Estrogen receptor-α expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice

The estrogen receptor-alpha (ER alpha) is a critical transcription factor that regulates epithelial cell proliferation and ductal morphogenesis during postnatal mammary gland development. Tissue recombination and transplantation studies using the first generation of ER alpha knockout (ERKO) mice suggested that this steroid hormone receptor is required in the mammary stroma that subsequently exerts its effect on the epithelium through additional paracrine signaling events. A more detailed analysis revealed that ERKO mice produce a truncated ERa protein with detectable transactivation activity, and it is likely that this functional ER alpha variant has masked the biological significance of this steroid receptor in the mammary epithelium. In this article, we describe the generation a Cre-lox-based conditional knockout of the ER alpha gene to study the biological function of this steroid receptor in the epithelial compartment at defined stages of mammary gland development. The mouse mammary tumor virus (MMTV)-Cre-mediated, epithelial-specific ablation of exon 3 of the ER alpha gene in virgin mice severely impaired ductal elongation and side branching. The conditional knockout resulted in ablation of the ER alpha protein, and the progesterone receptor (PR), whose expression is under the control of ER alpha, was largely absent. The whey acidic protein (WAP)-Cre-mediated deletion of ER alpha during successive gestation cycles resulted in a loss of ductal side-branching and lobuloalveolar structures, ductal dilation, and decreased proliferation of alveolar progenitors. These abnormalities compromised milk production and led to malnourishment of the offspring by the second lactation. These observations suggest that ER alpha expression in the mammary epithelium is essential for normal ductal morphogenesis during puberty and alveologenesis during pregnancy and lactation.