Hovey Russell C, Harris Jessica, Hadsell Darryl L, Lee Adrian V, Ormandy Christopher J, Vonderhaar Barbara K
Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1402, USA.
Mol Endocrinol. 2003 Mar;17(3):460-71. doi: 10.1210/me.2002-0214. Epub 2002 Dec 23.
Prolactin (PRL) is a major determinant of mammary epithelial cell proliferation during alveolar development in sexually mature and pregnant mice. To date, it has not been clear whether PRL effects these responses alone or by also invoking the action of autocrine/paracrine growth factors. In this study, we provide evidence that part of the effect of PRL on mammary gland growth is mediated by IGF-II. During sexual maturity and in early pregnancy, the level of IGF-II mRNA in the mammary gland was increased concurrent with increased PRL receptor expression. The level of IGF-II mRNA was reduced in mammary tissue from PRL receptor-/- mice during early pregnancy, and explants of mouse mammary gland and HC11 mammary epithelial cells both increased their expression of IGF-II after exposure to PRL in vitro. These findings coincided with the demonstration that IGF-II stimulated alveolar development in mammary glands in whole organ culture. PRL was most efficacious in stimulating IGF-II gene transcription from promoter 3 of the mouse IGF-II gene in vitro. Insight into the mechanism by which PRL induced IGF-II expression was provided by the fact that it was blocked by the Jak2 inhibitor AG490 and the MAPK inhibitor PD98059. Finally, induction of insulin receptor substrate (IRS)-1 in the mammary glands of PRL-treated mice and induction of IRS-1 and IRS-2 after treatment with PRL plus progesterone indicates that these molecules are induced by PRL as potential signaling intermediates downstream from IGF-I/insulin receptors. Together, these data demonstrate a role for IGF-II as a mediator of PRL action in the mouse mammary gland during ductal branching and alveolar development.
催乳素（PRL）是性成熟和怀孕小鼠乳腺腺泡发育过程中乳腺上皮细胞增殖的主要决定因素。迄今为止，尚不清楚PRL是单独发挥这些作用，还是通过引发自分泌/旁分泌生长因子的作用来实现。在本研究中，我们提供证据表明PRL对乳腺生长的部分作用是由胰岛素样生长因子-II（IGF-II）介导的。在性成熟和妊娠早期，乳腺中IGF-II mRNA的水平随着PRL受体表达的增加而升高。妊娠早期，PRL受体基因敲除小鼠乳腺组织中IGF-II mRNA的水平降低，体外将小鼠乳腺外植体和HC11乳腺上皮细胞暴露于PRL后，二者的IGF-II表达均增加。这些发现与IGF-II在全器官培养中刺激乳腺腺泡发育的结果一致。在体外，PRL最有效地刺激小鼠IGF-II基因启动子3的IGF-II基因转录。PRL诱导IGF-II表达的机制可通过以下事实得以深入了解：它被Jak2抑制剂AG490和丝裂原活化蛋白激酶（MAPK）抑制剂PD98059阻断。最后，PRL处理的小鼠乳腺中胰岛素受体底物（IRS）-1的诱导以及PRL加孕酮处理后IRS-1和IRS-2的诱导表明，这些分子是由PRL诱导的，作为IGF-I/胰岛素受体下游潜在的信号传导中间体。总之，这些数据证明了IGF-II在小鼠乳腺导管分支和腺泡发育过程中作为PRL作用的介质所起的作用。
