title: Pttg1/securin is required for the branching morphogenesis of the mammary gland and suppresses mammary tumorigenesis.
abstract: Pituitary tumor transforming gene 1 (Pttg1) encodes the mammalian securin, which is an inhibitor of separase (a protease required for the separation of sister chromatids in mitosis and meiosis). PTTG1 is overexpressed in a number of human cancers and has been suggested to be an oncogene. However, we found that, in Pttg1-mutant females, the mammary epithelial cells showed increased proliferation and precocious branching morphogenesis. In accord with these phenotypic changes, progesterone receptor, cyclin D1, and Mmp2 were up-regulated whereas p21 (Cdkn1a) was down-regulated. These molecular changes provide explanation for the observed developmental defects, and suggest that Pttg1 is a tumor suppressor. Indeed, mice lacking Pttg1 developed spontaneous mammary tumors. Furthermore, in human breast tumors, PTTG1 protein levels were down-regulated and the reduction was significantly correlated with the tumor grade.
authors.affiliation: Department of Molecular Physiology and Biophysics, Lester and Sue Smith Breast Center, and Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Rashieda J
authors.initials: RJ
authors.lastname: Hatcher
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Guangxing
authors.initials: G
authors.lastname: Bian
authors.forename: Alejandro
authors.initials: A
authors.lastname: Contreras
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Pumin
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002842:Chromatids / Q000737:chemistry; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000502:physiology*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism; D064249:Securin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009363:Neoplasm Proteins; C578005:PTTG1 protein, mouse; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human