Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes

Oncogene. 1998 Feb 12;16(6):737-46. doi: 10.1038/sj.onc.1201829.


We have assessed five signal transduction pathways to determine the role each might play in the malignant transformation of mammary epithelium initiated by neu, heregulin/NDF, TGFalpha, v-Ha-ras and c-myc in transgenic mice. The study involves a molecular and pharmacologic assessment of Erk/MAP kinase, Jnk/SAP kinase, PI 3-kinase, protein kinase C, and the Src-related kinases Lck and Fyn. Our results indicate that oncogenes capable of transforming mammary gland epithelium activate and require specific signal transduction pathways. For example, mammary tumors initiated by neu, v-Ha-ras and c-myc have high levels of active Erk/MAP kinase and their anchorage independent growth is strongly inhibited by PD098059, an inhibitor of Mek/ MAP kinase kinase. By contrast, Erk/MAP kinase activity is weak in tumors initiated by TFGalpha and heregulin/NDF and the corresponding cell lines are not growth inhibited by PD098059. Similarly, PI 3-kinase is strongly activated in neu, TGFalpha and heregulin/NDF initiated tumor cell lines, but not in c-myc or v-Ha-ras initiated tumor cell lines. The anchorage independent growth of all these tumor cell lines are, however, inhibited by the specific PI 3-kinase inhibitor LY294001. Further illustrating this oncogene-based specificity, PP1, a specific inhibitor of the Src-like kinases, Lck and Fyn, blocks anchorage-independent cell growth only in the TGFalpha initiated mammary tumor cell line. Taken together with additional observations, we conclude that certain oncogenes reliably require the recruitment/activation of specific signal transduction pathways. Such specific relationships between the initiating oncogene and a required pathway may reflect a direct activating effect or the parallel activation of a pathway that is a necessary oncogenic collaborator for transformation in the mammary gland. The work points to a molecular basis for targeting therapy when an initiating oncogene can be implicated; for example, because of amplification, increased expression, genetic alteration, or heritable characteristics.

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Line, Transformed
  • Enzyme Activation
  • Epithelial Cells / cytology
  • Genes, erbB-2*
  • Genes, myc*
  • Genes, ras*
  • Glycoproteins / genetics*
  • JNK Mitogen-Activated Protein Kinases
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / metabolism*
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Neuregulins
  • Oncogenes
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase C / metabolism
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-fyn
  • Signal Transduction*
  • Transforming Growth Factor alpha / genetics*
  • Tumor Cells, Cultured


  • Glycoproteins
  • Neuregulins
  • Proto-Oncogene Proteins
  • Transforming Growth Factor alpha
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • Fyn protein, mouse
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Proto-Oncogene Proteins c-fyn
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases