An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells.
Ovarian cancer is a leading cause of death from gynecologic malignancies. Treatment for advanced-stage disease remains limited and, to date, targeted therapies have been incompletely explored. By systematically suppressing each human tyrosine kinase in ovarian cancer cell lines by RNAi, we found that an autocrine signal-transducing loop involving NRG1 and activated ErbB3 operates in a subset of primary ovarian cancers and ovarian cancer cell lines. Perturbation of this circuit with ErbB3-directed RNAi decreased cell growth in three-dimensional culture and resulted in decreased disease progression and prolonged survival in a xenograft mouse model of ovarian cancer. Furthermore, a monoclonal ErbB3-directed antibody (MM-121) also significantly inhibited tumor growth in vivo. These findings identify ErbB3 as a potential therapeutic target in ovarian cancer.
Sheng
Qing
Q
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Liu
Xinggang
X
Fleming
Eleanor
E
Yuan
Karen
K
Piao
Huiying
H
Chen
Jinyun
J
Moustafa
Zeinab
Z
Thomas
Roman K
RK
Greulich
Heidi
H
Schinzel
Anna
A
Zaghlul
Sara
S
Batt
David
D
Ettenberg
Seth
S
Meyerson
Matthew
M
Schoeberl
Birgit
B
Kung
Andrew L
AL
Hahn
William C
WC
Drapkin
Ronny
R
Livingston
David M
DM
Liu
Joyce F
JF
D000818:Animals; D019898:Autocrine Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D020890:Neuregulin-1 / Q000378:metabolism / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D034622:RNA Interference; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D020890:Neuregulin-1; D020893:Receptor, ErbB-3