title: mda-7/IL-24 expression inhibits breast cancer through upregulation of growth arrest-specific gene 3 (gas3) and disruption of β1 integrin function.
abstract: Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressing MDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of β1 integrin with fibronectin. A mutated GAS3, which is unable to bind β1 integrin, was also unable to inhibit fibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of β1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of β1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P = 1.02 × 10(-9)), and the incidence of metastases is significantly reduced in patients with HER2(+) breast cancer expressing high-levels of IL-20R1. Together, our results identify a novel MDA-7/IL-24-GAS3-β1integrin-fibronectin signaling pathway that suppresses breast cancer growth and can be targeted for therapy.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: You-Jun
authors.initials: YJ
authors.lastname: Li
authors.forename: Guodong
authors.initials: G
authors.lastname: Liu
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Li
authors.forename: Laura M
authors.initials: LM
authors.lastname: Vecchiarelli-Federico
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Liu
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
authors.forename: Sze W
authors.initials: SW
authors.lastname: Shan
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Michael C
authors.initials: MC
authors.lastname: Archer
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Ben-David
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005353:Fibronectins / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D008024:Ligands; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D018123:Receptors, Interleukin / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation / Q000235:genetics; D000099180:Interleukin-24
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; D007378:Interleukins; D008024:Ligands; D009185:Myelin Proteins; D018123:Receptors, Interleukin; D000099180:Interleukin-24; C073687:PMP22 protein, human; C489546:Pmp22 protein, rat; C492510:interleukin-20 receptor