TY - JOUR
T1 - Epstein–Barr Virus Infection of Mammary Epithelial Cells Promotes Malignant Transformation
AU - Hu, Hai
AU - Luo, Man Li
AU - Desmedt, Christine
AU - Nabavi, Sheida
AU - Yadegarynia, Sina
AU - Hong, Alex
AU - Konstantinopoulos, Panagiotis A.
AU - Gabrielson, Edward
AU - Hines-Boykin, Rebecca
AU - Pihan, German
AU - Yuan, Xin
AU - Sotirious, Christos
AU - Dittmer, Dirk P.
AU - Fingeroth, Joyce D.
AU - Wulf, Gerburg M.
N1 - Publisher Copyright:
© 2016
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ebiom.2016.05.025
DO - 10.1016/j.ebiom.2016.05.025
M3 - Article
C2 - 27333046
AN - SCOPUS:84971663736
SN - 2352-3964
VL - 9
SP - 148
EP - 160
JO - EBioMedicine
JF - EBioMedicine
ER -