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LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

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 no...

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Autores principales: Chang, Joan, Nicolau, Monica M, Cox, Thomas R, Wetterskog, Daniel, Martens, John WM, E Barker, Holly, Erler, Janine T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978831/
https://www.ncbi.nlm.nih.gov/pubmed/23971878
http://dx.doi.org/10.1186/bcr3461
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author Chang, Joan
Nicolau, Monica M
Cox, Thomas R
Wetterskog, Daniel
Martens, John WM
E Barker, Holly
Erler, Janine T
author_facet Chang, Joan
Nicolau, Monica M
Cox, Thomas R
Wetterskog, Daniel
Martens, John WM
E Barker, Holly
Erler, Janine T
author_sort Chang, Joan
collection PubMed
description 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.
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spelling pubmed-39788312014-04-08 LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling Chang, Joan Nicolau, Monica M Cox, Thomas R Wetterskog, Daniel Martens, John WM E Barker, Holly Erler, Janine T Breast Cancer Res Research Article 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. BioMed Central 2013 2013-08-23 /pmc/articles/PMC3978831/ /pubmed/23971878 http://dx.doi.org/10.1186/bcr3461 Text en Copyright © 2013 Chang et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Chang, Joan
Nicolau, Monica M
Cox, Thomas R
Wetterskog, Daniel
Martens, John WM
E Barker, Holly
Erler, Janine T
LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling
title LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling
title_full LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling
title_fullStr LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling
title_full_unstemmed LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling
title_short LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling
title_sort loxl2 induces aberrant acinar morphogenesis via erbb2 signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978831/
https://www.ncbi.nlm.nih.gov/pubmed/23971878
http://dx.doi.org/10.1186/bcr3461
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