title: Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization.
abstract: Epithelial-mesenchymal transition (EMT) has been associated with increased aggressiveness and acquisition of migratory properties providing tumor cells with the ability to invade into adjacent tissues. Downregulation of E-cadherin, a hallmark of EMT, is mediated by several transcription factors (EMT-TFs) that act also as EMT inducers, among them, Snail1 and the bHLH transcription factor E47. We previously described lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family, as a Snail1 regulator and EMT inducer. Here we show that LOXL2 is also an E47-interacting partner and functionally collaborates in the repression of E-cadherin promoter. Loss and gain of function analyses combined with in vivo studies in syngeneic breast cancer models demonstrate the participation of LOXL2 and E47 in tumor growth and their requirement for lung metastasis. Furthermore, LOXL2 and E47 contribute to early steps of metastatic colonization by cell and noncell autonomous functions regulating the recruitment of bone marrow progenitor cells to the lungs and by direct transcriptional regulation of fibronectin and cytokines TNFα, ANG-1 and GM-CSF. Moreover, fibronectin and GM-CSF proved to be necessary for LOXL2/E47-mediated modulation of tumor growth and lung metastasis.
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Canesin
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: E P
authors.initials: EP
authors.lastname: Cuevas
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Santos
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: López-Menéndez
authors.affiliation: 1] Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, IdiPAZ, Madrid, Spain [2] Fundación MD Anderson International Madrid, Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Moreno-Bueno
authors.affiliation: Department of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
authors.forename: K
authors.initials: K
authors.lastname: Csiszar
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Portillo
authors.affiliation: Department of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Peinado
authors.affiliation: Department of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lyden
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Cano
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D004285:Dogs; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics*; D058127:Transcription Factor 3 / Q000502:physiology*
chemical_list: D015820:Cadherins; D058127:Transcription Factor 3; D000594:Amino Acid Oxidoreductases; C485601:Loxl2 protein, mouse