Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells

Alexey A. Leontovich, Shuya Zhang, Cosima Quatraro, Ianko Iankov, Pier Francesco Veroux, Mario W. Gambino, Amy C Degnim, James McCubrey, James Ingle, Evanthia Galanis, Antonio D'Assoro

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Aberrant activation of the Raf/MEK/MAPK pathway plays a key role in breast cancer development and progression. Dysregulation of Raf/MEK/MAPK oncogenic signaling often results from overexpression of the HER-2/Neu tyrosine kinase receptor leading to chemoendocrine resistance, development of distant metastases and ultimately poor prognosis in breast cancer patients. HER-2/Neu overexpression is also linked to activation of the epithelial to mesenchymal transition (EMT) pathway, loss of adhesion molecules and metastasis. Recently, it has been demonstrated that cancer cells that undergo EMT acquire a CD44 +/CD24 -/low basal cancer stem cell-like phenotype and are characterized by activation of HER-2/Neu and TGFβ oncogenic signaling pathways with increased capacity of self-renewal, drug resistance, invasion and distant metastases. Following metastatic dissemination, cancer cells re-activate certain epithelial properties through mesenchymal to epithelial transition (MET) to establish neoplastic lesions at secondary sites, although the molecular mechanisms regulating MET remain elusive. In this study we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces HER-2/Neu overexpression leading to the development of distant metastases in ERα + MCF-7 breast cancer xenografts. Importantly, development of distant metastases in xenograft models was linked to activation of the MET pathway characterized by reduced expression of EMT inducer genes (TGFB2, TWIST1 and FOXC1) and overexpression of BMB7, CXCR7 and EGR family of transcription factors. In summary, our results demonstrate for the first time that amplification of Raf/MEK/MAPK oncogenic signaling during tumor growth promotes the genesis of metastatic lesions from primary tumors by activating the mesenchymal epithelial transition.

Original languageEnglish (US)
Pages (from-to)1858-1864
Number of pages7
JournalInternational Journal of Oncology
Volume40
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Epithelial-Mesenchymal Transition
Breast Neoplasms
Neoplasm Metastasis
Mitogen-Activated Protein Kinase Kinases
Heterografts
Early Growth Response Transcription Factors
Neoplasms
Neoplastic Stem Cells
Receptor Protein-Tyrosine Kinases
Drug Resistance
Phenotype
Growth
Genes

Keywords

  • Breast cancer
  • HER-2/Neu
  • Raf-1
  • Raf/MEK/MAPK pathway
  • Tyrosine kinase receptor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells. / Leontovich, Alexey A.; Zhang, Shuya; Quatraro, Cosima; Iankov, Ianko; Veroux, Pier Francesco; Gambino, Mario W.; Degnim, Amy C; McCubrey, James; Ingle, James; Galanis, Evanthia; D'Assoro, Antonio.

In: International Journal of Oncology, Vol. 40, No. 6, 06.2012, p. 1858-1864.

Research output: Contribution to journalArticle

Leontovich, Alexey A. ; Zhang, Shuya ; Quatraro, Cosima ; Iankov, Ianko ; Veroux, Pier Francesco ; Gambino, Mario W. ; Degnim, Amy C ; McCubrey, James ; Ingle, James ; Galanis, Evanthia ; D'Assoro, Antonio. / Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells. In: International Journal of Oncology. 2012 ; Vol. 40, No. 6. pp. 1858-1864.
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abstract = "Aberrant activation of the Raf/MEK/MAPK pathway plays a key role in breast cancer development and progression. Dysregulation of Raf/MEK/MAPK oncogenic signaling often results from overexpression of the HER-2/Neu tyrosine kinase receptor leading to chemoendocrine resistance, development of distant metastases and ultimately poor prognosis in breast cancer patients. HER-2/Neu overexpression is also linked to activation of the epithelial to mesenchymal transition (EMT) pathway, loss of adhesion molecules and metastasis. Recently, it has been demonstrated that cancer cells that undergo EMT acquire a CD44 +/CD24 -/low basal cancer stem cell-like phenotype and are characterized by activation of HER-2/Neu and TGFβ oncogenic signaling pathways with increased capacity of self-renewal, drug resistance, invasion and distant metastases. Following metastatic dissemination, cancer cells re-activate certain epithelial properties through mesenchymal to epithelial transition (MET) to establish neoplastic lesions at secondary sites, although the molecular mechanisms regulating MET remain elusive. In this study we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces HER-2/Neu overexpression leading to the development of distant metastases in ERα + MCF-7 breast cancer xenografts. Importantly, development of distant metastases in xenograft models was linked to activation of the MET pathway characterized by reduced expression of EMT inducer genes (TGFB2, TWIST1 and FOXC1) and overexpression of BMB7, CXCR7 and EGR family of transcription factors. In summary, our results demonstrate for the first time that amplification of Raf/MEK/MAPK oncogenic signaling during tumor growth promotes the genesis of metastatic lesions from primary tumors by activating the mesenchymal epithelial transition.",
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AU - Veroux, Pier Francesco

AU - Gambino, Mario W.

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AU - Galanis, Evanthia

AU - D'Assoro, Antonio

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AB - Aberrant activation of the Raf/MEK/MAPK pathway plays a key role in breast cancer development and progression. Dysregulation of Raf/MEK/MAPK oncogenic signaling often results from overexpression of the HER-2/Neu tyrosine kinase receptor leading to chemoendocrine resistance, development of distant metastases and ultimately poor prognosis in breast cancer patients. HER-2/Neu overexpression is also linked to activation of the epithelial to mesenchymal transition (EMT) pathway, loss of adhesion molecules and metastasis. Recently, it has been demonstrated that cancer cells that undergo EMT acquire a CD44 +/CD24 -/low basal cancer stem cell-like phenotype and are characterized by activation of HER-2/Neu and TGFβ oncogenic signaling pathways with increased capacity of self-renewal, drug resistance, invasion and distant metastases. Following metastatic dissemination, cancer cells re-activate certain epithelial properties through mesenchymal to epithelial transition (MET) to establish neoplastic lesions at secondary sites, although the molecular mechanisms regulating MET remain elusive. In this study we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces HER-2/Neu overexpression leading to the development of distant metastases in ERα + MCF-7 breast cancer xenografts. Importantly, development of distant metastases in xenograft models was linked to activation of the MET pathway characterized by reduced expression of EMT inducer genes (TGFB2, TWIST1 and FOXC1) and overexpression of BMB7, CXCR7 and EGR family of transcription factors. In summary, our results demonstrate for the first time that amplification of Raf/MEK/MAPK oncogenic signaling during tumor growth promotes the genesis of metastatic lesions from primary tumors by activating the mesenchymal epithelial transition.

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