Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin.
Urokinase plasminogen activator (uPA) expression in breast cancer is associated with relapse and a reduction in disease-specific survival. Thus, efforts are under way to identify uPA inhibitors. By screening a chemical library of >1000 compounds, 17-allyaminogeldanamycin (17AAG) was identified as a potent inhibitor of uPA by the National Cancer Institute and is now in Phase I clinical trials. At this time, it remains unclear how 17AAG blocks uPA; one possibility is through disruption of the insulin-like growth factor I receptor (IGF-IR) pathway. This would be consistent with studies from our laboratory showing that activation of IGF-IR results in the induction of uPA protein. In the study described herein, we observed that IGF-IR and uPA were highly expressed in 87 and 55% of breast cancer by screening tumor tissue microarrays representing 930 cases. A significant proportion (52.1% = 354 of 680 cases, P < 0.0001) of the patients had tumors expressing both proteins. uPA alone (P = 0.033) or in combination with IGF-IR (P = 0.0104) was indicative of decreased disease-specific survival. Next, we demonstrated that treating MDA-MB-231 cells with increasing concentrations of 17AAG resulted in IGF-IR degradation (IC(50) = 1.0 micro M) and blocked signal transduction through the Akt and mitogen-activated protein kinase pathways. Finally, we found that 17AAG had a robust inhibitory effect on the production of uPA mRNAand protein in the presence of IGF-I. Thus, our study raises the possibility that 17AAG could prove to be an effective therapeutic agent for a large number of breast cancer patients by inhibiting the IGF-IR and ultimately uPA.
Nielsen
Torsten O
TO
British Columbia Research Institute for Children's and Women's Health, Department of Pediatrics, Laboratory for Oncogenomic Research, University of British Columbia, Vancouver British Columbia, Canada.
Andrews
Heather N
HN
Cheang
Maggie
M
Kucab
Jill E
JE
Hsu
Forrest D
FD
Ragaz
Joseph
J
Gilks
C Blake
CB
Makretsov
Nikita
N
Bajdik
Chris D
CD
Brookes
Christy
C
Neckers
Leonard M
LM
Evdokimova
Valentina
V
Huntsman
David G
DG
Dunn
Sandra E
SE
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D016227:Benzoquinones; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D017931:DNA Primers; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D047029:Lactams, Macrocyclic; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D017931:DNA Primers; D047029:Lactams, Macrocyclic; D012333:RNA, Messenger; D017828:Rifabutin; C112765:tanespimycin; D017526:Receptor, IGF Type 1; D017346:Protein Serine-Threonine Kinases; D014568:Urokinase-Type Plasminogen Activator