LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling
Chang, J., Nicolau, M. M., Cox, T. R., Wetterskog, D., Martens, J. W. M., Barker, H. E., Erler, J. T.
(2013)
LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling.
BREAST CANCER RESEARCH, 15 (4).
ISSN 1465-5411
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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.
Item Type: | Article |
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Authors (ICR Faculty only): | Erler, Janine |
All Authors: | Chang, J., Nicolau, M. M., Cox, T. R., Wetterskog, D., Martens, J. W. M., Barker, H. E., Erler, J. T. |
Additional Information: | ISI Document Delivery No.: AB1HV Times Cited: 0 Cited Reference Count: 55 Chang, Joan Nicolau, Monica M. Cox, Thomas R. Wetterskog, Daniel Martens, John W. M. Barker, Holly E. Erler, Janine T. Breast Cancer Campaign; Institute of Cancer Research; Cancer Research UK; AICR; BRIC; Novo Nordisk Foundation The authors thank Prof. Arne Ostman from the Karolinska Institute for the suggestion to investigate ROS-mediated receptor activation. The authors also thank Dr. Nicholas Turner from the ICR for providing the drug trastuzumab (Herceptin). This work was supported by funding from the Breast Cancer Campaign (JC), Institute of Cancer Research (HEB, DW, JTE), Cancer Research UK (TRC, DW, JTE), AICR (HEB), and BRIC (JC, JTE, TRC). JTE is additionally supported by a Hallas Moller Stipendum from the Novo Nordisk Foundation. JC is a PhD student registered at the Institute of Cancer Research (University of London). 0 BIOMED CENTRAL LTD LONDON BREAST CANCER RES |
Uncontrolled Keywords: | BREAST-CANCER PROGRESSION MAMMARY EPITHELIAL ACINI LYSYL OXIDASE GENE-EXPRESSION ULTRAVIOLET-IRRADIATION EXTRACELLULAR-MATRIX TUMOR PROGRESSION MOLECULAR ROLE AMINE OXIDASE CELL POLARITY |
Research teams: | ICR divisions > Breast Cancer Research > Gene Function ICR divisions > Molecular Pathology > Gene Function Closed research groups > Hypoxia & Metastasis |
Depositing User: | Users 11 not found. |
Date Deposited: | 20 Mar 2014 12:10 |
Last Modified: | 11 Nov 2014 20:46 |
URI: | http://publications.icr.ac.uk/id/eprint/13140 |
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