Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer

Clin Exp Metastasis. 2002;19(4):301-11. doi: 10.1023/a:1015518114931.


Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer known. IBC carries a guarded prognosis primarily due to rapid onset of disease, typically within six months, and the propensity of tumor emboli to invade the dermal lymphatics and spread systemically. Although the clinical manifestations of IBC have been well documented, until recently little was known about the genetic mechanisms underlying the disease. In a comprehensive study aimed at identifying the molecular mechanisms responsible for the unique IBC phenotype, our laboratory identified overexpression of RhoC GTPase in over 90% of IBC tumors in contrast to 36% of stage-matched non-IBC tumors. We also demonstrated that overexpression of RhoC GTPase in human mammary epithelial (HME) cells nearly recapitulated the IBC phenotype with regards to invasion, motility and angiogenesis. In the current study we sought to delineate which signaling pathways were responsible for each aspect of the IBC phenotype. Using well-established inhibitors to the mitogen activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) pathways. We found that activation of the MAPK pathway was responsible for motility, invasion and production of angiogenic factors. In contrast, growth under anchorage independent conditions was dependent on the PI3K pathway.

Publication types

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

MeSH terms

  • ADP Ribose Transferases / pharmacology
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / pathology*
  • Botulinum Toxins*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Chromones / pharmacology
  • Endothelial Growth Factors / biosynthesis
  • Endothelial Growth Factors / genetics
  • Enzyme Induction
  • Enzyme Inhibitors / pharmacology
  • Female
  • GTP Phosphohydrolases / antagonists & inhibitors
  • GTP Phosphohydrolases / physiology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inflammation
  • Lymphokines / biosynthesis
  • Lymphokines / genetics
  • MAP Kinase Signaling System* / drug effects
  • Morpholines / pharmacology
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology*
  • Neovascularization, Pathologic / enzymology
  • Phenotype
  • Phosphoinositide-3 Kinase Inhibitors
  • Transfection
  • Tumor Cells, Cultured / enzymology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • rho GTP-Binding Proteins / antagonists & inhibitors
  • rho GTP-Binding Proteins / physiology*
  • rhoC GTP-Binding Protein


  • Chromones
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Lymphokines
  • Morpholines
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • ADP Ribose Transferases
  • exoenzyme C3, Clostridium botulinum
  • Botulinum Toxins
  • GTP Phosphohydrolases
  • RHOC protein, human
  • rho GTP-Binding Proteins
  • rhoC GTP-Binding Protein