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

Abstract

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 (E2)-induced tumor progression, we blocked E2-signaling with MEK-inhibitor CI-1040 and/or tamoxifen (Tam). Our data show that both MEK-inhibitor CI-1040 and Tam blocked E2-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 E2-induced tumor growth. This suggests that the combination of CI-1040 and Tam may not be synergistic in inhibiting E2-induced tumor growth. However, these findings also indicate that MAPK plays a critical role in E2-induced tumor growth, and that this could be a potential therapeutic target to combat hormonally regulated growth in ER-positive tumors.

• Authors: Kaladhar B Reddy, Selina Glaros
• Journal: International journal of oncology (Int J Oncol) Vol. 30 Issue 4 Pg. 971-5 (Apr 2007) ISSN: 1019-6439 [Print] Greece
• PMID: 17332937 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
• Benzamides
• Estrogen Antagonists
• Estrogens
• Tamoxifen
• Estradiol
• MAP Kinase Kinase Kinases

Topics

• Benzamides (pharmacology)
• Breast Neoplasms (enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Estradiol (pharmacology)
• Estrogen Antagonists (pharmacology)
• Estrogens (pharmacology)
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Phosphorylation (drug effects)
• Signal Transduction (drug effects)
• Tamoxifen (pharmacology)