Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Genes Dev. 2012 Oct 1;26(19):2154-68. doi: 10.1101/gad.197343.112.
Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten-PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)-Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl(-/-), Prlr(-/-), and Stat5(-/-) mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1(-/-);Akt2(+/-) mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway.
脑垂体外催乳素（Prl）在人类和啮齿动物中产生；然而，其体内调节或生理功能知之甚少。我们现在报告说，自分泌催乳素是妊娠期间终末乳腺上皮分化所必需的，其产生受 Pten-PI3K-Akt 途径调节。在处女小鼠的乳腺中，通过 Akt1 表达或 Pten 缺失使 PI3K-Akt 途径的条件激活，迅速诱导终末乳腺上皮分化，尽管没有小叶泡发育，但伴随着乳汁的合成。令人惊讶的是，我们发现乳腺分化是由于 PI3K-Akt 依赖性的自分泌催乳素的合成和分泌以及下游催乳素受体（Prlr）-Jak-Stat5 途径的激活。与此一致，在 Prl(-/-)、Prlr(-/-)和 Stat5(-/-)小鼠中，Akt 诱导的乳腺分化被阻断。此外，用来自激活 Akt 的乳腺的条件培养基处理的细胞迅速发生 Stat5 磷酸化，该磷酸化被 Jak2 抑制、用抗催乳素抗体处理或删除催乳素基因所阻断。自分泌催乳素的生理需求表明，尽管循环血清催乳素和垂体催乳素产生正常，但在哺乳期 Akt1(-/-);Akt2(+/-) 小鼠的乳腺在妊娠后期未能表达自分泌催乳素或激活 Stat5。我们的研究结果表明，PI3K-Akt 途径的激活是诱导乳腺自分泌催乳素产生、Stat5 激活和终末乳腺上皮分化所必需且充分的，即使在没有为泌乳准备乳腺的正常发育程序的情况下也是如此。总之，这些发现确定了自分泌催乳素在正常发育过程中的作用，并证明了其通过 PI3K-Akt 途径的内源性调节。
