Growth inhibition of both MCF-7 and Hs578T human breast cancer cell lines by vitamin D analogues is associated with increased expression of insulin-like growth factor binding protein-3

Abstract

The effects of two vitamin D analogues, EB1089 and CB1093, on insulin-like growth factor binding protein (IGFBP) expression have been examined in MCF-7 and Hs578T human breast cancer cell lines. Both vitamin D analogues inhibited IGF-1 stimulated growth of MCF-7 cells and enhanced the production of IGFBP-3 as determined by Western-ligand blotting. Recombinant human IGFBP-3 inhibited the growth of MCF-7 cells over the concentration range 1-235 ng/ml. Hs578T cells were unresponsive to the mitogenic effects of IGF-1 but growth was inhibited by the two vitamin D analogues. Treatment of Hs578T cells with EB1089 and CB1093 (10 nM) as well as 100 nM 9-cis retinoic acid (9-cis RA) or all-trans retinoic acid (ATRA) was associated with increased accumulation of IGFBP-3 in conditioned medium. Furthermore, cotreatment of Hs578T cells with EB1089 and 9-cis RA led to augmented effects on both inhibition of cell growth and IGFBP-3 accumulation in conditioned medium as assessed by Western ligand blotting and radioimmunoassay. These findings suggest a role for IGFBP-3 in the growth inhibitory effects of vitamin D analogues.

Differential interactions between IGFBP-3 and transforming growth factor-beta (TGF-β) in normal vs cancerous breast epithelial cells

“…Growth inhibition by IGFBP-3 has been reported in many cell lines such as Hs578T and MCF-7 breast cancer cells (Colston et al, 1998;Oh et al, 1993a). In the normal breast epithelial cell line, MCF-10A, it was recently reported that IGFBP-3 at 30 ng ml 71 also induced growth inhibition (Martin and Baxter, 1999).…”

“…TGF-b is a growth stimulator of fibroblast cells but is growth inhibitory in breast epithelial cells and mammary tumours (Daniel et al, 1996;Gold, 1999). Growth inhibitors such as TGF-b, retinoic acid and vitamin D (Colston et al, 1998) are potent regulators of IGFBP-3 and can stimulate IGFBP-3 at the mRNA level. TGF-b-induced growth inhibition seen in Hs578T breast cancer cells, as well as the TGF-b-induced proliferation seen in colon cancer cells and human airway smooth muscle cells is at least partially mediated by IGFBP-3 (Oh et al, 1995;Cohen et al, 2000;Kansra et al, 2000).…”

Anti-oestrogen resistant human breast cancer cell lines are more sensitive towards treatment with the vitamin D analogue EB1089 than parent MCF-7 cells

“…It has been reported that both EB1089 and the anti-oestrogens tamoxifen and ICI 182 780 up-regulate IGFBP-3 and IGFBP-5 in MCF-7 cells, and suggested that both EB1089 and the anti-oestrogens mediate their growth inhibitory effect via up-regulation of IGFBP-3 and IGFBP-5 (Rozen et al, 1997;Colston et al, 1998), which are known to induce apoptosis in MCF-7 cells (Huynh et al, 1996a(Huynh et al, , 1996b. Our data showing the lack of cross-resistance between tamoxifen, ICI 182 780 and EB1089 reported in this study and in Lykkesfeldt et al (1995) indicate that different mechanisms are responsible for growth inhibition mediated by these drugs.…”

Effects of sodium butyrate on expression of members of the IGF-binding protein superfamily in human mammary epithelial cells

“…In addition, recent evidence suggests that some IGFBPs may have direct receptor-mediated effects independent of IGFs (Oh et al 1993). IGFBP-3, for example, has been demonstrated to be an important mediator of other growth inhibitory agents, such as retinoic acid , vitamin D (Colston et al 1998), TGF- (Oh et al 1995, Rajah et al 1997, anti-estrogens (Huynh et al 1996), tumor necrosis factor- (Rozen et al 1998) and p53 (Buckbinder et al 1995), independently of the IGF signaling system. Furthermore, the importance of IGF-independent biological effects of the IGFBP superfamily, such as IGFBP-3 (Oh et al 1993), IGFBP-rP1 (Burger et al 1998) and -rP2 (Hishikawa et al 1999) on cell replication has been demonstrated in human breast cancer cell systems.…”