Ligand-free estrogen receptor activity complements IGF1R to induce the proliferation of the MCF-7 breast cancer cells.

Background: Ligand-dependent activation of the estrogen receptor (ER) as well as of the insulin-like growth factor type 1 (IGF1R) induces the proliferation of luminal breast cancer cells. These two pathways cooperate and are interdependent. We addressed the question of the mechanisms of crosstalk between the ER and IGF1R.

Indirect participation of Hsp90 in the regulation of the cyclin E turnover.

Cyclin E is the Cdk2-regulatory subunit required for the initiation of DNA replication at the G1/S transition. It accumulates in late G1 phase and gets rapidly degraded by the ubiquitin/proteasome pathway during S phase. The degradation of cyclin E is a consequence of its phosphorylation and subsequent isomerization by the peptidyl-prolyl isomerase Pin1.

Mitogenic activity of estrogens in human breast cancer cells does not rely on direct induction of mitogen-activated protein kinase/extracellularly regulated kinase or phosphatidylinositol 3-kinase.

We have addressed the question of rapid, nongenomic mechanisms that may be involved in the mitogenic action of estrogens in hormone-dependent breast cancer cells. In quiescent, estrogen-deprived MCF-7 cells, estradiol did not induce a rapid activation of either the MAPK/ERK or phosphatidylinositol-3 kinase (PI-3K)/Akt pathway, whereas the entry into the cell cycle was documented by the successive inductions of cyclin D1 expression, hyperphosphorylation of the retinoblastoma protein (Rb), activity of the promoter of the cyclin A gene, and DNA synthesis. However, pharmacological inhibitors of the src family kinases, 4-amino-5-(4-methylphenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP1) or of the PI-3K (LY294002) did prevent the entry of the cells into the cell cycle and inhibited the late G1 phase progression, whereas the inhibitor of MAPK/ERK activation (U0126) had only a partial inhibitory effect in the early G1 phase.

Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest.

The effects of GA, an ansamycin antibiotic in development as a lead anticancer drug, were studied in mouse BP-A31 fibroblasts and in human cancer-derived cell lines. GA and related molecules act by inhibiting the chaperone function of the Hsp90 protein through competition for ATP binding. The antiproliferative effects of GA have been attributed to destabilization of the Raf-1 protein, one of the targets of Hsp90, and to the resulting inhibition of MAPK.

Rapamycin inhibits cdk4 activation, p 21(WAF1/CIP1) expression and G1-phase progression in transformed mouse fibroblasts.

Rapamycin, a bacterial macrolide antibiotic, is a potent immunosuppressant agent that blocks cell proliferation by inhibiting the G1/S transition in several cell types. In sensitive cells, rapamycin inhibits the phosphorylation of p70 S6K and of Rb; however, the precise mechanisms involved have not been elucidated. In the mouse BP-A31 fibroblasts, synchronised in G0/G1 phase by serum starvation and induced to reinitiate the G1-phase progression, rapamycin inhibited the entry into S phase.

The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy.

The c-kit tyrosine kinase inhibitor STI571 exhibits a substantial therapeutic activity in patients with chronic myeloid leukemia and gastrointestinal stromal tumors respectively associated with constitutive activation of the BCR-ABL and c-kit tyrosine kinases. Human colorectal tumors also express the c-kit proto-oncogene. The present study focuses on the anticancer activity of STI571 in human colorectal tumor cells in vitro and in vivo.