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Submitted on February 20, 2007
Accepted on May 11, 2007
Departments of Internal Medicine and Biomolecular Research Facility, University of Virginia School of Medicine, Charlottesville, VA 22903
* To whom correspondence should be addressed. E-mail: rjs5y{at}virginia.edu.
We present an integrated model of an extra-nuclear, ER
-mediated, rapid MAPK activation pathway in breast cancer cells. In non-cancer cells, IGF-1 initiates a linear process involving activation of the insulin-like growth factor-1 receptor (IGF-1R) and matrix metalloproteinases (MMP), release of heparin-binding EGF (HB-EGF) and activation of EGF receptor (EGFR)-dependent MAPK. 17
-estradiol (E2) rapidly activates IGF-1R in breast cancer cells. We hypothesize that E2 induces a similar linear pathway involving IGF-1R, MMP, HB-EGF, EGFR and MAPK. Using MCF-7 breast cancer cells, we for the first time demonstrated that a sequential activation of IGF-1R, MMP and EGFR existed in E2 and IGF-1 actions, which was supported by evidence that the selective inhibitors of IGF-1R and MMP or knockdown of IGF-1R all inhibited E2- or IGF-1-induced EGFR phosphorylation. Using the inhibitors and siRNA strategies, we also demonstrated that the same sequential activation of the receptors occurred in E2-, IGF-1-, but not EGF-induced, MAPK phosphorylation. Additionally, a HB-EGF neutralizing antibody significantly blocked E2-induced MAPK activation, further supporting our hypothesis. The biologic effects of sequential activation of IGF-1R and EGFR on E2 stimulation of cell proliferation were also investigated. Knockdown or blockade of IGF-1R significantly inhibited E2- or IGF-1-stimulated, but not EGF-induced cell growth. Knockdown or blockade of EGFR abrogated cell growth induced by all E2, IGF-1 and EGF, indicating that EGFR is a downstream molecule of IGF-1R in E2 and IGF-1 action. Together, our data support the novel view that E2 can activate a linear pathway involving the sequential activation of IGF-1R, MMP, HB-EGF, EGFR and MAPK.
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