Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015, Lausanne, Switzerland.
Department of Biochemistry, University of Lausanne, CH-1066, Epalinges, Switzerland.
Nat Commun. 2018 Nov 9;9(1):4723. doi: 10.1038/s41467-018-07175-0.
Oestrogen receptor α (ERα) 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 ERα-positive by immunohistochemistry (IHC) and secrete paracrine factors, which stimulate ERα-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 ERα-negative by IHC but express Esr1 transcripts. This low level ERα expression through AF-2 is essential for cell expansion during puberty and growth-inhibitory during pregnancy. Cell-intrinsic ERα 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 ERα as a key regulator of mammary epithelial cell plasticity.
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。雌激素通过免疫组织化学（IHC）检测到的一组称为感应细胞的乳腺上皮细胞（MEC）发挥作用，控制着出生后的乳腺发育，并分泌旁分泌因子，刺激 ERα 阴性的反应细胞。在这里，我们表明，AF-1 或 AF-2 的缺失会阻止青春期导管生长和随后的发育，因为它们都需要表达必需的旁分泌介质。通过 IHC，30%的腔细胞呈 ERα 阴性，但表达 Esr1 转录本。这种通过 AF-2 的低水平 ERα 表达对于青春期的细胞扩张和妊娠期间的生长抑制是必不可少的。细胞内在的 ERα对于细胞增殖或分泌分化都不是必需的，但控制着细胞迁移和细胞黏附基因的转录水平，以及一个干细胞和上皮间质转化（EMT）特征，将 ERα 鉴定为乳腺上皮细胞可塑性的关键调节因子。
