Nielsen TO, Andrews HN, Cheang M, Kucab JE, Hsu FD, Ragaz J,
Gilks CB, Makretsov N, Bajdik CD, Brookes C, Neckers LM,
Evdokimova V, Huntsman DG, Dunn SE.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
(17AAG).
Cancer Res. 2004 Jan 1;64(1):286-91.
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.
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-allyamino geldanamycin (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.
PMID: 14729636
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