Dysregulation of HER2/HER3 signaling axis in Epstein-Barr virus-infected breast carcinoma cells.
The role of Epstein-Barr virus (EBV) in the pathogenesis of breast cancer has been of long-standing interest to the field. Breast epithelial cells can be infected by EBV through direct contact with EBV-bearing lymphoblastoid cells, and EBV infection has recently been shown to confer breast cancer cells an increased resistance to chemotherapeutic drugs. In this study, we established EBV-infected breast cancer MCF7 and BT474 cells and demonstrated that EBV infection promotes tumorigenic activity of breast cancer cells. Firstly, we showed that the EBV-infected MCF7-A and BT474-A cells exhibited increased anchorage-independent growth in soft agar. The increased colony formation capacity in soft agar was associated with increased expression and activation of HER2/HER3 signaling cascades, as evidenced by the findings that the treatment of HER2 antibody trastuzumab (Herceptin), phosphatidylinositol 3-kinase inhibitor, or MEK inhibitor completely abolished the tumorigenic capacity. In the EBV-infected breast cancer cells, the expression of EBV latency genes including EBNA1, EBER1, and BARF0 was detected. We next showed that BARF0 alone was sufficient to efficiently up-regulate HER2/HER3 expression and promoted tumorigenic activity in MCF7 and BT474 cells by the use of both overexpression and small interfering RNA knock-down. Collectively, we demonstrated that EBV-encoded BARF0 promotes the tumorigenic activity of breast cancer cells through activation of HER2/HER3 signaling cascades.
Lin
Jiun-Han
JH
Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Tsai
Ching-Hwa
CH
Chu
Jan-Show
JS
Chen
Jeou-Yuan
JY
Takada
Kenzo
K
Shew
Jin-Yuh
JY
D001943:Breast Neoplasms / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020031:Epstein-Barr Virus Infections / Q000473:pathology / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology
D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3