title: Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes.
abstract: 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.
authors.affiliation: Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: L T
authors.initials: LT
authors.lastname: Amundadottir
authors.forename: P
authors.initials: P
authors.lastname: Leder
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002461:Cell Line, Transformed; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology; D018734:Genes, erbB-2; D016259:Genes, myc; D011905:Genes, ras; D006023:Glycoproteins / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020880:Neuregulins; D009857:Oncogenes; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D006023:Glycoproteins; D020880:Neuregulins; D011518:Proto-Oncogene Proteins; D016211:Transforming Growth Factor alpha; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; C494960:Fyn protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases