Dissecting the roles of beta-catenin and cyclin D1 during mammary development and neoplasia.
A considerable body of circumstantial data suggests that cyclin D1 is an attractive candidate to mediate the effects of beta-catenin in mammary tissue. To test the functional significance of these correlative findings, we investigated the genetic interaction between transcriptionally active beta-catenin (DeltaN89beta-catenin) and its target gene cyclin D1 in the mouse mammary gland during pubertal development, pregnancy, and tumorigenesis. Our data demonstrate that cyclin D1 is dispensable for the DeltaN89beta-catenin-stimulated 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 hyperplastic and tumorigenic DeltaN89beta-catenin phenotypes. Although alveologenesis is initiated by DeltaN89beta-catenin in a cyclin D1-independent fashion, up-regulation of cyclin D1 occurs in DeltaN89beta-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 beta-catenin target genes that successfully drive proliferation at earlier stages.
D000818:Animals; D019938:Cyclin D1 / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000502:physiology*; D005260:Female; D008321:Mammary Glands, Animal / Q000254:growth & development*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D015534:Trans-Activators / Q000502:physiology*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1