Oestrogen receptor α AF-1 and AF-2 domains have cell population-specific functions in the mammary epithelium
Oestrogen receptor α AF-1 and AF-2 domains have cell population-specific functions in the mammary epithelium
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DOI：
10.1038/s41467-018-07175-0
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发表时间：
2018-11-09
影响因子：
16.6
通讯作者：
Brisken, Cathrin
中科院分区：
文献类型：
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作者：
Cagnet, Stephanie;Ataca, Dalya;Brisken, Cathrin
雌激素受体α(ERα)是一种转录因子，具有配体非依赖性和配体依赖性激活功能(AF)-1和-2。雌激素控制着出生后乳腺的发育，作用于乳腺上皮细胞(MECs)亚群，被称为传感细胞，经免疫组织化学(IHC)检测ERα阳性，并分泌旁分泌因子，刺激ERα阴性反应细胞。在这里，我们表明，AF-1或AF-2的缺失阻碍了青春期导管的生长和随后的发育，因为两者都是表达必需的旁分泌介质所必需的。30%的腔细胞在IHC检测中ERα阴性，但表达ESR1转录本。这种通过AF-2的低水平ERα表达对于青春期细胞的扩张和怀孕期间的生长抑制是必不可少的。细胞固有的ERα不是细胞增殖或分泌分化所必需的，但控制着细胞运动和细胞黏附基因的转录水平，以及干细胞和上皮间充质转化(EMT)信号，识别ERα是乳腺上皮细胞可塑性的关键调节因子。
Oestrogen receptor alpha (ER alpha) is a transcription factor with ligand-independent and ligand-dependent activation functions (AF)-1 and -2. Oestrogens control postnatal mammary gland development acting on a subset of mammary epithelial cells (MECs), termed sensor cells, which are ER alpha-positive by immunohistochemistry (IHC) and secrete paracrine factors, which stimulate ER alpha-negative responder cells. Here we show that deletion of AF-1 or AF-2 blocks pubertal ductal growth and subsequent development because both are required for expression of essential paracrine mediators. Thirty percent of the luminal cells are ER alpha-negative by IHC but express Esr1 transcripts. This low level ER alpha expression through AF-2 is essential for cell expansion during puberty and growth-inhibitory during pregnancy. Cell-intrinsic ER alpha is not required for cell proliferation nor for secretory differentiation but controls transcript levels of cell motility and cell adhesion genes and a stem cell and epithelial mesenchymal transition (EMT) signature identifying ER alpha as a key regulator of mammary epithelial cell plasticity.