title: LOXL2-mediated matrix remodeling in metastasis and mammary gland involution.
abstract: More than 90% of cancer patient mortality is attributed to metastasis. In this study, we investigated a role for the lysyl oxidase-related enzyme lysyl oxidase-like 2 (LOXL2) in breast cancer metastasis, in both patient samples and in vivo models. Analysis of a published microarray data set revealed that LOXL2 expression is correlated with metastasis and decreased survival in patients with aggressive breast cancer. In immunocompetent or immunocompromised orthotopic and transgenic breast cancer models we showed that genetic, chemical or antibody-mediated inhibition of LOXL2 resulted in decreased metastasis. Mechanistic investigations revealed that LOXL2 promotes invasion by regulating the expression and activity of the extracellular proteins tissue inhibitor of metalloproteinase-1 (TIMP1) and matrix metalloproteinase-9 (MMP9). We found that LOXL2, TIMP1, and MMP9 are coexpressed during mammary gland involution, suggesting they function together in glandular remodeling after weaning. Finally, we found that LOXL2 is highly expressed in the basal/myoepithelial mammary cell lineage, like many other genes that are upregulated in basal-like breast cancers. Our findings highlight the importance of LOXL2 in breast cancer progression and support the development of anti-LOXL2 therapeutics for the treatment of metastatic breast cancer.
authors.affiliation: Section of Cell and Molecular Biology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Barker
authors.forename: Joan
authors.initials: J
authors.lastname: Chang
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cox
authors.forename: Georgina
authors.initials: G
authors.lastname: Lang
authors.forename: Demelza
authors.initials: D
authors.lastname: Bird
authors.forename: Monica
authors.initials: M
authors.lastname: Nicolau
authors.forename: Holly R
authors.initials: HR
authors.lastname: Evans
authors.forename: Alison
authors.initials: A
authors.lastname: Gartland
authors.forename: Janine T
authors.initials: JT
authors.lastname: Erler
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; D020780:Matrix Metalloproteinase 9