Dissecting the roles of β-catenin and cyclin D1 during mammary development and neoplasia

摘要

A considerable body of circumstantial data suggests that cyclin D1 is an attractive candidate to mediate the effects of β-catenin in mammary tissue. To test the functional significance of these correlative findings, we investigated the genetic interaction between transcriptionally active β-catenin (ΔN89β-catenin) and its target gene cyclin D1 in the mouse mammary gland during puber-tal development, pregnancy, and tumorigenesis. Our data demonstrate that cyclin D1 is dispensable for the ΔN89β-catenin-stimu-lated initiation of alveologenesis in virgin females, for the de novo induction of alveoli in males, and for the formation of tumors. Indeed, lack of cyclin D1 accentuates and enhances these hyper-plastic and tumorigenic ΔN89β-catenin phenotypes. Although alveologenesis is initiated by ΔN89β-catenin in a cyclin D1-independent fashion, up-regulation of cyclin D1 occurs in ΔN89β-catenin mice and its expression remains essential for the completion of alveolar development during the later stages of pregnancy. Thus, alveologenesis is a two-step process, and cyclin D1 activity during late alveologenesis cannot be replaced by the activity of other β-catenin target genes that successfully drive proliferation at earlier stages.