Jl. Martin et Rc. Baxter, Oncogenic ras causes resistance to the growth inhibitor insulin-like growth factor binding protein-3 (IGFBP-3) in breast cancer cells, J BIOL CHEM, 274(23), 1999, pp. 16407-16411
Insulin-like growth factor binding protein-3 (IG-FBP-3) inhibits proliferat
ion and promotes apoptosis in normal and malignant cells. In MCF-10A human
mammary epithelial cells, 30 ng/ml human plasma-derived IGFBP-3 inhibited D
NA synthesis to 70% of control. This inhibition appeared IGF-independent, s
ince neither an IGF-receptor antibody nor IGFBP-6 inhibited DNA synthesis.
Malignant transformation of MCF-10A cells by transfection with Ha-ras oncog
ene abolished the inhibitory effect of IGFBP-3, concomitant with an increas
e in IGFBP-3 secretion and cell association of approximately 60 and 300%, r
espectively. When mitogen-activated protein (MAP) kinase activation was par
tially inhibited using PD 98059, IGFBP-3 sensitivity in ras-transfected cel
ls was restored, with a significant inhibitory effect at 10 ng/ml IGFBP-3.
PD 98059 had no effect on IGFBP-3 secretion or cell association by ras-tran
sfected or parent MCF-10A cells. Hs578T, a tumor-derived breast cancer cell
line that expresses activated Ha-ras, similarly has a high level of secret
ed and cell-associated IGFBP-3. In the absence of PD 98059, DNA synthesis b
y Hs578T cells was reduced to 70% of control by 1000 ng/ml IGFBP-S. PD 9805
9 increased sensitivity to IGFBP-3, so that this level of inhibition was ac
hieved with 100 ng/ml IGFBP-3. These results suggest that MAP kinase activa
tion by oncogenic ras expression causes IGFBP-3 resistance, a possible fact
or in the dysregulation of breast cancer cell growth.