title: Inhibition of metastasis by HEXIM1 through effects on cell invasion and angiogenesis.
abstract: We report on the role of hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) as an inhibitor of metastasis. HEXIM1 expression is decreased in human metastatic breast cancers when compared with matched primary breast tumors. Similarly we observed decreased expression of HEXIM1 in lung metastasis when compared with primary mammary tumors in a mouse model of metastatic breast cancer, the polyoma middle T antigen (PyMT) transgenic mouse. Re-expression of HEXIM1 (through transgene expression or localized delivery of a small molecule inducer of HEXIM1 expression, hexamethylene-bis-acetamide) in PyMT mice resulted in inhibition of metastasis to the lung. Our present studies indicate that HEXIM1 downregulation of HIF(-)1α protein allows not only for inhibition of vascular endothelial growth factor-regulated angiogenesis, but also for inhibition of compensatory pro-angiogenic pathways and recruitment of bone marrow-derived cells (BMDCs). Another novel finding is that HEXIM1 inhibits cell migration and invasion that can be partly attributed to decreased membrane localization of the 67 kDa laminin receptor, 67LR, and inhibition of the functional interaction of 67LR with laminin. Thus, HEXIM1 re-expression in breast cancer has therapeutic advantages by simultaneously targeting more than one pathway involved in angiogenesis and metastasis. Our results also support the potential for HEXIM1 to indirectly act on multiple cell types to suppress metastatic cancer.
authors.affiliation: Department of Pharmacology, Case Western Reserve University Cleveland, Cleveland, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Ketchart
authors.forename: K M
authors.initials: KM
authors.lastname: Smith
authors.forename: T
authors.initials: T
authors.lastname: Krupka
authors.forename: B M
authors.initials: BM
authors.lastname: Wittmann
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.forename: P A
authors.initials: PA
authors.lastname: Rayman
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Doughman
authors.forename: J M
authors.initials: JM
authors.lastname: Albert
authors.forename: X
authors.initials: X
authors.lastname: Bai
authors.forename: J H
authors.initials: JH
authors.lastname: Finke
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: A A
authors.initials: AA
authors.lastname: Exner
authors.forename: M M
authors.initials: MM
authors.lastname: Montano
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: C118642:Hexim1 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016601:RNA-Binding Proteins; D014157:Transcription Factors