Inhibition of gp130 signaling in breast cancer blocks constitutive activation of Stat3 and inhibits in vivo malignancy.
The cytokine receptor gp130 is the common signaling subunit of receptors used by the interleukin (IL)-6 cytokine family. gp130 is widely expressed in breast cancer cell lines and primary tumors. The role of gp130 in breast cancer in vivo is unknown. To study the effect of gp130 inhibition in breast cancer, endogenous gp130 signaling in breast cancer cell lines was blocked with a dominant-negative gp130 protein (DN gp130). DN gp130 inhibited constitutive Stat3 activation in breast cancer cells. Both gp130 and epidermal growth factor receptor (EGFR) have been implicated in constitutive Stat3 activation in breast cancer. There are known physical and functional interactions between gp130 and EGFR. Consistent with this, we show that DN gp130 inhibits signaling downstream of the EGFR in breast cancer cells. The effect of DN gp130 on breast cancer in vivo was assessed with an orthotopic nude mouse model. DN gp130 MDA-231 cells had markedly decreased engraftment, size, and metastasis compared with control cells. These results are particularly striking considering that DN gp130-expressing breast cancer cells grow faster in vitro. We hypothesized that DN gp130 expression results in inhibition of invasion and metastasis in vivo. Marked angiogenesis was present in tumors from control animals and was absent in tumors from DN gp130 animals. We additionally show that tissue inhibitor of metalloproteinase-3, an inhibitor of tumor invasion and angiogenesis, is up-regulated in both MDA-231 DN gp130 cells and tumors. These results, in light of the availability of several potential pharmacological inhibitors of gp130, suggest novel approaches to breast cancer therapy.
Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA.
Katri S
KS
Selander
Li
L
Li
Latania
L
Watson
Melinda
M
Merrell
Heike
H
Dahmen
Peter C
PC
Heinrich
Gerhard
G
Müller-Newen
Kevin W
KW
Harris
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019556:COS Cells; D002455:Cell Division; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism*; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D019717:Tissue Inhibitor of Metalloproteinase-3; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D066246:ErbB Receptors