件也有助于乳腺癌中观察到的不当增殖。值得注意的是，孕激素的增殖作用需要 PR-B 同工型特异性与生长因子驱动的途径进行交叉对话。事实上，PR 作为高度磷酸化的转录因子“传感器”，可检测丝裂原蛋白激酶，这些激酶在侵袭性乳腺癌中经常升高和/或持续激活。此外，磷酸化 PR 靶基因通常包括有丝分裂信号通路的组成部分，揭示了一种正向信号传导的机制，赋予 PR+乳腺上皮细胞对这些相同有丝分裂刺激的反应性增加。了解 PR/激酶相互作用的机制和同工型选择性可能会进一步深入了解针对临床中改变的信号网络的靶向治疗，这些信号网络存在于乳腺和其他激素反应性癌症（如肺、子宫和卵巢）中。本综述重点介绍了丝裂原蛋白激酶对 PR 的磷酸化作用以及导致细胞增殖增加的 PR 靶基因选择机制。
