Inhibition of the MAP kinase activity suppresses estrogen-induced breast tumor growth both in vitro and in vivo

Elevated expression of mitogen-activated protein kinase (Erk/MAPK) has been noted in a significant percentage of primary human breast cancers. To directly assess the importance of Erk/MAPK activation in estrogen (E-2)-induced tumor progression, we blocked E-2-signaling with MEK-inhibitor CI-1040 and/or tamoxifen (TAM). Our data show that both MEK-inhibitor CI-1040 and TAM blocked E-2- induced MAPK phosphorylation and cell proliferation in MCF-7 breast cancer cells in vitro. However, in vivo studies show that anti-tumor efficacy of combining the CI-1040 and TAM was similar to single agent(s). Furthermore, sequential treatment with TAM followed by CI-1040 or CI-1040 followed by TAM did not significantly reduce E-2-induced tumor growth. This suggests that the combination of CI-1040 and TAM may not be synergistic in inhibiting E-2-induced tumor growth. However, these findings also indicate that MAPK plays a critical role in E-2-induced tumor growth, and that this could be a potential therapeutic target to combat hormonally regulated growth in ER-positive tumors.