Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland

Abstract

Estradiol is a major regulator of postnatal mammary gland development and thought to exert its effects through estrogen receptor α (ERα) expressed in the mammary gland stroma and epithelium. Previous studies, however, were confounded by the use of an ERα mutant strain that retains some of the protein with transactivation activity. Here, we use an ERα −/− mouse strain in which no ERα transcript can be detected to analyze mammary gland development in the complete absence of ERα signaling. The ERα −/− females show no development beyond a rudimentary ductal system. By grafting ERα −/− epithelium or stroma in combination with ERα 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 ERα −/− mammary epithelium exposed to pregnancy hormones show increased transcription of milk protein genes, indicating that ERα signaling is not an absolute requirement for a transcriptional response to pregnancy hormones. When ERα −/− mammary epithelial cells are in close vicinity to ERα 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.