Progesterone signaling in mammary gland development.

Abstract

The mammary gland undergoes extensive epithelial expansion and differentiation during pregnancy, leading ultimately to the development of functional milk-producing alveolar lobules. This phase of mammary gland remodeling is controlled primarily by the cooperative interplay between hormonal signals initiated by both progesterone and prolactin. Abrogation of mammary epithelial expression of receptors for either one of the hormones results in failure of alveologenesis and an absence of pregnancy-induced tertiary ductal side branches in the case of progesterone receptor-null (PRKO) mammary glands. By combining gene array approaches to identify PR- and prolactin (PRL)-dependent downstream signaling pathways and by using genetic mouse models to address the consequences of abrogation and/or misexpression of potential downstream genes, recent studies have begun to illuminate key signaling pathways that mediate the morphogenic effects of these hormones during pregnancy-induced mammary gland remodeling. Analysis of deregulated expression of PR-dependent gene transcripts in PRKO mammary glands has revealed that convergence between progesterone and prolactin signaling occurs in part through progesterone-dependent induction of mammary epithelial PRL receptors to prime the mammary epithelium to respond to PRL. Additional genes activated by PRs encode epithelial paracrine growth factor signals that regulate ductal and alveolar epithelial proliferation and survival, lineage-restricted transcription factors that control luminal and alveolar cell fate establishment and maintenance, and gap junction proteins that play a critical role in alveolar morphogenesis by establishment of epithelial cell polarity. Finally, two distinct isoforms of PRs (PR-A and PR-B) are coexpressed in the mammary gland and display extensively overlapping but partially distinct gene regulatory properties in relaying the progesterone signal.