title: Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium.
abstract: Overexpression of cyclin D1 is believed to endow mammary epithelial cells (MEC) with a proliferative advantage by virtue of its contribution to pRB inactivation. Accordingly, abrogation of the kinase-dependent function of cyclin D1 is sufficient to render mice resistant to breast cancer initiated by ErbB2. Here, we report that mouse cyclin D1(KE/KE) MECs (deficient in cyclin D1 activity) upregulate an autophagy-like process but fail to implement ErbB2-induced senescence in vivo. In addition, immortalized cyclin D1(KE/KE) MECs retain high rates of autophagy and reduced ErbB2-mediated transformation in vitro. However, highlighting its dual role during tumorigenesis, downregulation of autophagy led to an increase in senescence in cyclin D1(KE/KE) MECs. Autophagy upregulation was also confirmed in human mammary epithelial cells (HMEC) subjected to genetic and pharmacologic inhibition of cyclin D1 activity and, similar to our murine system, simultaneous inhibition of Cdk4/6 and autophagy in HMECs enhanced the senescence response. Collectively, our findings suggest a previously unrecognized function of cyclin D1 in suppressing autophagy in the mammary epithelium.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA. nbrown@utalca.cl
authors.forename: Nelson E
authors.initials: NE
authors.lastname: Brown
authors.forename: Rinath
authors.initials: R
authors.lastname: Jeselsohn
authors.forename: Teeru
authors.initials: T
authors.lastname: Bihani
authors.forename: Miaofen G
authors.initials: MG
authors.lastname: Hu
authors.forename: Parthena
authors.initials: P
authors.lastname: Foltopoulou
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kuperwasser
authors.forename: Philip W
authors.initials: PW
authors.lastname: Hinds
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004848:Epithelium / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic
chemical_list: D019938:Cyclin D1