title: Bmi-1 cooperates with H-Ras to transform human mammary epithelial cells via dysregulation of multiple growth-regulatory pathways.
abstract: Elevated expression of Bmi-1 is associated with many cancers, including breast cancer. Here, we examined the oncogenic potential of Bmi-1 in MCF10A cells, a spontaneously immortalized, nontransformed strain of human mammary epithelial cells (HMEC). Bmi-1 overexpression alone in MCF10A cells did not result in oncogenic transformation. However, Bmi-1 co-overexpression with activated H-Ras (RasG12V) resulted in efficient transformation of MCF10A cells in vitro. Although early-passage H-Ras-expressing MCF10A cells were not transformed, late-passage H-Ras-expressing cells exhibited features of transformation in vitro. Early- and late-passage H-Ras-expressing cells also differed in levels of expression of H-Ras and Ki-67, a marker of proliferation. Subsets of early-passage H-Ras-expressing cells exhibited high Ras expression and were negative for Ki-67, whereas most late-passage H-Ras-expressing cells expressed low levels of Ras and were Ki-67 positive. Injection of late-passage H-Ras-expressing cells in severe combined immunodeficient mice formed carcinomas with leiomatous, hemangiomatous, and mast cell components; these tumors were quite distinct from those induced by late-passage cells co-overexpressing Bmi-1 and H-Ras, which formed poorly differentiated carcinomas with spindle cell features. Bmi-1 and H-Ras co-overexpression in MCF10A cells also induced features of epithelial-to-mesenchymal transition. Importantly, Bmi-1 inhibited senescence and permitted proliferation of cells expressing high levels of Ras. Examination of various growth-regulatory pathways suggested that Bmi-1 overexpression together with H-Ras promotes HMEC transformation and breast oncogenesis by deregulation of multiple growth-regulatory pathways by p16(INK4a)-independent mechanisms.
authors.affiliation: Division of Cancer Biology and Department of Medicine, Feinberg School of Medicine, Northwestern University, Evanston, IL 60201, USA.
authors.forename: Sonal
authors.initials: S
authors.lastname: Datta
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hoenerhoff
authors.forename: Prashant
authors.initials: P
authors.lastname: Bommi
authors.forename: Rachana
authors.initials: R
authors.lastname: Sainger
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Guo
authors.forename: Manjari
authors.initials: M
authors.lastname: Dimri
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Green
authors.forename: Goberdhan P
authors.initials: GP
authors.lastname: Dimri
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D004249:DNA Damage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D019940:Genes, bcl-1; D011905:Genes, ras; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D019394:Ki-67 Antigen / Q000032:analysis; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D063150:Polycomb Repressive Complex 1; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C069077:BMI1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C111049:MAP-kinase-activated kinase 5; D063150:Polycomb Repressive Complex 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051358:Cyclin-Dependent Kinase 4; D048049:Extracellular Signal-Regulated MAP Kinases