Jp. Parisot et al., Induction of insulin-like growth factor binding protein expression by ICI 182,780 in a tamoxifen-resistant human breast cancer cell line, BREAST CANC, 55(3), 1999, pp. 231-242
Earlier studies in our laboratory demonstrated that the steroidal antiestro
gen ICI 182,780 is very effective in abolishing the tamoxifen-resistant pro
liferation of MCF 7/5-23 cells [1]. In addition, preliminary binding studie
s showed that ICI 182,780 increased the binding of insulin-like growth fact
or (IGF)-I to the MCF 7/5-23 cells, although this finding was not the resul
t of an increase in the expression of the insulin-like growth factor-I rece
ptor (IGF-IR). Hence, we reasoned that the inhibition of tamoxifen-resistan
t cell growth by ICI 182,780 might have been due to increased expression of
insulin-like growth factor binding proteins (IGFBPs).
We observed the up-regulation of non-insulin-suppressible IGF-I binding in
both the tamoxifen-sensitive MCF 7/5-21 cell line (1.5-fold) and the tamoxi
fen-resistant MCF 7/5-23 cell line (2.5-fold) after 5 days of treatment wit
h ICI 182,780 (10(-7) M) in serum-free medium, suggesting a role for cell-a
ssociated IGFBPs. Affinity cross-linking experiments confirmed the presence
of an IGF-I:IGFBP complex of approximately 38-kDa in tamoxifen or ICI 182,
780-treated cells. Western ligand blots showed higher levels of a soluble 3
0-kDa IGFBP in media conditioned by either of the subclones that had been t
reated with ICI 182,780, an effect consistently opposed by estrogen (E-2:10
(-9) M). RT-PCR showed higher levels of IGFBP-5 mRNA than any of the other
known IGFBPs, suggesting that this was the major IGFBP subtype. The protein
was subsequently identified by Western immunoblotting as IGFBP-5. In concl
usion, we postulate that this may be a mechanism contributing to the greate
r potency of ICI 182,780 in the growth inhibition of the MCF 7/5-23, tamoxi
fen-resistant cell line.