Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival

Molecular Cancer

Research

C. Taylor Wardwell¹  Sarah E. Kemp²  Andrew C. Nelson²  Mariya Farooqui²  Laura R. Bohrer²  Kathryn L. Schwertfeger³  Pavlina Chuntova⁴  Nicholas J. Brady⁴ 

[1] College of Veterinary Medicine, University of Minnesota, 55455, Minneapolis, MN, USA;Department of Lab Medicine and Pathology, University of Minnesota, 2231 6th St SE, 55455, Minneapolis, MN, USA;Department of Lab Medicine and Pathology, University of Minnesota, 2231 6th St SE, 55455, Minneapolis, MN, USA;Masonic Cancer Center, University of Minnesota, 55455, Minneapolis, MN, USA;Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, 55455, Minneapolis, MN, USA;

关键词: Breast cancer;    Epiregulin;    MMP-1;    FGFR;    in situ;   

DOI  :  10.1186/s12943-015-0408-z

 received in 2015-02-16, accepted in 2015-07-06,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe epidermal growth factor (EGF) family of ligands has been implicated in promoting breast cancer initiation, growth and progression. The contributions of EGF family ligands and their receptors to breast cancer are complex, and the specific mechanisms through which different ligands regulate breast tumor initiation and growth are not well-defined. These studies focus on the EGF family member epiregulin (EREG) as a mediator of early stage breast tumorigenesis.MethodsEREG expression levels were assessed in both cell lines and human samples of ductal carcinoma in situ (DCIS) using quantitative RT-PCR, ELISA and immunohistochemistry. Gene knock-down approaches using shRNA-based strategies were used to determine the requirement of EREG for growth of MCF10DCIS cells in vivo, and for identifying mechanisms through which EREG promotes tumor cell survival. Experiments were performed using a combination of two-dimensional culture, three-dimensional culture and tumor growth in vivo.ResultsIn comparison with other EGF family members, EREG was induced in MCF10DCIS cells compared with MCF10A and MCF10AT cells and its expression was partially regulated by fibroblast growth factor receptor (FGFR) activity. Reduced EREG expression in MCF10DCIS cells led to decreased tumor growth in vivo, which was associated with reduced cell survival. Furthermore, treatment of MCF10A cells with exogenous EREG enhanced cell survival both in three-dimensional culture and in response to chemotherapeutic agents. Examination of EREG-induced signaling pathways demonstrated that EREG promoted survival of MCF10A cells through regulating expression of matrix metalloproteinase-1 (MMP-1). To determine the relevance of these findings in human tumors, samples of DCIS were analyzed for EREG and MMP-1 expression. EREG was induced in DCIS lesions compared to normal breast epithelium, and EREG and MMP-1 were correlated in a subset of DCIS samples.ConclusionsTogether, these studies lead to identification of a novel pathway involving EREG and MMP-1 that contributes to the formation of early stage breast cancer. Understanding these complex pathways could ultimately lead to the development of novel biomarkers of neoplastic progression and/or new therapeutic strategies for patients with early stage cancer.

【 授权许可】

Unknown   
© Farooqui et al. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.