title: Autocrine motility factor modulates EGF-mediated invasion signaling.
abstract: Autocrine motility factor (AMF) enhances invasion by breast cancer cells, but how its secretion and effector signaling are controlled in the tumor microenvironment is not fully understood. In this study, we investigated these issues with a chimeric AMF that is secreted at high levels through a canonical endoplasmic reticulum (ER)/Golgi pathway. Using this tool, we found that AMF enhances tumor cell motility by activating AKT/ERK, altering actin organization, and stimulating β-catenin/TCF and activating protein 1 transcription. EGF enhanced secretion of AMF through its casein kinase II-mediated phosphorylation. RNA interference-mediated attenuation of AMF expression inhibited EGF-induced invasion by suppressing extracellular signal-regulated kinase signaling. Conversely, exogenous AMF overcame the inhibitory effect of EGF receptor inhibitor gefitinib on invasive motility by activating HER2 signaling. Taken together, our findings show how AMF modulates EGF-induced invasion while affecting acquired resistance to cytotoxic drugs in the tumor microenvironment.
authors.affiliation: Authors' Affiliations: Departments of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Dhong Hyo
authors.initials: DH
authors.lastname: Kho
authors.forename: Tianpeng
authors.initials: T
authors.lastname: Zhang
authors.forename: Vitaly
authors.initials: V
authors.lastname: Balan
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Ha
authors.forename: Youming
authors.initials: Y
authors.lastname: Xie
authors.forename: Avraham
authors.initials: A
authors.lastname: Raz
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005956:Glucose-6-Phosphate Isomerase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D059016:Tumor Microenvironment; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D018808:Transcription Factor AP-1; D051176:beta Catenin; D004815:Epidermal Growth Factor; D003577:Cytochrome P-450 Enzyme System; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; D005956:Glucose-6-Phosphate Isomerase; C022461:prostacyclin synthetase