title: Epstein-Barr Virus Infection of Mammary Epithelial Cells Promotes Malignant Transformation.
abstract: Whether the human tumor virus, Epstein-Barr Virus (EBV), promotes breast cancer remains controversial and a potential mechanism has remained elusive. Here we show that EBV can infect primary mammary epithelial cells (MECs) that express the receptor CD21. EBV infection leads to the expansion of early MEC progenitor cells with a stem cell phenotype, activates MET signaling and enforces a differentiation block. When MECs were implanted as xenografts, EBV infection cooperated with activated Ras and accelerated the formation of breast cancer. Infection in EBV-related tumors was of a latency type II pattern, similar to nasopharyngeal carcinoma (NPC). A human gene expression signature for MECs infected with EBV, termed EBVness, was associated with high grade, estrogen-receptor-negative status, p53 mutation and poor survival. In 11/33 EBVness-positive tumors, EBV-DNA was detected by fluorescent in situ hybridization for the viral LMP1 and BXLF2 genes. In an analysis of the TCGA breast cancer data EBVness correlated with the presence of the APOBEC mutational signature. We conclude that a contribution of EBV to breast cancer etiology is plausible, through a mechanism in which EBV infection predisposes mammary epithelial cells to malignant transformation, but is no longer required once malignant transformation has occurred.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, USA; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China.
authors.forename: Man-Li
authors.initials: ML
authors.lastname: Luo
authors.affiliation: Institut Jules Bordet, 121 Boulevard de Waterloolaan, Bruxelles 1000, Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.affiliation: University of Connecticut, Computer Science and Engineering, 371 Fairfield Way, Storrs, CT 06268, USA.
authors.forename: Sheida
authors.initials: S
authors.lastname: Nabavi
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Yadegarynia
authors.affiliation: Massachusetts Institute for Technology, Department of Biology, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Hong
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
authors.affiliation: Department of Pathology, Johns Hopkins University, 4940 Eastern Ave, Baltimore, MD 21224, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Gabrielson
authors.affiliation: Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hines-Boykin
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, USA.
authors.forename: German
authors.initials: G
authors.lastname: Pihan
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Institut Jules Bordet, 121 Boulevard de Waterloolaan, Bruxelles 1000, Brussels, Belgium.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.affiliation: Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Dirk P
authors.initials: DP
authors.lastname: Dittmer
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Joyce D
authors.initials: JD
authors.lastname: Fingeroth
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, USA. Electronic address: gwulf@bidmc.harvard.edu.
authors.forename: Gerburg M
authors.initials: GM
authors.lastname: Wulf
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016000:Cluster Analysis; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D004847:Epithelial Cells / Q000166:cytology / Q000637:transplantation / Q000821:virology; D058750:Epithelial-Mesenchymal Transition; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017464:Receptors, Complement 3d / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D059467:Transcriptome; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004279:DNA, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D034741:RNA, Small Interfering; D017464:Receptors, Complement 3d; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D014763:Viral Matrix Proteins