Autocrine/paracrine regulation of breast cancer cell proliferation by growth hormone releasing hormone via Ras, Raf, and mitogen-activated protein kinase

Mol Endocrinol. 2006 Sep;20(9):2010-9. doi: 10.1210/me.2005-0001. Epub 2006 Apr 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Autocrine Communication / drug effects*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Growth Hormone-Releasing Hormone / pharmacology*
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism*
  • Paracrine Communication / drug effects*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Neuropeptide / genetics
  • Receptors, Neuropeptide / metabolism
  • Receptors, Pituitary Hormone-Regulating Hormone / genetics
  • Receptors, Pituitary Hormone-Regulating Hormone / metabolism
  • raf Kinases / antagonists & inhibitors
  • raf Kinases / metabolism*
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / metabolism*


  • Protein Kinase Inhibitors
  • Receptors, Neuropeptide
  • Receptors, Pituitary Hormone-Regulating Hormone
  • Growth Hormone-Releasing Hormone
  • raf Kinases
  • Mitogen-Activated Protein Kinases
  • ras Proteins
  • somatotropin releasing hormone receptor