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Submitted on October 12, 2005
Accepted on November 29, 2005
Dept. of Molecular & Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
* To whom correspondence should be addressed. E-mail: rkumar{at}mdanderson.org.
Much research effort has been directed toward understanding how estrogen (17
-estradiol, E2) regulates cell proliferation and motility through the rapid, direct activation of cytoplasmic signaling cascades (i.e. non genomic signaling). Cell migration is critical to cancer cell invasion and metastasis and involves dynamic F-actin cytoskeletal remodeling and disassembly of focal adhesion sites. Although estrogen is recognized to induce cell migration in some model systems, very little information is available regarding the underlying pathways and potential influence of selective estrogen receptor modulators (SERMs) such as 4-OH-tamoxifen (Tam) on these processes. Using the human endometrial cancer cell lines Hec 1A and Hec 1B as model systems, we have investigated the effects of E2 and Tam on endometrial non genomic signaling, cytoskeletal remodeling and cell motility. Results indicate that both E2 and Tam triggered rapid activation of ERK 1/2, c-Src and FAK signaling pathways and F-actin cytoskeletal changes. These changes included dissolution of stress fibers, dynamic actin accumulation at the cell periphery, and formation of lamellipodia, filopodia and membrane spikes. Longer treatments with either agent induced cell migration in wound healing and Boyden chamber assays. Agent-induced cytoskeletal remodeling and cell migration were blocked by the Src inhibitor PP2. These findings define cytoskeletal remodeling and cell migration as processes regulated by E2 and Tam non genomic signaling in endometrial cancer. This new information may serve as the foundation for the development of new clinical therapeutic strategies.
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