Oestrogen receptor alpha AF-1 and AF-2 domains have cell population-specific functions in the mammary epithelium

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.