title: p16 loss rescues functional decline of Brca1-deficient mammary stem cells.
abstract: Recent evidence indicates that the accumulation of endogenous DNA damage can induce senescence and limit the function of adult stem cells. It remains elusive whether deficiency in DNA damage repair is associated with the functional alteration of mammary stem cells. In this article, we reported that senescence was induced in mammary epithelial cells during aging along with increased expression of p16Ink4a (p16), an inhibitor of CDK4 and CKD6. Loss of p16 abrogated the age-induced senescence in mammary epithelial cells and significantly increased mammary stem cell function. We showed that loss of Brca1, a tumor suppressor that functions in DNA damage repair, in the mammary epithelium induced senescence with induction of p16 and a decline of stem cell function, which was rescued by p16 loss. These data not only answer the question as to whether deficiency in DNA damage repair is associated with the functional decline of mammary stem cells, but also identify the role of p16 in suppressing Brca1-deficient mammary stem cell function.
authors.affiliation: a Molecular Oncology Program, Department of Surgery , Miller School of Medicine, University of Miami , Miami , FL , USA.|b The Sheila and David Fuente Graduate Program in Cancer Biology , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Scott
authors.affiliation: a Molecular Oncology Program, Department of Surgery , Miller School of Medicine, University of Miami , Miami , FL , USA.|d Sylvester Cancer Center , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.affiliation: a Molecular Oncology Program, Department of Surgery , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Ho Lam
authors.initials: HL
authors.lastname: Chan
authors.affiliation: a Molecular Oncology Program, Department of Surgery , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Shiqin
authors.initials: S
authors.lastname: Liu
authors.affiliation: c Braman Family Breast Cancer Institute, Sylvester Cancer Center , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Slingerland
authors.affiliation: a Molecular Oncology Program, Department of Surgery , Miller School of Medicine, University of Miami , Miami , FL , USA.|d Sylvester Cancer Center , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
authors.affiliation: a Molecular Oncology Program, Department of Surgery , Miller School of Medicine, University of Miami , Miami , FL , USA.|d Sylvester Cancer Center , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Capobianco
authors.affiliation: a Molecular Oncology Program, Department of Surgery , Miller School of Medicine, University of Miami , Miami , FL , USA.|b The Sheila and David Fuente Graduate Program in Cancer Biology , Miller School of Medicine, University of Miami , Miami , FL , USA.|d Sylvester Cancer Center , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Xin-Hai
authors.initials: XH
authors.lastname: Pei
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D019313:BRCA1 Protein; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D013234:Stem Cells / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C000605931:Brca1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins
keywords: Brca1; p16INK4a; senescence; stem cell function