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Regulation of Cyclin D1 and p16^INK4A Is Critical for Growth Arrest during Mammary Involution¹

Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129 [M. G., C. P., J. B., V. I-T., Z. N., C. Y., G. M. S., E. V. S.]; Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114 [M. G.]; Department of Medicine, University of Massachusetts Medical School, University of Massachusetts Memorial Healthcare, Worcester, Massachusetts 01655 [T. W.]; Department of Pathology, School of Medicine, University of California at Davis, Davis, California 95616 [R. D. C.]; The Pediatric Service, Massachusetts General Hospital, Boston, Massachusetts 02114 [Z. N., E. V. S.]; and Division of Hematology-Oncology, Children’s Hospital of Los Angeles, Los Angeles, California 90027 [G. M. S.]

A coordinated growth arrest during mammary involution completes the dramatic changes in mammary cell proliferation seen during pregnancy and lactation. Signals regulating this arrest are poorly understood, despite their potential relevance to oncogenesis. Here we report that the arrest involves a unique pulse of p16^INK4A expression in vivo, which accompanies decreased cyclin D1 expression and a shift to an active repressor E2F4 complex. We used INK4A/ARF-/- mice as well as cyclin D1 and p16^INK4A transgenic strains to examine the physiological significance of these patterns. p16^INK4A directly regulated the in vivo transition from E2F3 to E2F4 as the major E2F DNA binding activity, and its contribution to growth arrest was independent of cyclin D1. Transgenic cyclin D1 expression prevented normal terminal differentiation by ablating the p16^INK4A pulse, abolishing the shift from E2F3 to E2F4, derepressing E2F target genes, and expanding a stem cell population. The effects of cyclin D1 were reversed by restoring p16^INK4A but were not seen in INK4A/ARF-/- mice. Our results indicate that cyclin D1 may contribute to tumorigenesis by altering cell differentiation and demonstrate a significant function for p16^INK4A in development in vivo. These regulatory mechanisms used during mammary involution offer a potential explanation for the protective effect of pregnancy against breast cancer.

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