Leehy Katherine A, Truong Thu H, Mauro Laura J, Lange Carol A
Departments of Medicine and Pharmacology, University of Minnesota Masonic Cancer Center, Minneapolis, MN, 55455, United States.
Department of Animal Sciences, University of Minnesota Masonic Cancer Center, Minneapolis, MN, 55455, United States.
J Steroid Biochem Mol Biol. 2018 Feb;176:88-93. doi: 10.1016/j.jsbmb.2017.04.011. Epub 2017 Apr 23.
Estrogen is the major mitogenic stimulus of mammary gland development during puberty wherein ER signaling acts to induce abundant PR expression. PR signaling, in contrast, is the primary driver of mammary epithelial cell proliferation in adulthood. The high circulating levels of progesterone during pregnancy signal through PR, inducing expression of the prolactin receptor (PRLR). Cooperation between PR and prolactin (PRL) signaling, via regulation of downstream components in the PRL signaling pathway including JAKs and STATs, facilitates the alveolar morphogenesis observed during pregnancy. Indeed, these pathways are fully integrated via activation of shared signaling pathways (i.e. JAKs, MAPKs) as well as by the convergence of PRs and STATs at target genes relevant to both mammary gland biology and breast cancer progression (i.e. proliferation, stem cell outgrowth, tissue cell type heterogeneity). Thus, rather than a single mediator such as ER, transcription factor cascades (ER>PR>STATs) are responsible for rapid proliferative and developmental programming in the normal mammary gland. It is not surprising that these same mediators typify uncontrolled proliferation in a majority of breast cancers, where ER and PR are most often co-expressed and may cooperate to drive malignant tumor progression. This review will primarily focus on the integration of PR and PRL signaling in breast cancer models and the importance of this cross-talk in cancer progression in the context of mammographic density. Components of these PR/PRL signaling pathways could offer alternative drug targets and logical complements to anti-ER or anti-estrogen-based endocrine therapies.
雌激素是青春期乳腺发育的主要促有丝分裂刺激因子，其中雌激素受体（ER）信号传导可诱导大量孕激素受体（PR）表达。相比之下，PR信号传导是成年期乳腺上皮细胞增殖的主要驱动因素。孕期高循环水平的孕酮通过PR发出信号，诱导催乳素受体（PRLR）表达。PR与催乳素（PRL）信号传导之间的协同作用，通过调节PRL信号通路中的下游成分（包括JAK和STAT），促进孕期观察到的腺泡形态发生。事实上，这些信号通路通过共享信号通路（即JAK、丝裂原活化蛋白激酶）的激活以及PR和STAT在与乳腺生物学和乳腺癌进展相关的靶基因（即增殖、干细胞生长、组织细胞类型异质性）处的汇聚而完全整合。因此，正常乳腺中快速增殖和发育编程的是转录因子级联反应（ER>PR>STAT），而非单一介质如ER。毫不奇怪，这些相同的介质在大多数乳腺癌中代表着不受控制的增殖，其中ER和PR最常共表达，并可能协同驱动恶性肿瘤进展。本综述将主要关注PR和PRL信号传导在乳腺癌模型中的整合，以及这种相互作用在乳腺X线密度背景下对癌症进展的重要性。这些PR/PRL信号通路的成分可为基于抗ER或抗雌激素的内分泌治疗提供替代药物靶点和合理补充。
