title: Oncostatin M-specific receptor mediates inhibition of breast cancer cell growth and down-regulation of the c-myc proto-oncogene.
abstract: Human oncostatin M (OM) is a M(r) 28,000 glycoprotein that has been shown to regulate cell proliferation and differentiation. The biological activities of OM can be mediated by two different heterodimeric receptor complexes, the leukemia inhibitory factor (LIF)/OM shared receptor and the OM-specific receptor. In this study, we have examined the growth-regulatory effect of OM on 10 breast cancer cell lines derived from human tumors. The cellular proliferation of seven of these breast cancer cell lines was inhibited by OM. The three cell lines that did not respond to OM treatment lacked the expression of OM receptors. The growth-inhibitory activity of OM is examined further in the H3922 breast cancer cell line, which expresses the high-affinity OM receptor at a relatively higher level. We found that the cellular proliferation of H3922 cells was induced strongly by extrogenous epidermal growth factor (EGF), EGF-like factor, and basic fibroblast growth factor. The proliferative activities of these growth factors can be abolished totally by cotreatment of H3922 cells with OM. Treatment of H3922 cells with OM for 24 h did not block EGF binding or the induction of EGF receptor tyrosine phosphorylation. This finding suggests that OM interferes with the mitogenic signal at steps distal to the EGF receptor. Examination of proto-oncogene expression demonstrated that OM down-regulates the c-myc gene in H3922 cells. The biological effects reported herein are not shared by the OM-related cytokines interleukin 6 or LIF, as demonstrated by the inability of these proteins to inhibit cell growth or modulate c-myc gene expression in breast cancer cells. Additionally, the high-affinity binding of labeled OM cannot be displaced by LIF. Together, these data suggest that OM is a growth inhibitor for breast cancer cells. The inhibitory activity is mediated predominantly through the OM-specific receptor, and activation of this receptor abrogates growth factor stimulation and down-regulates the c-myc proto-oncogene.
authors.affiliation: Mountain States Medical Research Institute, Boise, Idaho, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: M J
authors.initials: MJ
authors.lastname: Spence
authors.forename: P M
authors.initials: PM
authors.lastname: Wallace
authors.forename: K
authors.initials: K
authors.lastname: Forcier
authors.forename: I
authors.initials: I
authors.lastname: Hellström
authors.forename: R E
authors.initials: RE
authors.lastname: Vestal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000235:genetics; D015870:Gene Expression; D016259:Genes, myc / Q000235:genetics / Q000502:physiology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000819:agonists; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases; D000090063:Proto-Oncogene Mas; D018121:Receptors, Cytokine / Q000819:agonists / Q000502:physiology*; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; C000715470:MAS1 protein, human; C508351:OSM protein, human; D010455:Peptides; D000090063:Proto-Oncogene Mas; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D053683:Oncostatin M; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases