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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Qing
Q
Sheng
Xinggang
X
Liu
Eleanor
E
Fleming
Karen
K
Yuan
Huiying
H
Piao
Jinyun
J
Chen
Zeinab
Z
Moustafa
Roman K
RK
Thomas
Heidi
H
Greulich
Anna
A
Schinzel
Sara
S
Zaghlul
David
D
Batt
Seth
S
Ettenberg
Matthew
M
Meyerson
Birgit
B
Schoeberl
Andrew L
AL
Kung
William C
WC
Hahn
Ronny
R
Drapkin
David M
DM
Livingston
Joyce F
JF
Liu
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