LOXL2-mediated matrix remodeling in metastasis and mammary gland involution

TY - JOUR

T1 - LOXL2-mediated matrix remodeling in metastasis and mammary gland involution

AU - Barker, Holly E

AU - Chang, Joan

AU - Cox, Thomas Robert

AU - Lang, Georgina

AU - Bird, Demelza

AU - Nicolau, Monica

AU - Evans, Holly R

AU - Gartland, Alison

AU - Erler, Janine Terra

N1 - ©2011 AACR.

PY - 2011/3/1

Y1 - 2011/3/1

N2 - 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.

AB - 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.

KW - Amino Acid Oxidoreductases

KW - Animals

KW - Blotting, Western

KW - Breast Neoplasms

KW - Extracellular Matrix

KW - Female

KW - Fluorescent Antibody Technique

KW - Gene Expression

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunohistochemistry

KW - Kaplan-Meier Estimate

KW - Matrix Metalloproteinase 9

KW - Mice

KW - Neoplasm Invasiveness

KW - Neoplasm Metastasis

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Tissue Array Analysis

KW - Tissue Inhibitor of Metalloproteinase-1

U2 - 10.1158/0008-5472.CAN-10-2868

DO - 10.1158/0008-5472.CAN-10-2868

M3 - Journal article

C2 - 21233336

SN - 0008-5472

VL - 71

SP - 1561

EP - 1572

JO - Cancer Research

JF - Cancer Research

IS - 5

ER -