This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Siriwardana, G. Articles by Zeitler, P. Search for Related Content PubMed PubMed Citation Articles by Siriwardana, G. Articles by Zeitler, P.

Autocrine/Paracrine Regulation of Breast Cancer Cell Proliferation by Growth Hormone Releasing Hormone via Ras, Raf, and Mitogen-Activated Protein Kinase

Departments of Pediatrics (G.S.) and Obstetrics and Gynecology (A.B., P.Z.), University of Colorado Health Sciences Center, Denver, Colorado 80262; and Department of Medicine (D.C.), Tulane University School of Medicine, New Orleans, Louisiana 70146

Address all correspondence and requests for reprints to: Dr. Philip S. Zeitler, Children’s Hospital/University of Colorado, Division of Endocrinology, 1056 19th Avenue, Denver, Colorado 80218. E-mail: zeitler.philip{at}tchden.org.

Although 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 kinase 1 inhibitor. The inhibition of Ras and Raf, as well as the inhibition of MAPK phosphorylation by PD98059, 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 MDA-231 cell population maintenance. Taken together, the studies provide further insight into the possible role of GHRH as a growth factor in breast cancer.

This article has been cited by other articles:

				N. Barabutis, A. Siejka, A. V Schally, N. L Block, R. Cai, and J. L Varga Activation of mitogen-activated protein kinases by a splice variant of GHRH receptor J. Mol. Endocrinol., February 1, 2010; 44(2): 127 - 134. [Abstract] [Full Text] [PDF]

				R. Granata, L. Trovato, M. P. Gallo, S. Destefanis, F. Settanni, F. Scarlatti, A. Brero, R. Ramella, M. Volante, J. Isgaard, et al. Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia-reperfusion injury in rat heart Cardiovasc Res, July 15, 2009; 83(2): 303 - 312. [Abstract] [Full Text] [PDF]

				D. L. Kleinberg, T. L. Wood, P. A. Furth, and A. V. Lee Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions Endocr. Rev., February 1, 2009; 30(1): 51 - 74. [Abstract] [Full Text] [PDF]

				N. Barabutis and A. V. Schally Antioxidant activity of growth hormone-releasing hormone antagonists in LNCaP human prostate cancer line PNAS, December 23, 2008; 105(51): 20470 - 20475. [Abstract] [Full Text] [PDF]

				A.-A. Volakaki, D. Lafkas, E. Kassi, A. V Schally, A. G Papavassiliou, and H. Kiaris Essential role of p21/waf1 in the mediation of the anti-proliferative effects of GHRH antagonist JMR-132 J. Mol. Endocrinol., November 1, 2008; 41(5): 389 - 392. [Abstract] [Full Text] [PDF]

				F. Barbieri, A. Pattarozzi, M. Gatti, C. Porcile, A. Bajetto, A. Ferrari, M. D. Culler, and T. Florio Somatostatin Receptors 1, 2, and 5 Cooperate in the Somatostatin Inhibition of C6 Glioma Cell Proliferation in Vitro via a Phosphotyrosine Phosphatase-{eta}-Dependent Inhibition of Extracellularly Regulated Kinase-1/2 Endocrinology, September 1, 2008; 149(9): 4736 - 4746. [Abstract] [Full Text] [PDF]

				L. Dal Lago, V. D'Hondt, and A. Awada Selected Combination Therapy with Sorafenib: A Review of Clinical Data and Perspectives in Advanced Solid Tumors Oncologist, August 1, 2008; 13(8): 845 - 858. [Abstract] [Full Text] [PDF]

				N. Barabutis, E. Tsellou, A. V. Schally, S. Kouloheri, A. Kalofoutis, and H. Kiaris Stimulation of proliferation of MCF-7 breast cancer cells by a transfected splice variant of growth hormone-releasing hormone receptor PNAS, March 27, 2007; 104(13): 5575 - 5579. [Abstract] [Full Text] [PDF]