Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas

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Abstract

Basal-like breast carcinoma is characterized by the expression of basal/myoepithelial markers, undifferentiated phenotype, highly aggressive behaviour and frequent triple negative status (ESR−, PR−, Her2neu−). We have previously shown that epithelial–mesenchymal transition (EMT) occurs in basal-like breast tumours and identified Lysyl-oxidase-like 2 (LOXL2) as an EMT player and poor prognosis marker in squamous cell carcinomas. We now show that LOXL2 mRNA is overexpressed in basal-like human breast carcinomas. Breast carcinoma cell lines with basal-like phenotype show a specific cytoplasmic/perinuclear LOXL2 expression, and this subcellular distribution is significantly associated with distant metastatic incidence in basal-like breast carcinomas. LOXL2 silencing in basal-like carcinoma cells induces a mesenchymal-epithelial transition (MET) associated with a decrease of tumourigenicity and suppression of metastatic potential. Mechanistic studies indicate that LOXL2 maintains the mesenchymal phenotype of basal-like carcinoma cells by a novel mechanism involving transcriptional downregulation of Lgl2 and claudin1 and disorganization of cell polarity and tight junction complexes. Therefore, intracellular LOXL2 is a new candidate marker of basal-like carcinomas and a target to block metastatic dissemination of this aggressive breast tumour subtype.

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Most cited references 39

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Epithelial-mesenchymal transitions in development and disease.

Jean Paul Thiery, Hervé Acloque, Ruby Y J Huang … (2009)

The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.

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Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype.

David Sarrió, Socorro Maria Rodríguez-Pinilla, David Hardisson … (2008)

Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. In carcinoma cells, EMT can be associated with increased aggressiveness, and invasive and metastatic potential. To assess the occurrence of EMT in human breast tumors, we conducted a tissue microarray-based immunohistochemical study in 479 invasive breast carcinomas and 12 carcinosarcomas using 28 different markers. Unsupervised hierarchical clustering of the tumors and statistical analysis showed that up-regulation of EMT markers (vimentin, smooth-muscle-actin, N-cadherin, and cadherin-11) and overexpression of proteins involved in extracellular matrix remodeling and invasion (SPARC, laminin, and fascin), together with reduction of characteristic epithelial markers (E-cadherin and cytokeratins), preferentially occur in breast tumors with the "basal-like phenotype." Moreover, most breast carcinosarcomas also had a basal-like phenotype and showed expression of mesenchymal markers in their sarcomatous and epithelial components. To assess whether basal-like cells have intrinsic phenotypic plasticity for mesenchymal transition, we performed in vitro studies with the MCF10A cell line. In response to low cell density, MCF10A cells suffer spontaneous morphologic and phenotypic EMT-like changes, including cytoskeleton reorganization, vimentin and Slug up-regulation, cadherin switching, and diffuse cytosolic relocalization of the catenins. Moreover, these phenotypic changes are associated with modifications in the global genetic differentiation program characteristic of the EMT process. In summary, our data indicate that in breast tumors, EMT likely occurs within a specific genetic context, the basal phenotype, and suggests that this proclivity to mesenchymal transition may be related to the high aggressiveness and the characteristic metastatic spread of these tumors.

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Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.

Vivian Barry-Hamilton, Rhyannon Spangler, Derek Marshall … (2010)

We have identified a new role for the matrix enzyme lysyl oxidase-like-2 (LOXL2) in the creation and maintenance of the pathologic microenvironment of cancer and fibrotic disease. Our analysis of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-associated stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked reduction in activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors and cytokines and decreased transforming growth factor-beta (TGF-beta) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor beta-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.

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Author and article information

Journal

Journal ID (nlm-ta): EMBO Mol Med

Journal ID (iso-abbrev): EMBO Mol Med

Journal ID (publisher-id): emmm

Title: EMBO Molecular Medicine

Publisher: WILEY-VCH Verlag (Weinheim )

ISSN (Print): 1757-4676

ISSN (Electronic): 1757-4684

Publication date (Print): September 2011

Volume: 3

Issue: 9

Pages: 528-544

Affiliations

[1 ]simpleDepartamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols”, CSIC-UAM, IdiPAZ, Instituto de Investigación Sanitaria La Paz Madrid, Spain

[2 ]simpleMD Anderson Cancer Center Madrid Spain

[3 ]simpleUnidad de Gestión Clínica de Anatomía Patológica and Grupo de Patología Molecular del Cáncer, Hospital Virgen del Rocío-IBIS, Instituto Biosanitario de Sevilla Sevilla, Spain

[4 ]simpleDepartamento de Anatomía Patológica. Hospital La Paz-IdiPAZ, Instituto de Investigación Sanitaria La Paz Madrid, Spain

[5 ]simpleJohn A Burns School of Medicine, University of Hawaii Honolulu, HI, USA

Author notes

* Corresponding author: Tel: +34 91 4976798; Fax: +34 91 5854401; E-mail: gmoreno@ 123456iib.uam.es

** Corresponding author: Tel: +34 91 4975400; Fax: +34 91 5854401; E-mail: acano@ 123456iib.uam.es

[†]

Present address: Departments of Pediatrics, Weill Medical College of Cornell University, 515E 71 ^st Street, New York 10021, USA

Article

DOI: 10.1002/emmm.201100156

PMC ID: 3377095

PubMed ID: 21732535

SO-VID: 062b2907-cae2-4b5a-bef7-a870d9907760

History

Date received : 03 December 2010

Date revision received : 06 June 2011

Date accepted : 07 June 2011

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