Mallepell Sonia, Krust Andrée, Chambon Pierre, Brisken Cathrin
National Center of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, 155 Chemin des Boveresses, CH-1066 Epalinges s/Lausanne, Switzerland.
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2196-201. doi: 10.1073/pnas.0510974103. Epub 2006 Feb 1.
Estradiol is a major regulator of postnatal mammary gland development and thought to exert its effects through estrogen receptor alpha (ERalpha) expressed in the mammary gland stroma and epithelium. Previous studies, however, were confounded by the use of an ERalpha mutant strain that retains some of the protein with transactivation activity. Here, we use an ERalpha-/- mouse strain in which no ERalpha transcript can be detected to analyze mammary gland development in the complete absence of ERalpha signaling. The ERalpha-/- females show no development beyond a rudimentary ductal system. By grafting ERalpha-/- epithelium or stroma in combination with ERalpha WT stroma or epithelium, we show that the primary target for estradiol is the mammary epithelium, whereas a direct response of the mammary stroma is not required for mammary gland development to proceed normally. Mammary glands reconstituted with ERalpha-/- mammary epithelium exposed to pregnancy hormones show increased transcription of milk protein genes, indicating that ERalpha signaling is not an absolute requirement for a transcriptional response to pregnancy hormones. When ERalpha-/- mammary epithelial cells are in close vicinity to ERalpha WT cells, they proliferate and contribute to all aspects of mammary gland development, indicating that estradiol, like progesterone, orchestrates proliferation and morphogenesis by a paracrine mechanism, affecting nearby cells in the mammary epithelium.
雌二醇是产后乳腺发育的主要调节因子，被认为通过乳腺基质和上皮中表达的雌激素受体α（ERα）发挥作用。然而，以往的研究因使用了一种保留了部分具有反式激活活性蛋白质的ERα突变株而受到混淆。在此，我们使用一种无法检测到ERα转录本的ERα-/-小鼠品系，以分析在完全缺乏ERα信号的情况下乳腺的发育情况。ERα-/-雌性小鼠的乳腺发育仅停留在基本的导管系统阶段，不会进一步发育。通过将ERα-/-上皮或基质与ERα野生型基质或上皮组合移植，我们发现雌二醇的主要作用靶点是乳腺上皮，而乳腺基质的直接反应并非乳腺正常发育所必需。用暴露于妊娠激素的ERα-/-乳腺上皮重建的乳腺显示乳蛋白基因转录增加，这表明ERα信号并非对妊娠激素转录反应的绝对必需条件。当ERα-/-乳腺上皮细胞与ERα野生型细胞紧密相邻时，它们会增殖并对乳腺发育的各个方面都有贡献，这表明雌二醇与孕酮一样，通过旁分泌机制协调增殖和形态发生，影响乳腺上皮中的邻近细胞。
