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Open Access Research article

LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

Joan Chang12, Monica M Nicolau3, Thomas R Cox12, Daniel Wetterskog4, John WM Martens5, Holly E Barker1 and Janine T Erler12*

Author Affiliations

1 Hypoxia and Metastasis Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, UK SW3 6JB

2 Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen 2200, Denmark

3 Department of Mathematics, Stanford University, 450 Serra Mall Stanford, CA 94305, USA

4 Gene Function Team, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London, UK SW3 6JB

5 Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Breast Cancer Research 2013, 15:R67  doi:10.1186/bcr3461

Published: 23 August 2013

Abstract

Introduction

Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigated the effects of LOXL2 expression in normal mammary epithelial cells to gain insight into how LOXL2 mediates cancer progression.

Methods

LOXL2 was expressed in MCF10A normal human mammary epithelial cells. The 3D acinar morphogenesis of these cells was assessed, as well as the ability of the cells to form branching structures on extracellular matrix (ECM)-coated surfaces. Transwell-invasion assays were used to assess the invasive properties of the cells. Clinically relevant inhibitors of ErbB2, lapatinib and Herceptin (traztuzumab), were used to investigate the role of ErbB2 signaling in this model. A retrospective study on a previously published breast cancer patient dataset was carried out by using Disease Specific Genomic Analysis (DSGA) to investigate the correlation of LOXL2 mRNA expression level with metastasis and survival of ErbB2-positive breast cancer patients.

Results

Fluorescence staining of the acini revealed increased proliferation, decreased apoptosis, and disrupted polarity, leading to abnormal lumen formation in response to LOXL2 expression in MCF10A cells. When plated onto ECM, the LOXL2-expressing cells formed branching structures and displayed increased invasion. We noted that LOXL2 induced ErbB2 activation through reactive oxygen species (ROS) production, and ErbB2 inhibition by using Herceptin or lapatinib abrogated the effects of LOXL2 on MCF10A cells. Finally, we found LOXL2 expression to be correlated with decreased overall survival and metastasis-free survival in breast cancer patients with ErbB2-positive tumors.

Conclusions

These findings suggest that LOXL2 expression in normal epithelial cells can induce abnormal changes that resemble oncogenic transformation and cancer progression, and that these effects are driven by LOXL2-mediated activation of ErbB2. LOXL2 may also be a beneficial marker for breast cancer patients that could benefit most from anti-ErbB2 therapy.