Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA; Molecular and Environmental Toxicology Graduate Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
Stem Cell Reports. 2017 Oct 10;9(4):1167-1179. doi: 10.1016/j.stemcr.2017.08.011. Epub 2017 Sep 14.
Hormones drive mammary development and function and play critical roles in breast cancer. Epidemiologic studies link prolactin (PRL) to increased risk for aggressive cancers that express estrogen receptor α (ERα). However, in contrast to ovarian steroids, PRL actions on the mammary gland outside of pregnancy are poorly understood. We employed the transgenic NRL-PRL model to examine the effects of PRL alone and with defined estrogen/progesterone exposure on stem/progenitor activity and regulatory networks that drive epithelial differentiation. PRL increased progenitors and modulated transcriptional programs, even without ovarian steroids, and with steroids further raised stem cell activity associated with elevated canonical Wnt signaling. However, despite facilitating some steroid actions, PRL opposed steroid-driven luminal maturation and increased CD61 luminal cells. Our findings demonstrate that PRL can powerfully influence the epithelial hierarchy alone and temper the actions of ovarian steroids, which may underlie its role in the development of breast cancer.
激素驱动乳腺的发育和功能，并在乳腺癌中发挥关键作用。流行病学研究将催乳素（PRL）与表达雌激素受体α（ERα）的侵袭性癌症风险增加联系起来。然而，与卵巢类固醇不同，PRL 在妊娠以外对乳腺的作用知之甚少。我们利用 NRL-PRL 转基因模型来研究 PRL 单独作用以及与特定雌激素/孕激素暴露对驱动上皮分化的干细胞/祖细胞活性和调控网络的影响。PRL 增加了祖细胞并调节了转录程序，即使没有卵巢类固醇，而且类固醇进一步提高了与经典 Wnt 信号升高相关的干细胞活性。然而，尽管促进了一些类固醇的作用，PRL 还是反对类固醇驱动的腔成熟并增加了 CD61 腔细胞。我们的研究结果表明，PRL 可以单独有力地影响上皮层次结构，并调节卵巢类固醇的作用，这可能是其在乳腺癌发展中的作用基础。
