Deroo Bonnie J, Hewitt Sylvia C, Collins Jennifer B, Grissom Sherry F, Hamilton Katherine J, Korach Kenneth S
Receptor Biology Section, NIEHS, NIH, Research Triangle Park, North Carolina 27709, USA.
Mol Reprod Dev. 2009 Aug;76(8):733-50. doi: 10.1002/mrd.21041.
Both ovarian and pituitary hormones are required for the pubertal development of the mouse mammary gland. Estradiol directs ductal elongation and branching, while progesterone leads to tertiary branching and alveolar development. The purpose of this investigation was to identify estrogen-responsive genes associated with pubertal ductal growth in the mouse mammary gland in the absence of other ovarian hormones and at different stages of development. We hypothesized that the estrogen-induced genes and their associated functions at early stages of ductal elongation would be distinct from those induced after significant ductal elongation had occurred. Therefore, ovariectomized prepubertal mice were exposed to 17beta-estradiol from two to 28 days, and mammary gland global gene expression analyzed by microarray analysis at various times during this period. We found that: (a) gene expression changes in our estrogen-only model mimic those changes that occur in normal pubertal development in intact mice, (b) both distinct and overlapping gene profiles were observed at varying extents of ductal elongation, and (c) cell proliferation, the immune response, and metabolism/catabolism were the most common functional categories associated with mammary ductal growth. Particularly striking was the novel observation that genes active during carbohydrate metabolism were rapidly and robustly decreased in response to estradiol. Lastly, we identified mammary estradiol-responsive genes that are also co-expressed with estrogen receptor alpha in human breast cancer. In conclusion, our genomic data support the physiological observation that estradiol is one of the primary hormonal signals driving ductal elongation during pubertal mammary development.
小鼠乳腺的青春期发育需要卵巢激素和垂体激素共同作用。雌二醇引导导管伸长和分支，而孕酮则导致三级分支和腺泡发育。本研究的目的是在没有其他卵巢激素的情况下，以及在不同发育阶段，鉴定与小鼠乳腺青春期导管生长相关的雌激素反应基因。我们假设，在导管伸长早期由雌激素诱导的基因及其相关功能，将与在导管显著伸长后诱导的基因不同。因此，对青春期前切除卵巢的小鼠从第2天到第28天给予17β-雌二醇，并在此期间的不同时间通过微阵列分析对乳腺整体基因表达进行分析。我们发现：（a）我们的仅雌激素模型中的基因表达变化模拟了完整小鼠正常青春期发育中发生的变化；（b）在不同程度的导管伸长过程中观察到了不同和重叠的基因谱；（c）细胞增殖、免疫反应和代谢/分解代谢是与乳腺导管生长相关的最常见功能类别。特别引人注目的是一个新发现，即参与碳水化合物代谢的活跃基因对雌二醇反应迅速且显著减少。最后，我们鉴定出在人类乳腺癌中也与雌激素受体α共表达的乳腺雌二醇反应基因。总之，我们的基因组数据支持了生理学观察结果，即雌二醇是青春期乳腺发育过程中驱动导管伸长的主要激素信号之一。
