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Submitted on January 4, 2005
Accepted on April 4, 2006
Department of Pediatrics, University of Colorado Health Sciences Center, Denver CO 80262; Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver CO 80262; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70146
* To whom correspondence should be addressed. E-mail: zeitler.philip{at}tchden.org.
Although growth hormone releasing hormone (GHRH) has previously been shown to regulate proliferation of breast cancer cells and prevent apoptosis, the intracellular pathways mediating this effect have not been clarified. Exogenous GHRH stimulated a dose-dependent proliferative response within 24 h in MDA 231, as well as in T47D cells and in MCF-7 cells transfected with the GHRH receptor. The proliferation of MDA-MB-231 (MDA-231) cells was associated with an increase in tritiated thymidine uptake. In addition, phosphorylation of MAPK was rapidly stimulated by GHRH. The phosphorylation of MAPK by GHRH was prevented by transfection of the cells with dominant negative Ras or Raf or by pretreatment of cells with Raf Kinase1 inhibitor. The inhibition of Ras and Raf, as well as the inhibition of MAPK phosphorylation by PD 98059 also prevented GHRH-induced cell proliferation. Finally, pretreatment of cells with the somatostatin analog, BIM23014, also prevented GHRH-induced MAPK phosphorylation and cell proliferation. These results indicate that GHRH stimulates dose-dependent cell proliferation of MDA 231 breast cancer cells through a pathway that requires Ras, Raf, and MAPK phosphorylation. The results also provide support for a possible autocrine/paracrine antagonism between GHRH and somatostatin in the regulation of MDA231 cell population maintenance. Taken together, the studies provide further insight into the possible role of GHRH as a growth factor in breast cancer.
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